WO1997039023A1

WO1997039023A1 - Cysteine-containing or methioine-containing peptides with immunomodulatory effects

Info

Publication number: WO1997039023A1
Application number: PCT/SE1997/000574
Authority: WO
Inventors: Håkan BERGSTRAND; Tomas Eriksson; Magnus Lindvall; Bengt Särnstrand
Original assignee: Astra Aktiebolag
Priority date: 1996-04-12
Filing date: 1997-04-04
Publication date: 1997-10-23
Also published as: EP0923604A1; JP2000508898A; ID16421A; CA2250707A1; AU2417597A; AR006641A1

Abstract

Nucleic acid molecules encoding cysteine-containing or methioine-containing peptides that function to stimulate or suppress the immune response in a mammal are disclosed. Typically, these peptides contain no more than 30 amino acid residues and may be optionally linked to a mammalian secretory signal peptide at their amino terminal end.

Description

CYSTEINE-CONTAINING OR METHIOINE-CONTAINING PEPTIDES WITH IMMUNOMODULATORY EFFECTS

EXPRESSION OF RECOMBINANT PEPTIDES The field of the invention is non-antigen-specific immunomodulation, including both immunosuppression and immunostimulation.

Background of the Invention The immune system, when working properly, protects the individual from infection and from the growth of cancers. In order to carry out these functions, it must be able to recognize and mount an attack against foreign antigens, including cancer-specific antigens, but not against antigens that are normally present on cells throughout the body. It is possible to stimulate the immune system in order to improve the level of protection it affords. Immune stimulation is potentially beneficial where the individual is under attack from a chronic or an acute infection, or a malignant disease. Vaccines, including single-protein antigens such as diphtheria toxoid, are widely used to generate immunity against a specific antigen and thus against a specific disease. Where global stimulation of the immune system is desired, this can sometimes be achieved with nonspecific agents such as adjuvants, interleukins, interferons, and colony-stimulating f ctors. Occasionally, the immune system loses its ability to distinguish self from non-self. As a result, the individual may develop an autoimmune disease such as systemic lupus erythrematosis, Type I diabetes, or rheumatoid arthritis. These individuals would benefit greatly from suppression of the immune response, as would recipients of a transplanted organ or tissue.

The iiTunune response may be generally suppressed by treatment with corticosteroids, azathioprine, cyclosporine, tacrolimus (FK506) , rapamycin, or mycophenolate mofetil. In addition, certain immunoglobulins, including the monoclonal antibody OKT3 , have been used for this purpose. It may also be possible to suppress the immune response to a specific antigen. This procedure, which has been called "tolerance induction, " can be achieved by intravenous or repeated topical administration of the antigen in dilute form, treatment with a very high dose of the antigen, or oral administration of the antigen.

Summary of the Invention It has been discovered that DNA molecules encoding certain immunoactive peptides can be used to treat animals in need of immunomodulation. When introduced into cells of the animal, the DNA molecules are transcribed, and a therapeutic amount of the peptide is produced at an appropriate site. Some of the peptides are immunostimulatory, and so are useful for treating conditions such as cancer. Other peptides are immunosuppressive, and so would be used to treat, e.g., autoimmune diseases or transplant rejection. The immunomodulatory effect appears to be generalized rather than antigen-specific, and is believed to be related to the function of T lymphocytes.

The DNA molecules of the invention encode Cys-containing or Met-containing peptides that fall within one of five motifs described by the formulas below. The peptide is optionally linked to a signal peptide that is cleaved off by cellular proteases.

In one embodiment, the DNA molecule of the invention encodes a peptide consisting of 4-30 amino acid residues (preferably 4-10, and more preferably 4-8, e.g., 4-7 or 4-6 residues) that conforms to the motif represented by Formula I:

An-X-Cys-Cys-Y-B_m (Formula I) where each A and each B is independently selected from any of the 20 common, naturally occurring amino acids;

X is selected from the group consisting of Ala, Val, Leu, lie, Gly, Asp, Glu, Asn, Gin, His, and Pro;

Y is selected from the group consisting Ala, Val, Leu, lie, Gly, Ser, Thr, Asp, Glu, Asp, Gin, Tyr, Phe, and Pro; n and m are whole integers chosen with the proviso that the sum of n and m is zero to twenty-six, inclusive; and the nucleic acid molecule optionally further encodes a mammalian signal peptide linked to the immunoactive peptide at A_n.

Preferably: X is Gly, Pro, lie, Val, Asp, Leu, Glu, Gin, or Ala; Y is Gly, Pro, lie, Val, Asp, Leu, Glu, Ser, Phe, Tyr, or Thr; the sum of n and is zero to eleven, inclusive; and the nucleic acid molecule optionally further encodes a mammalian signal peptide linked to the immunoactive peptide at A_n.

More preferably, the DNA molecule of the invention encodes a peptide conforming to the motif of Formula I, optionally linked to a signal peptide, wherein X is Gly and Y is Gly,

X is Pro and Y is Pro,

X is Pro and Y is Val,

X is lie and Y is Leu, X is Pro and Y is Glu,

X is Glu and Y is Tyr,

X is Pro and Y is Phe,

X is Glu and Y is Phe,

X is Ala and Y is Val, X is Val and Y is lie,

X is Gin and Y is Ser,

X is lie and Y is Thr,

X is Leu and Y is Asp, or

X is Asp and Y is lie; A and B vary according to the parameters above; and the sum of n and m is zero to eleven, inclusive.

Most preferably, the peptide represented by Formula I consists of 6-8 amino acid residues.

Examples of such peptides of Formula I include the following:

Glu-Glu-Cys-Cys-Phe-Tyr (SEQ ID N0.:1. D22041AX) ,

Pro-Gly-Cys-Cys-Gly-Pro (SEQ ID NO.:2:

Pro-Gly-Cys-Cys-Pro-Gly (SEQ ID NO. :3 D22139AA) ,

Gly-Pro-Cys-Cys-Pro-Gly (SEQ ID NO. :4; Ala-Pro-Cys-Cys-Val-Pro (SEQ ID NO.:5 D22037AX)

Val-Ile-Cys-Cys-Leu-Thr (SEQ ID NO.:6;

Lys-Pro-Cys-Cys-Glu-Arg (SEQ ID NO.:7

Lys-Glu-Cys-Cys-Tyr-Val (SEQ ID NO.:8!

Thr-Pro-Cys-Cys-Phe-Ala (SEQ ID NO.:9; D22040AX) ,

Leu-Ala-Cys-Cys-Val-Val (SEQ ID NO. :10; Pro-Val-Cys-Cys-Ile-Gly (SEQ ID NO. :ll), Ser-Gln-Cys-Cys-Ser-Leu (SEQ ID NO. :12), Ser-Ile-Cys-Cys-Thr-Lys (SEQ ID NO. :13), Lys-Leu-Cys-Cys-Asp-Ile (SEQ ID NO. :14), Pro-Ala-Cys-Cys-Gly-Pro (SEQ ID NO. :15) ,

Pro-Asp-Cys-Cys-Ile-Pro (SEQ ID NO. :16), and Arg-Cys-Ser-Gly-Cys-Cys-Asn (SEQ ID N0..17) . The nucleic acid molecule of the invention could encode a peptide where, for example, A is Gly, Lys, Arg, Cys, Ser, Val, Ala, Thr, Glu, Pro, Trp, Leu, Asp, Phe, or lie; B is Leu, Arg, lie, Val, Pro, Ala, Tyr, Gly, Trp, Thr, Lys, Met, Asp, Glu, or Phe; and the sum of n and m is two to four, inclusive. The nucleic acid molecule could also encode a peptide where, for example, A is Pro, Gly, Glu, Ala, Val, Lys, Thr, Leu, or Ser; B is Tyr, Pro, Gly, Thr, Arg, Val, Ala, Leu, Lys, or lie; n is one; and m is one.

In a second embodiment, the DNA molecule of the invention may encode a peptide consisting of 5-30 amino acid residues (preferably 5-10, more preferably 5-9, e.g., 5, 6, 7, or 8 residues) that conforms to the motif represented by Formula II:

A_n-X-Cys-Z-Cys-Y-B_m (Formula II) where each A and each B is independently selected from any of the 20 common, naturally occurring amino acids;

X is selected from the group consisting of Ala, Val, Leu, lie, Gly, Asp, Glu, Asn, Gin, Lys, Phe, His, and Pro;

Z is selected from the group consisting of Ala, Val, Leu, lie, Gly, Ser, Thr, Lys, His, Phe, Tyr, Arg, and Pro; Y is selected from the group consisting of Ala, Val, Leu, lie, Gly, Asp, Glu, Lys, Arg, Gin, Tyr, Phe, Ser, Thr, and Pro; and n and m are whole integers chosen with the proviso that the sum of n and m is zero to twenty-five, inclusive; and the nucleic acid molecule optionally further encodes a mammalian signal peptide linked to the immunoactive peptide at A_n.

Preferably: X is Gly, Pro, lie, Val, Asp, Leu, Glu, Gin, or Ala; Y is selected from the group consisting of Gly, Glu, Val, Gin, Arg, Leu, Tyr, Phe, lie, Ser, Thr, Asp, and Pro; Z is selected from the group consisting of lie, Gly, Thr, Ala, Arg, and Lys; the sum of n and m is zero to ten, inclusive; and the nucleic acid molecule optionally further encodes a mammalian signal peptide linked to the immunoactive peptide at A_n.

More preferably, the DNA molecule of the invention encodes a peptide conforming to the motif represented by Formula II, optionally linked to a signal peptide, wherein X is Gly and Y is Gly,

X is Pro and Y is Pro,

X is Pro and Y is Val,

X is lie and Y is Leu,

X is Pro and Y is Glu, X is Glu and Y is Tyr,

X is Pro and Y is Phe,

X is Glu and Y is Phe,

X is Ala and Y is Val,

X is Val and Y is lie, X is Gin and Y is Ser, X is lie and Y is Thr, X is Leu and Y is Asp, or

X is Asp and Y is lie; Z is lie, Gly, Thr, Ala, or Lys; A and B vary according to the parameters above; the sum of n and m is zero to ten, inclusive; and the nucleic acid molecule optionally further encodes a mammalian signal peptide linked to the immunoactive peptide at A_n.

Examples of such peptides of Formula II include the following: Val-Cys-Ile-Cys-Gln (SEQ ID N0..18) ,

Val-Cys-Gly-Cys-Arg (SEQ ID N0..19), Lys-Cys-Arg-Cys-Lys (SEQ ID NO..20), Asp-Cys-Ile-Cys-Gln (SEQ ID NO.:21) , Ile-Cys-Thr-Cys-Glu (SEQ ID NO. :22) , Ile-Cys-Thr-Cys-Arg (SEQ ID N0..23) ,

Leu-Cys-Ala-Cys-Val (SEQ ID NO.:24), Phe-Cys-Ile-Cys-Lys (SEQ ID NO.:25), Ala-Cys-Lys-Cys-Gln (SEQ ID NO. :26), and Gly-Pro-Cys-Ile-Cys-Pro-Gly (SEQ ID NO.:27) . The nucleic acid molecule of the invention could encode a peptide where, for example, X is Val, Ala, Leu, lie, Lys, Asp, Phe or Pro; Y is Glu, Val, Gin, Arg, Lys, or Pro; Z is Gly, Ala, lie, Arg, Thr, or Lys; and the sum of n and m is one to three, inclusive. In a third embodiment, the DNA molecule of the invention may encode a peptide consisting of 4-30 amino acid residues that conforms to the motif represented by Formula III :

A_n-X-Y-Cys-Z-B_m (Formula III) where each A and each B is independently selected from any of the 20 common, naturally occurring amino acids;

X is selected from the group consisting of Ala, Val, Leu, lie, Gly, Ser, Thr, Asp, Glu, Lys, Arg, His, Trp, Tyr, and Phe;

Y is selected from the group consisting of Ala, Val, Leu, lie, Gly and Pro;

Z is selected from the group consisting of Ala, Val, Leu, He, Gly, Lys, Arg, His, Phe, and Pro; n and m are whole integers chosen with the proviso that the sum of n and m is zero to twenty-six, inclusive; and the nucleic acid molecule optionally further encodes a mammalian signal peptide linked to the immunoactive peptide at A_n. Preferably: X is Gly, Ala, He, Asp, Thr, Ser, Arg, or Trp; Y is He, Gly, or Pro; Z is Lys, He, Phe, Pro, Ala, Tyr or Gly; and the sum of n and m is zero to eleven, inclusive .

More preferably, the DNA molecule of the invention encodes a peptide conforming to the motif represented by Formula III, optionally linked to a signal peptide, where

X is Gly, Y is Pro, and Z is He,

X is Gly, Y is Pro, and Z is Gly,

X is Ala, Y is Pro, and Z is Ala, X is He, Y is Pro, and Z is Tyr,

X is Ala, Y is Pro, and Z is He,

X is Arg, Y is Pro, and Z is He,

X is He, Y is Pro, and Z is He,

X is Asp, Y is Pro, and Z is He, X is Trp, Y is Pro, and Z is He, X is Trp, Y is Pro, and Z is Gly,

X is Gly, Y is He, and Z is He,

X is Thr, Y is Pro, and Z is Tyr,

X is Ala, Y is Pro, and Z is Phe,

X is Ser, Y is Pro, and Z is Phe,

X is Gly, Y is Pro, and Z is Pro, or

X is Gly, Y is Pro, and Z is Tyr; A and B vary according to the parameters above; and the sum of n and m is zero to eleven, inclusive.

Examples of such peptides of Formula III include the following:

Gly-Pro-Cys-Gly (SEQ ID N0..28),

Ala-Pro-Cys-Ala (SEQ ID N0..29) ,

Ile-Pro-Cys-Tyr (SEQ ID NO. :30) ,

Trp-Pro-Cys-Gly (SEQ ID N0..31) ,

Gly-Pro-Cys-He-Leu-Asn (SEQ ID NO.:32),

Gly-Pro-Cys-He (SEQ ID NO. :33 ; D22078AX) ,

Leu-Leu -Phe-Gly- ^■ Pro-Cys-Ile (SEQ ID NO. :34) Leu-Leu -Phe-Ala- Pro-Cys-Ile (SEQ ID NO. :35) Leu-Leu -Phe-Arg- ^■Pro-Cys-Ile (SEQ ID NO. :36) Leu-Leu -Phe-Ile- Pro-Cys-Ile (SEQ ID NO. :37) Leu-Leu -Phe-Asp- Pro-Cys-Ile (SEQ ID NO. :38) Ala-Val -Trp-Thr- ^•Pro-Cys-Tyr (SEQ ID NO. :39) Phe-Val -Met -Ala- Pro-Cys -Phe (SEQ ID NO. :40) Leu-Leu -Tyr-Ser- Pro -Cys -Phe (SEQ ID NO. :41) Ile-Ser -Gly-Pro- Cys-Pro-Lys (SEQ ID NO. :42) Phe-Leu -Phe-Gly- Pro-Cys-Ile (SEQ ID NO. :43) Leu-Phe -Gly-Pro- ^■Cys -He-Leu (SEQ ID NO. :44) Glu-Lys -Gly-Pro- Cys -Tyr-Arg (SEQ ID NO. :45) Phe-Cys -Leu-Gly- Pro-Cys -Pro (SEQ ID NO. :46) Phe-Gly-Pro-Cys-He (SEQ ID NO.:47; D22077AX) , Phe-Leu-Phe-Gly-Pro-Cys-He-Leu-Asn (SEQ ID NO. :48) ,

Gly-Pro-Cys-He-Leu-Asn-Arg (SEQ ID NO. 49; D22087AX) , Leu-Leu-Phe-Trp-Pro-Cys-He (SEQ ID NO. 50; D22023AX) , Leu-Leu-Phe-Gly-Ile-Cys-He (SEQ ID NO. 51; D22022AX) ,

Leu-Leu-Phe-Gly-Pro-Cys-He-Leu-Asn

(SEQ ID NO.: 52; D22014AX) , Leu-Leu-Phe-Gly-Pro-Cys-He-Leu-Asn-Arg (SEQ ID NO. :53; D22087AX), Trp-Cys-Gly-Pro-Cys-Lys-Met-Ile-Lys-Pro-Phe-Phe

(SEQ ID NO. :54; D7233) , Leu-Leu-Phe-Gly-Pro-Cys-He-Leu-Asn-Arg-Leu-Met-Glu

(SEQ ID NO. :55) , and Phe-Leu-Phe-Gly-Pro-Cys-He-Leu-Asn-Arg-Leu-Met-Glu (SEQ ID NO. :56) .

The nucleic acid molecule of the invention may encode, for example, a peptide where X is Gly, Ala, He, Arg, Asp, Trp, Thr, or Ser; Y is Pro, Gly, or He; Z is Gly, Ala, He, Tyr, Phe, or Pro; and the sum of n and m is one to three, inclusive. In a fourth embodiment, the DNA molecule of the invention encodes an immunoactive peptide consisting of 3-30 amino acid residues that conforms to the motif represented by Formula IV:

A_n-Xp-Y-Cys-Zq-B_π, (Formula IV) where each A and each B is independently selected from any of the 20 common, naturally occurring amino acids;

X is selected from the group consisting of Ser, Glu, Gly, Ala, Leu, Pro, Thr, Val, Asn, and Lys; Y is selected from the group consisting of Leu, Arg, Pro, Tyr, He, Val, Ser, Ala, and Phe;

Z is selected from the group consisting of Met, Trp, Tyr, Phe, Gly, Pro, Arg, Asn, Gin, Ala, and Lys; n, , p, and q are whole integers chosen with the following provisos: p and q are independently zero or 1 but are not both simultaneously zero; when q is zero, m is zero; and the sum of n, m, p, and q is 1 to 28, inclusive.

The nucleic acid molecule encoding a peptide conforming to Formula IV optionally further encodes a mammalian signal peptide linked to the amino terminus of the immunoactive peptide.

Preferably, both p and q are 1, and the peptide consists of 4-20 amino acid residues. More preferably, the peptide consists of 4-15 amino acid residues (e.g., 4-9 or

4-10 amino acid residues) . Most preferably, the peptide consists of 4-7 amino acid residues, optionally linked to a signal peptide.

More preferably, the DNA molecule of the invention encodes a peptide conforming to the motif represented by Formula IV, optionally linked to a signal peptide, where

X is Glu, Y is Pro, and Z is Met,

X is Gly, Y is Pro, and Z is Met,

X is Ala, Y is Pro, and Z is Trp, X is Ala, Y is Pro, and Z is Met,

X is Glu, Y is Pro, and Z is Trp,

X is Ser, Y is Pro, and Z is Trp,

X is Leu, Y is Leu, and Z is Gly,

X is Pro, Y is Arg, and Z is Arg, X is Gly, Y is Tyr, and Z is Pro, X is Val, Y is Val, and Z is Asn,

X is Leu, Y is Ser, and Z is Gin,

X is Ser, Y is Pro, and Z is Tyr,

X is Ala, Y is Leu, and Z is Arg, X is Ala, Y is Pro, and Z is Tyr,

X is Gly, Y is Ala, and Z is Pro,

X is Lys, Y is Ser, and Z is Lys,

X is Glu, Y is Pro, and Z is Phe,

X is Glu, Y is Pro, and Z is Tyr, X is Ser, Y is Pro, and Z is Met,

X is Ala, Y is Pro, and Z is Tyr,

X is absent, Y is Leu, and Z is Phe, or

X is Gly, Y is Pro, and Z is Trp; A and B are selected independently from the 20 common, naturally occurring amino acids; and n, m, p, and q are whole integers chosen with the provisos specified above.

Preferably, peptides conforming to Formula IV are chosen with the proviso that: when Y is Pro or He, and q is 1, and Z is Tyr, Phe, Gly, Pro, or Ala, then

(i) when p is 1, X is not Ser, Gly, Ala, or Thr, or (ii) when p is 0, any amino acid residue of A adjacent to Y is not Ser, Gly, Ala, or Thr.

Examples of peptides of Formula IV include the following:

Gln-Cys-Ala-Leu-Cys-Arg (SEQ ID N0..81),

Val-Ala-Leu-Ser-Cys-Gln (SEQ ID NO. :82) ,

He-Val-Lys-Ser-Cys-Lys (SEQ ID NO. :83) ,

Leu-Ala-Phe-Glu-Pro-Cys-Met (SEQ ID NO. :84) , Leu-Leu-Pro-Gly-Pro-Cys-Met (SEQ ID NO. :85) , Met-Ala-Pro-Ala-Pro-Cys-Trp (SEQ ID NO. :86) , Ala-Leu-Tyr-Ala-Pro-Cys-Met (SEQ ID N0..87) , Val-Leu-Trp-Glu-Pro-Cys-Trp (SEQ ID NO.:88) , Met-Leu-Phe-Ser-Pro-Cys-Trp (SEQ ID NO.:89) , Leu-Leu-Cys-Gly-Pro-Ala-He (SEQ ID NO.:90) ,

Leu-Cys-Phe-Gly-Pro-Ala-He (SEQ ID NO.:91) , Val-Met-Pro-Ser-Pro-Cys-Tyr (SEQ ID N0..92) , Val-Val-Phe-Ala-Pro-Cys-Tyr (SEQ ID NO.:93) , Ala-Val-Pro-Glu-Pro-Cys-Phe (SEQ ID NO.:94) , Met-Met-Tyr-Glu-Pro-Cys-Tyr (SEQ ID NO.:95) ,

Ala-Ala-Trp-Ser-Pro-Cys-Met (SEQ ID NO. :96), Val-Ala-Tyr-Gly-Pro-Cys-Trp (SEQ ID NO.:97) Leu-Arg-Pro-Arg-Cys-Arg-Pro-He (SEQ ID NO. :98), Ala-Gly-Tyr-Cys-Pro-Thr-Met-Thr (SEQ ID NO.:99), Pro-Gln-Val-Val-Cys-Asn-Tyr-Arg (SEQ ID NO..100), or

Ala-Asn-Phe-Cys-Ala-Gly-Ala-Cys-Pro-Tyr-Leu-Trp (SEQ ID NO. :101) ; A and B are selected independently from the 20 common, naturally occurring amino acids; and n, m, p, and q are whole integers chosen with the provisos specified above.

Examples of peptides of Formula IV that contain a mammalian signal peptide sequence include the following:

Met-Arg-Leu-Arg-Leu-Leu-Val-Ser-Ala-Gly-Met-Leu-Leu-Val- Ala-Leu-Ser-Pro-Cys-Leu-Pro-Cys-Arg-Ala-Leu-Ala-Phe-Glu-Pro- Cys-Met (SEQ ID NO.:102; D22184AA) ,

Met-His-Leu-Ser-Leu-Ser-His-Gln-Trp-Ser-Ser-Trp-Thr-Val- Leu-Leu-Leu-Leu-Val-Ser-Asn-Leu-Leu-Leu-Trp-Glu-Asn-Thr-Ala- Ser-Ala-Met-Ala-Pro-Ala-Pro-Cys-Trp (SEQ ID NO.:103; D22183AA) , Met-Gly-Phe-Leu-Lys-Phe-Ser-Pro-Phe-Leu-Val-Val-Ser-He- Leu-Leu-Leu-Tyr-Gln-Ala-Cys-Gly-Leu-Gln-Ala-Val-Leu-Trp-Glu- Pro-Cys-Trp (SEQ ID NO. :104; D22196AA) ,

Met-Gly-Phe-Leu-Lys-Phe-Ser-Pro-Phe-Leu-Val-Val-Ser-Ile- Leu-Leu-Leu-Tyr-Gln-Ala-Cys-Gly-Leu-Gln-Ala-Val-Met-Pro-Ser- Pro-Cys-Tyr (SEQ ID NO. :105; D22197AA) ,

Met-His-Leu-Ser-Leu-Ser-His-Gln-Trp-Ser-Ser-Trp-Thr-Val- Leu-Leu-Leu-Leu-Val-Ser-Asn-Leu-Leu-Leu-Trp-Glu-Asn-Thr-Ala- Ser-Ala-Met-Leu-Phe-Ser-Pro-Cys-Trp (SEQ ID NO. :106; D22217AA) , and

Met-Gly-Phe-Leu-Lys-Phe-Ser-Pro-Phe-Leu-Val-Val-Ser-He- Leu-Leu-Leu-Tyr-Gln-Ala-Cys-Gly-Leu-Gln-Ala-Val-Val-Phe-Ala- Pro-Cys-Tyr (SEQ ID NO. :107; D22215AA) .

In a fifth embodiment, the DNA molecule of the invention encodes an immunoactive peptide consisting of 3-30 amino acid residues that conforms to the motif represented by Formula V:

A_n-W-X-Y-Zp-B_m (Formula V) where each A and each B is independently selected from any of the 20 common, naturally occurring amino acids;

W is selected from the group consisting of Gly, Pro, Asp, Arg, Ala, He, Trp, Ser, Met, Cys, and Glu;

X is selected from the group consisting of Cys, Pro, He, Met, Tyr, Thr, and Arg; Y is selected from the group consisting of Cys and Met;

Z is selected from the group consisting of Gly, Phe, Val, He, Pro, Tyr, Trp, Glu, Leu, and Met;

W, X, and Y are chosen with the proviso that at least one of W, X, or Y is Met, and not more than one of W, X, or Y is Cys; n, m, and p are whole integers chosen with the provisos that p is zero or 1; when p is zero, m is zero; and the sum of n, m, and p is zero to 27, inclusive.

The nucleic acid molecule encoding a peptide conforming to Formula V optionally further encodes a mammalian signal peptide linked to the amino terminus of the immunoactive peptide.

Preferably, p is 1, and the peptide consists of 4-20 amino acid residues. More preferably, the peptide consists of 4-15 amino acid residues (e.g., 4-9 or 4-10 amino acid residues) . Most preferably, the peptide consists of 4-7 amino acid residues.

More preferably, the DNA molecule of the invention encodes a peptide conforming to the motif of Formula V, optionally linked to a signal peptide, wherein

W is selected from the group consisting of Gly, Pro, Asp, Arg, Ala, He, Trp, and Ser;

X is selected from the group consisting of Cys, Pro, He, and Met; Y is selected from the group consisting of Cys and Met; and

Z is selected from the group consisting of Gly, Phe, Val, He, Pro, and Leu.

More preferably, at least one of X and Y is Met. More preferably, the DNA molecule of the invention encodes a peptide conforming to the motif of Formula V, optionally linked to a signal peptide, wherein

W is selected from the group consisting of Gly, Asp, Arg, Ala, Trp, and Ser; X is selected from the group consisting of Pro and He; Y is Met ; and

Z is selected from the group consisting of Phe, He, and Pro.

Most preferably, the DNA molecule of the invention encodes a peptide conforming to the motif of Formula V, optionally linked to a signal peptide, wherein

W is selected from the group consisting of Gly and Ser;

X is Pro;

Y is Met; and Z is selected from the group consisting of Phe, He, and

Pro.

The nucleic acid molecule of the invention may encode a peptide having Met and Cys or Met and Met aligned contiguously. For example, the encoded peptide may conform in sequence to A-W-Met-Met-Z-B,

A-W-Met-Cys-Z-B, or A-W-Cys-Met-Z-B.

Alternatively, the nucleic acid molecule of the invention may encode a peptide in which Met and Cys are separated by no more than one amino acid. For example, the encoded peptide may conform in sequence to A-Met-X-Cys-Z-B or A-Cys-X-Met-Z-B.

Examples of such peptides of Formula V include the following:

Gly-Pro-Met-He (SEQ ID N0..114) , Lys-Met-Arg-Met-Lys (SEQ ID NO. : 115) Phe-Met-He-Met-Lys (SEQ ID N0..116), Ile-Cys-Thr-Met-Glu (SEQ ID N0..117), Leu-Met-Ala-Met-Val (SEQ ID N0. :118), He-Met-Tyr-Met-Glu (SEQ ID NO. :119) ,

Ala-Pro-Met-Met-Val-Pro (SEQ ID NO. :120) ,

Gly-Pro-Met-Met-Pro-Gly (SEQ ID NO. :121) ,

Gly-Pro-Cys-Met-Pro-Gly (SEQ ID NO. :122) ,

Gly-Pro-Met-Cys-Pro-Gly (SEQ ID NO. :123) ,

Pro-Gly-Met-Met-Gly-Pro (SEQ ID NO. :124) ,

Val-He-Met-Met-Leu-Thr (SEQ ID NO. :125) ,

Leu-Ala- Phe-Glu-Pro-Met -Met SEQ ID NO 126)

Met-Leu-Phe-Ser-Pro-Met-Trp SEQ ID NO 127) Val-Val-Phe-Ala-Pro-Met-Tyr SEQ ID NO 128)

Leu-Leu-Phe-Gly-Pro-Met-He SEQ ID NO 129)

Leu-Leu-Tyr-Ser-Pro-Met-Phe SEQ ID NO 130)

Leu-Leu-Phe-Asp-Pro-Met-He SEQ ID NO 131)

Leu-Leu-Phe-Trp-Pro-Met-He SEQ ID NO 132) Leu-Leu-Phe-Arg-Pro-Met-He SEQ ID NO 133)

Leu-Leu-Phe-Ala-Pro-Met-He SEQ ID NO 134)

Leu-Leu-Phe-Gly-Ile-Met-He ( SSEEQQ IIDD NNOO.: 113355)), and

Phe-Met-Leu-Gly-Pro-Met-Pro SEQ ID NO 136)

An example of a peptide of Forumula V that contains a mammalian signal peptide is:

Met-Arg-Leu-Arg-Leu-Leu-Val-Ser-Ala-Gly-Met-Leu-Leu-Val- Ala-Leu-Ser-Pro-Cys-Leu-Pro-Cys-Arg-Ala-Leu-Leu-Phe-Gly-Pro- Met-Ile (SEQ ID NO. :137; D22020AX) .

Furthermore, each of the peptides conforming to the motifs represented by Forumula III, IV, or V, are selected with the proviso that the following peptides are excluded:

Arg-Asn-Arg-Cys-Lys-Gly-Thr-Asp-Val-Gln-Ala-Trp-He-Arg- Gly-Cys-Arg-Leu (SEQ ID NO.:139),

He-Asn-Thr-Lys-Cys-Tyr-Lys-Leu-Glu-His-Pro-Val-Thr-Gly- Cys-Gly (SEQ ID NO..140) , Asp-Asn-Tyr-Arg-Gly-Tyr-Ser-Leu-Gly-Asn-Trp-Val-Cys-Ala- Ala-Lys-Phe-Glu-Ser-Asn-Phe-Thr-Gln (SEQ ID NO. :141) ,

Ala-Pro-Ser-Pro-Leu-Pro-Glu-Thr-Thr-Glu-Asn-Val-Val-Cys- Ala-Leu-Gly (SEQ ID NO. :176), Ala -Pro- Ser- Pro-Leu- Pro-Glu-Thr-Thr-Glu- Asn- Val -Val -Cys -

Ala-Leu-Gly-Leu-Thr-Val (SEQ ID NO. : 142) ,

Gly-Asp-Met-Tyr-Pro-Lys-Thr-Trp-Ser-Gly-Met-Leu-Val-Gly- Ala-Leu-Cys-Ala-Leu-Ala-Gly-Val-Leu-Thr-He (SEQ ID NO. :143) ,

Val-Pro-Gly-Leu-Tyr-Ser-Pro-Cys-Arg-Ala-Phe-Phe-Asn-Lys (SEQ ID NO. :144) ,

Val -Pro-Gly-Leu-Tyr- Ser- Pro-Cys -Arg- Ala- Phe- Phe-Asn-Lys- Glu-Glu-Leu-Leu (SEQ ID NO. :145) ,

Val -Pro -Gly -Leu-Tyr- Ser- Pro-Cys-Arg-Ala- Phe -Phe-Asn-Lys (SEQ ID NO. :146) , Glu-Ala-Ile-Tyr-Asp-Ile-Cys-Arg-Arg-Asn-Leu-Asp-He-Glu-

Arg-Pro-Thr (SEQ ID N0..147) ,

Glu-Ala-Ile-Tyr-Asp-Ile-Cys-Arg-Arg-Asn-Leu-Asp-Ile ( SEQ ID NO. :148) ,

Asp-Leu-Leu-Glu-Gln-Arg-Arg-Ala-Ala-Val-Asp-Thr-Tyr-Cys- Arg-His-Asn-Tyr-Gly-Val-Gly-Glu-Ser-Phe-Thr (SEQ ID NO. :149) ,

Thr-Ser-Ile-Leu-Cys-Tyr-Arg-Lys-Arg-Glu-Trp-He-Lys (SEQ ID NO. :150) ,

Leu-Pro-Phe-Phe-Leu-Phe-Arg-Gln-Ala-Tyr-His-Pro-Asn-Asn- Ser-Ser-Pro-Val-Cys-Tyr (SEQ ID NO. :151) , Gln-Ala-Lys-Phe-Phe-Ala-Cys-He-Lys-Arg-Ser-Asp-Gly-Ser-

Cys-Ala-Trp-Tyr-Arg-Gly-Ala-Ala-Pro-Pro-Lys-Gln-Glu-Phe (SEQ ID NO. :152) ,

Gln-Ala-Lys-Phe-Phe-Ala-Cys-Ile-Lys-Arg-Ser-Asp-Gly-Ser- Cys-Ala-Trp-Tyr-Arg (SEQ ID NO. :153) , Lys-Val-Phe-Gly-Arg-Cys-Glu-Leu-Ala-Ala-Ala-Met-Lys-Arg-

His-Gly-Leu-Asp (SEQ ID NO. :154),

Ala-Glu-Ala-Leu-Glu-Arg-Met-Phe-Leu-Ser-Phe-Thr-Thr-Lys- Thr (SEQ ID NO. : 155), and Lys-Asn-He-Phe-His-Phe-Lys-Val-Asn-Gln-GLu-Gly-Leu-Lys-

Leu-Ser-Asn-Asp-Met-Met (SEQ ID NO.: 156) .

Preferably, the following sequences are excluded: Leu-Glu-Cys-Gly-Pro-Cys-Phe-Leu (SEQ ID NO.:157), Leu-Cys-Ala-Gly-Pro-Cys-Phe-Leu (SEQ ID NO.:158) , Tyr-Ile-Pro-Cys-Phe-Pro-Ser-Ser-Leu-Lys-Arg-Leu-Leu-Ile

(SEQ ID NO. :159) ,

Tyr-He-Pro-Cys-Phe-Pro-Ser-Ser-Leu-Lys-Arg-Leu-He (SEQ ID NO. :160) ,

Ser-Gly-Pro-Cys-Pro-Lys-Asp-Gly-Gln-Pro-Ser (SEQ ID NO. :161) ,

Thr-Pro-Pro-Thr-Pro-Cys-Pro-Ser (SEQ ID NO.:162) , Asp-Pro-Cys-He-Ile (SEQ ID NO. :163), Cys-Gly-Gly-Ile-Cys-He-Ala-Arg (SEQ ID N0..164) , Ser-Gly-Pro-Cys-Pro-Lys-Asp-Gly-Gln-Pro-Ser (SEQ ID NO. :165) ,

Cys-His-Gly-Ser-Asp-Pro-Cys (SEQ ID N0..166) , Ser-Gly-Pro-Cys-Pro-Lys-Asp-Gly-Gln-Pro-Ser (SEQ ID NO. -.167) ,

Tyr-Arg-Arg-Gly-Arg-Cys-Gly-Gly-Leu-Cys-Leu-Ala-Arg (SEQ ID NO. :168) ,

Tyr-Arg-Arg-Gly-Arg-Ala-Ala-Ala-Cys-Gly-Gly-Leu-Cys-Leu- Ala-Arg (SEQ ID NO.:169) ,

Tyr-Arg-Arg-Gly-Arg-Cys-Gly-Gly-Gly-Leu-Cys-Leu-Ala-Arg (SEQ ID NO. :170) , Tyr-Arg-Arg-Gly-Arg-Ala-Ala-Ala-Cys-Gly-Gly-Gly-Leu-Cys- Leu-Ala-Arg (SEQ ID NO. :171) ,

Tyr-Arg-Arg-Gly-Arg-Cys-Gly-Gly-Gly-Gly-Leu-Cys-Leu-Ala- Arg (SEQ ID NO. :172) , Tyr-Arg-Arg-Gly-Arg-Ala-Ala-Ala-Cys-Gly-Gly-Gly-Gly-Leu-

Cys-Leu-Ala-Arg (SEQ ID 0..173) ,

Cys-Gly-Gly-Leu-Cys-Ala-Arg (SEQ ID NO.:174), and

Ser-Pro-Tyr-Met-Glu-Ala (SEQ ID NO. :175) .

The nucleic acid molecule of the invention can be RNA (e.g., in a retrovirus) or DNA. It preferably encodes an immunoactive peptide that is not a naturally occurring human polypeptide nor a fragment of a naturally occurring human polypeptide. Even where the sequence of the immunoactive peptide happens to be that of a fragment of a naturally occurring polypeptide, the nucleic acid molecule of the invention differs from any naturally occurring nucleic acid molecule in that the coding sequence encodes just that peptide, optionally linked to a signal peptide. Of course, multiple coding sequences can be linked in tandem, separated by stop codons and potentially other noncoding sequence.

As stated above, the nucleic acid molecule may include a sequence encoding a mammalian signal peptide. That signal peptide would, when linked to the amino terminus of the immunoactive peptide within a mammalian cell, direct the secretion of the immunoactive peptide out of the cell. The signal peptide is typically enzymatically cleaved from the immunoactive peptide during the process of secretion. Selection of a particular signal peptide depends upon the species of the animal to be treated, and the amino-terminal amino acid sequence of the immunoactive peptide to be expressed. Numerous examples of secretory signal sequences linked to immunoactive gene sequences are shown in Figure 2. When a nucleic acid molecule is to be administered to a human patient, as described below, the signal peptide will usually be a human secretory signal peptide. The nucleic acid molecule of the invention will generally also include a eukaryotic expression control sequence, e.g. a mammalian expression control sequence, operatively linked to the coding sequence. The expression control sequence may be an inducible or constitutively active promoter that directs the expression of one or more immunoactive peptides encoded on the nucleic acid molecule in a tissue- or cell-specific manner. Selecting appropriate secretory signal sequences and expression control sequences is well within the abilities of skilled artisans, and further guidance regarding this selection is given below.

A related aspect of the invention is a mammalian expression vector, such as a viral, e.g. a retroviral, adenoviral, or adeno-associated vector, that has been modified by standard recombinant techniques to encode an immunoactive peptide. These viral vectors may be a part of a viral particle that is capable of infecting mammalian cells. The expression vector of the invention can be used to produce an immunoactive peptide by, for example, introducing the expression vector into a cultured mammalian cell, culturing the cell in vi tro under conditions that permit expression of the immunoactive peptide, and harvesting the immunoactive peptide from the cell. If the vector includes a secretory signal sequence, the immunoactive peptide may instead be harvested from the medium surrounding the cells. Alternatively, an immunoactive peptide may be produced in a mammal (e.g., a human, simian, mouse, rat, guinea pig, hamster, rabbit, dog, cat, cow, pig, goat, sheep or horse) by introducing into the mammal either (1) the nucleic acid molecule of the invention, (2) an expression vector containing the nucleic acid molecule of the invention, or (3) a cell that contains and expresses the nucleic acid. In the latter case, the cell or its descendent would be transduced with the nucleic acid ex vi vo . Such cells (particularly mammalian cells such as human cells) are considered to be within the invention.

Other non-integrating viral vectors include herpes simplex virus-based vectors, which have a broad cell specificity and can accept up to 36 kb of nonviral sequence, and the SV40 vector, which also targets a wide range of tissues. Other viruses known to be useful for gene transfer include adenoviruses, adeno associated virus, mumps virus, poliovirus, retroviruses, Sindbis virus, and vaccinia virus such as canary pox virus. Well-known methods of transducing cells that do not require a viral vector include calcium phosphate precipitation, lipofection, electroporation, or biolistic methods. The immunoactive peptides discussed herein were so named because of their ability to modulate an animal's immune response, as demonstrated by the biological assays described below. Thus, the invention features a method for modulating the immune response in a patient by administering to the patient a nucleic acid molecule encoding at least one peptide that functions either as an immunosuppressant or as an immunostimulant. The method may be carried out by administering to the patient either (1) the isolated nucleic acid molecule consisting essentially of the coding sequence linked to expression control elements, (2) the nucleic acid molecule within an expression vector, or (3) a cell that secretes the immunoactive peptide. In the latter case, cells of the patient could be transduced ex vivo by standard techniques, such as those described herein. The nucleic acid molecule, the vector containing it, or a cell secreting the immunoactive peptide could be administered to the patient by any route commonly known to skilled pharmacologists. These include introduction into the patient's bloodstream or cerebrospinal fluid, into the synovial fluid, into a tumor, or into the vicinity of a tumor. It will be apparent to skilled artisans that the nucleic acid molecule of the invention can be contained within a therapeutic composition that is formulated with a pharmaceutically acceptable carrier.

Nucleic acid molecules encoding peptides that function as immunosuppressants may be administered to a patient who has received a biological transplant e.g., of an organ such as a kidney, heart, liver, eye, or lung; of a tissue such as skin or bone marrow; or of cells such as fibroblasts, neural cells, islet cells, hepatocytes, or chondrocytes . These immunosuppressant-expressing nucleic acids can also be used to treat a person suffering from an autoimmune disease, including but not limited to the following: (1) a rheumatic disease such as rheumatoid arthritis, systemic lupus erythematosis, Sjogren's syndrome, scleroderma, mixed connective tissue disease, dermatomyositis, polymyositis, Reiter's syndrome, or Behcet ' s disease, (2) type I diabetes; (3) an autoimmune disease of the thyroid, such as Hashimoto's thyroiditis or Graves' Disease; (4) an autoimmune disease of the central nervous system, such as multiple sclerosis, myasthenia gravis, or encephalomyelitis; and (5) phemphigus such as phemphigus vulgaris, phemphigus vegetans, phemphigus foliaceus, Senear- Usher syndrome, or Brazilian phemphigus.

Nucleic acids encoding peptides that function as immunostimulants may be administered to a patient who is thought to be suffering from a chronic infection, an acute infection, or a cancer such as cancer of the breast, lung, colon stomach, skin, brain, cervix, uterus, liver, bone, pancreas, or hemotopoietic system.

Also within the invention is use of the nucleic acid molecule of the invention in the preparation of a medicament useful in treating any of the above conditions.

By "peptide" is meant any chain of more than two amino acid residues, regardless of post-translational modification such as glycosylation or phosphorylation. As referred to herein, naturally occurring amino acids are L-glycine (Gly; G) , L-alanine (Ala; A), L-valine (Val; V) , L-leucine (Leu; L) , L-isoleucine (He; I) , L-serine (Ser; S) , L-threonine (Thr; T) , L-aspartic acid (Asp; D) , L-glutamic acid (Glu; E) , L-lysine (Lys; K) , L-arginine (Arg; R) , L-histidine (His; H) , L-methionine (Met; M) , L-cysteine (Cys; C) , L- asparagine (Asn; N) , L-glutamine (Gin; Q) , L-tyrosine (Tyr; Y) , L-tryptophan (Trp; W) , L-phenylalanine (Phe; F) ; and L-proline (Pro; P) .

All publications, patents, and other references cited herein are incorporated by reference in their entirety.

The preferred methods, materials, and examples that will now be described are illustrative only and are not intended to be limiting. Other features and advantages of the invention will be apparent from the following detailed description, from the drawings, and from the claims. Brief Description of the Drawings Fig. 1 is a list of examples of nucleic acid molecules of the invention and the peptides they encode. An asterisk demarks the boundary between a rat secretory signal sequence and the sequence of each immunoactive peptide.

Fig. 2 is a schematic diagram of the Moloney murine sarcoma virus retroviral vector pLXSN.

Detailed Description

The experiments described herein utilize nucleic acid molecules that encode peptides which can be used to modulate the immune response. These nucleic acid molecules were cloned into expression vectors, transduced into mammalian cells, and shown to inhibit the formation of tumors in vivo, presumably by upregulating the activity of T lymphocytes in the treated animal .

Vector Construction

The following procedures were carried out in order to construct vectors that could be used to transduce malignant cells in vi tro . Each vector described below includes a sequence encoding (a) an immunoactive peptide that conforms to the motif represented in Formula I, II, III, IV, or V, and (b) a signal sequence that targets the peptide for export from the transduced cell, and a eukaryotic expression control sequence. Standard recombinant techniques were used to link these sequences and clone them into the vector of choice.

A first single-stranded oligodeoxynucleotide was synthesized, using standard techniques for DNA synthesis. This oligodeoxynucleotide consisted of, from the 5' end: 3-4 adenosine residues, a restriction enzyme site, a sequence encoding a signal peptide, a sequence encoding an immunoactive peptide, two stop codons, a second restriction enzyme site, and another 3-4 adenosine residues. The restriction enzyme sites were chosen to facilitate ligation between the oligodeoxynucleotide and the vector of choice. In the examples below, the restriction enzymes were chosen from the following: EcoRI, BamHl, Xhol, and Hpal.

In each case, the signal sequence was chosen on the basis of the first N-terminal amino acid of the immunoactive peptide. For example, immunoactive peptides having alanine as their N-terminal amino acid were linked to signal sequences that are naturally associated with peptides that have alanine as the N-terminal amino acid. For experiments conducted with rat cells, signal sequences were chosen from those which occur naturally in rat cells. For use in other species, appropriate signal sequences would be selected in an analogous way. Further guidance in selecting these sequences for use in humans is given below. The DNA sequence encoding each signal peptide used in the experiments described below was the naturally occurring rat DNA sequence, except where it was necessary to modify it to avoid including a restriction enzyme site that would complicate the cloning strategy. Similarly, the DNA sequence encoding each immunoactive peptide was chosen in part to avoid introducing problematic restriction sites.

The single-stranded oligodeoxynucleotide prepared as described above was made double-stranded as follows. An antisense oligodeoxynucleotide complementary to approximately 15 nucleotides at the 3 ' end of the first oligodeoxynucleotide was synthesized by standard synthetic means. In order to anneal these two DNA molecules to one another, they were placed in a solution of T7 DNA polymerase buffer (United States Biochemicals) , gradually heated to 60°C, and held at that temperature for 30 minutes. Once annealed, a complete double-stranded molecule was enzymatically generated with T7 DNA polymerase, according to the manufacturer's instructions (United States Biochemicals) . The double-stranded DNA was purified by passing it over a Sephadex G50 (Pharmacia, Uppsala, Sweden) column in TE buffer (10 mM Tris, 1 mM EDTA at pH 7.5) and digested with restriction enzymes corresponding to the restriction sites that had been placed at each end of the oligodeoxynucleotide. The DNA was extracted from the digest with phenol-chloroform, precipitated with absolute ethanol at - 70°C, and collected by centrifugation, according to standard methods. The DNA pellet was washed with 70% ethanol, dried under vacuum, and redissolved in TE buffer.

DNA prepared as described above can be inserted into any vector that has compatible restriction sites. In this case, the DNA was inserted into the Moloney murine sarcoma virus retroviral vector pLXSN (Fig. 2) which had been digested with restriction enzymes to create cohesive ends complementary to those created by digestion of the insert, i.e., with one of the following pairs of restriction enzymes: (1) EcoRI-BamHI, (2) EcoRI-Xhol, (3) EcoRI-Hpal, (4) Hpal-BamHl, (5) Hpal-Xhol, or (6) XhoI-BamHI. To insert the DNA into the vector, a ligation reaction containing approximately 20 ng of vector DNA and 4 ng of insert DNA was carried out at 16°C with T4 DNA ligase (Boehringer Mannheim) . The ligation reaction was then used to transform electrocompetent E. coli cells (DH5α strain) . Individual colonies that developed from transformed cells were picked at random and checked by the polymerase chain reaction (PCR) for the presence of vectors that contained insert. Colonies consisting of a clone of cells that contained the desired construct (vector with insert) were amplified, and the DNA construct was isolated and sequenced by standard methods . Once the presence and orientation of the insert was confirmed by sequencing, large scale cultures were established in LB medium supplemented with ampicillin (50 μg/ml) and grown until the OD at 600 nm was 0.8. Chloramphenicol was then added to a final concentration of 180 μg/ml, and the flasks were incubated at 37°C, on a shaker, overnight. The DNA constructs were isolated from the bacterial cultures using a QIAGEN aPlasimd kit (QIAGEN, GmbH, Hilden, Germany) , according to the manufacturer's instructions. Transduction of Cultured Cells

Cultured cells were obtained from two types of mammary carcinomas: SPMW1 cells were obtained from a tumor that developed spontaneously in a female Wistar rat, and Ad9-101 cells were obtained from a tumor that developed after newborn female Wistar rats were inoculated with adenovirus type 9

(Lindvall et al . , 1991, Cancer Immunol. Immunother. 33:21-27) . The tumors were kept in serial passage in syngeneic rats.

Cell lines were established from the tumors as follows. The tumor was excised from the animal, minced with a pair of scissors, and treated with Dispase grade II for 30 minutes (2.4 mg/ml; Boehringer Mannheim) in RPMI 1640 medium to disaggregate the cells. The SPMW1 cell line was established from the nineteenth in vivo passage of a tumor, and the Ad9-101 cell line was established at the fifth in vivo passage. The disaggregated cells were cultured in RPMI 1640 medium supplemented with 4 mM l-glutamine, 1 mM pyruvate, 10 mM HEPES buffer, 10 mM NaHC0₃, and 5% fetal calf serum (FCS) in vessels obtained from NUNC (Roskilde, Denmark) .

To transduce the cells, DNA constructs were prepared as described above and used to transfect a retroviral packaging cell line GP+E or Psi2 with TRANSFECTAM™ (Promega, USA) , according to the manufacturer's instructions. Transfectants were selected with G418 (300 μg/ml) in RPMI 1640 with 10% FCS. Virus-laden supernatant from the transfectants was then used to infect either SPMWl cells or Ad9-101 cells. Successfully transduced cells were selected in the presence of G418, and clonal cell lines were developed.

An assay based on the polymerase chain reaction (PCR) was used to demonstrate that the DNA encoding an immunoactive peptide was transcribed into mRNA within the transduced cells. In addition, an in vi tro biological assay of the effect on proliferation of activated T lymphocytes of supernatant from SPMWl cells which had been transduced with a nucleic acid of the invention is consistent with the conclusion that the immunoactive peptide (D22175AX) is expressed and secreted by the transduced cells, and overcomes the suppressive effect of wild type SPMWl cells on T lymphocyte proliferation. Implantation of Transduced Cells Transduced tumor cells were harvested from the culture vessels by the addition of trypsin, collected by centrifugation, and resuspended in phosphate buffered saline (PBS) supplemented with 5% normal syngeneic rat serum. Each rat in the experimental group received a subcutaneous injection in the right hindlimb of approximately 200 ml of resuspended cells. As a control, comparable rats received subcutaneous injections of the same type of tumor cells, but which had not been transduced, and thus did not express or secrete an immunoactive peptide.

Assessment of Tumor Size in vivo On the day the tumor cells were inoculated and at various intervals ranging up to 36 days afterward, the hindlimb was palpated at the site of injection. When a tumor could be felt, the largest diameter was measured with a caliper. A second measurement was taken perpendicular to the first. The volume of the tumor was calculated by using the formula

V=0.4(a-b²) , where V = volume (in mm³), a = the largest diameter (in mm), and b = the diameter perpendicular to the largest diameter (in mm) .

Example 1: Immunostimulation by D22175AX-expressing SPMWl Cells

SPMWl mammary carcinoma cells in cell culture were infected with a retroviral vector containing an insert encoding the immunoactive peptide D22175AX. Transduced cells were selected in G418, as described above, but not cloned. Approximately 25,000 transduced tumor cells were subcutaneously injected into the hindlimbs of each of 8 rats. As a control, an equivalent group of rats was similarly injected with approximately 25,000 wild type (i.e., non-transduced) SPMWl cells. The size of the tumor that developed in vivo was estimated according to the above formula in both groups for up to fifteen days following injection. On any given day after injection, the mean size of the tumor that developed from D22175AX-expressing SPMWl cells was less than one-tenth the size of the tumor that developed from wild type SPMWl cells (Table 1) . This result demonstrates that a construct encoding and presumably expressing D22175AX substantially impedes tumor growth in vivo .

Table 1: Estimated Volume (mm ) of Palpated Tumor

Day SPMWl wild type SPMWl (D22175AX)

0 0 0

4 0 0

7 72 4

9 482 16

13 2791 205

15 4704 423

20 1435

24 2955

Example 2: Lack of Immunostimulation by D22175AX- expressing SPMWl Cells in Nude Rats

D22175AX-expressing SPMWl cells were also injected subcutaneously into the right hindlimb of "nude" rats. These animals do not have a thymus and thus do not produce T lymphocytes. Five animals were injected subcutaneously with approximately 25,000 uncloned D22175AX-expressing SPMWl cells and five were injected with a comparable number of wild type SPMWl cells. The tumors that developed in these two groups of animals following inoculation grew at a comparable rate (Table 2), suggesting that the inhibition of tumor growth seen when immunocompetent rats are inoculated with D22175AX- expressing SPMWl cells involves a T cell-mediated immune response. Table 2: Estimated Volume (mm ) of Palpated Tumor

Day SPMWl wild type SPMWl (D22175AX)

0 0 0

6 0 0

13 470 555

17 1820 1930

20 5805 6461

Example 3: Immunostimulation by D22175AX-expressing Ad9-101 Cells Ad9-101 mammary carcinoma cells in cell culture were infected with a retroviral vector containing an insert encoding the immunoactive peptide D22175AX. As described in Example 1, the cells were selected in G418, but they were not cloned. Approximately 10,000 cells were subcutaneously injected into the hindlimbs of each of 5 rats. As a control, an equivalent group of rats was injected with 10,000 wild type Ad9-101 cells. On any given day after injection, the average size of the tumor that had developed from D22175AX-expressing Ad9-101 cells was less than one-tenth the size of the tumor that developed from wild type Ad9-101 cells (Table 3) . Therefore, expression of D22175AX significantly impedes tumor growth in at least two model systems. Table 3 : Estimated Volume (mm³) of Palpated Tumor

Day Ad9-101 wild type Ad9-101 (D22175AX)

0 0 0

8 0 0

14 34 0

16 87 2

20 465 23

23 1055 55

27 4165 366

30 997

Example 4: Immunostimulation by two D22175AX- expressing Ad9-101 clones; clone 8 and clone 9 Cells from four different D22175AX-expressing Ad9-101 clonal cell lines were injected into rats in order to determine whether different transduced clones expressing the same peptide were equally effective in impeding tumor growth. Wild type Ad9- 101 cells served as the control for this experiment. Five animals in each group received subcutaneous injections containing approximately 50,000 cells of uncloned, clone 6, clone 7, clone 8, clone 9, or wild type Ad9-101 lines. As shown in Table 4, all transduced clones exhibited significantly slower tumor growth than did wild type Ad9-101 cells, at least after day 13. Table 4: Estimated Volume (mm³) of Palpated Tumor

Day Wild Uncloned Clone 6 Clone 7 Clone 8 Clone 9 Type

0 0 0 0 0 0 0

7 0 0 0 0 0 0

10 2 0 2 28 0 0

13 64 7 4 80 0 2

17 646 28 37 230 14 3

21 3024 84 85 714 108 8

24 149 77 1679 500 9

28 757 279 2700 972 48

Example 5: Immunostimulation by D22175AX-expressing Ad9-101 Cells is Mediated by T Lymphocytes In order to determine whether T lymphocytes are activated in response to in vivo expression of an immunoactive peptide, the following experiment, which extends from Example 4, was performed. Rats were injected subcutaneously with either wild type Ad9-101 cells or D22175AX-expressing Ad9- 101 cells (clone 8 or clone 9) . Each animal was killed when its tumor reached 50-100 mm³ in size, and approximately 2.5 x IO⁵ cells were harvested from the lymph nodes associated with the tumor, i.e., the inguinal and para-aortal lymph nodes ipsilateral to the tumor. Cells were also harvested from the lymph nodes of normal rats (which were free of tumors) . The lymphatic cells from each rat were placed in culture either as a homogeneous population, or in co-culture with approximately 7.5 x IO³ lethally irradiated (8000 rad=80 Gray) wild type Ad9- 101 cells. The homogeneous and heterogeneous cultures were established in parallel in a total of 10 wells of a 96 well plate (NUNC, Roskilde, Denmark) , and grown for 5 days in RPMI 1640 medium supplemented with 4 mM L-glutamine, 1 mM pyruvate, 10 mM Hepes buffer, 15 mM NaHC0₃, 50 μM β-mercaptoethanol, and 10% FCS. On the fifth day in culture, the cells were exposed to [³H] -thymidine (0.5 μCi) for 6 hours. Although other cell types, such as monocytes, natural killer cells, and B lymphocytes are present, under the conditions of the culture, only T lymphocytes can respond with mitotic activity on day 5. The radioactivity incorporated into acid-insoluble material, which reflects the mitotic activity of the cells in culture, was measured with a scintillation counter. The amount of radioactivity incorporated into homogeneously cultured lymph cells was subtracted from the amount of radioactivity incorporated into heterogeneous cultures containing lymphatic and irradiated tumor cells. (The incorporated radioactivity is attributable solely to proliferation of the lymphatic cells, because the tumor cells were lethally irradiated prior to co- culture and so could not proliferate.) The data obtained from two trials, and expressed as counts per minute (cpm) , are presented in Table 5.

Table 5: ³H-thymidine Incorporation by Cultured Lymphatic Ce] 11 s

Lymphatic Cells from animal Trial 1 Trial 2 with:

No tumor 1,016 669

Wild type Tumor 680 0

Clone 8 Tumor 5,101 12,632

Clone 9 Tumor 18,394 59,026

These results demonstrate that, in the presence of lethally irradiated (but presumably still antigenic) wild type Ad9-101 cells, the mitotic activity of T lymphocytes harvested from animals that had been injected with D22175AX- expressing Ad9-101 cells (clone 8 or clone 9) is substantially greater than the mitotic activity of T lymphocytes from either normal (non-injected) animals or animals that were injected with wild type Ad9-101 tumor cells. The data suggest that "vaccination" with wild type tumor cells actually decreases the ability of the animal's T lymphocytes to respond to a subsequent challenge with wild type tumor cells, while vaccination with D22175AX-expressing tumor cells not only overcomes this inhibition, but renders the animal's T lymphocytes substantially more sensitive to challenge with wild type tumor cells than the T lymphocytes of an unimmunized animal . Example 6: Immunization with Irradiated D22175AX- expressing Ad9-101 Cells Impedes Subsequent Tumor formation by Wild Type Ad9-101 Cells

In this experiment, rats were inoculated with either Ad9-101 wild type cells that had been irradiated with

10,000 rad (100 Gray) , or clone 9 cells that had been similarly irradiated. (Irradiation prevents the cells from dividing more than once, but it does not immediately affect protein synthesis.) Animals received two subcutaneous injections of irradiated cells (1 x 10⁶ cells/animal/dose), 14 days apart, while a group of control animals received comparable injections of phosphate buffered saline (PBS) . Fourteen days following the second injection, by which time it is expected the irradiated cells had all been cleared from the injection site, the animals were challenged with an injection of 10,000 non-irradiated Ad9- 101 wild type cells, and tumor growth was assessed. The tumors that developed in animals that had been injected with irradiated clone 9 cells were on average substantially smaller than the tumors that developed in rats that were injected with PBS or with irradiated wild type Ad9-101 cells (Table 6) . Thus, the antitumor effect of D22175AX persists even after the D22175AX-expressing cells were presumably cleared from the test animals' bodies. Table 6: Estimated Volume (mm³) of Palpated Tumor

Day PBS immunized Wild type Clone 9 immunized immunized

0 0 0 0

7 0 0 0

12 0 0 0

15 1 7 1

19 158 347 102

21 395 618 193

26 2023 2136 882

28 4218 1481

Example 7: Immunomodulation by D22139AA-expressing, D22069AX-expressing, or D7208-expressing Ad9-101 cells

To compare the effects of three different immunoactive peptides on tumor growth, rats were inoculated with transduced Ad9-101 cells that expressed either D22139AA, D22069AX, or D7208 (see Fig. 1) . The immunoactive peptide D22139AA (without signal sequence) has previously been shown to be immunostimulatory when administered directly in a delayed-type hypersensitivity (DTH) assay, while D22069AX and D7208 (each without signal sequence) have shown activity consistent with immunosuppression. Approximately 20,000 transduced cells were injected subcutaneously into each rat (5 animals/group) , and the tumors which developed were measured. As shown in Table 7, uncloned cells expressing D22139AA formed tumors that grew somewhat more slowly than those which developed from wild type Ad9-101 cells, consistent with the immunostimulatory activity of this peptide observed in the DTH test. In contrast, the tumors that developed from uncloned cells expressing either D22069AX or D7208 grew faster than the tumors that developed from wild type Ad9-101 cells (at least after day 22), consistent with the immunosuppressant activity of these peptides in the DTH test. This suggests that the delayed-type hypersensitivity assay described below is a useful predictor of the immunomodulatory effect of peptides expressed from the nucleic acid molecules of the invention.

Table 7: Estimated Volume (mm³) of Palpated Tumor

Day Wild type D22139AA D22069AX D7208

0 0 0 0 0

12 0 0 0 0

15 6 0 7 10

19 95 38 148 107

22 502 248 674 488

26 582 328 1035 767

29 1206 766 1546 1734

34 1936 1728 3842 2681

36 3047 2792 5306 3493 Example 8: Inoculation of Various Clones of D22139AX- expressing Cells

Several clones of D22139AX-expressing Ad9-101 cells were established. Each rat (n=5 animals/group) received an injection of either wild type AD9-101 cells, uncloned D22139AX-expressing Ad9-101 cells, or cells from one of the D22139AX-expressing Ad9-101 clones designated 1, 2, 3, 5, 6, 7, and 9. Tumor growth was assessed as described above. The data gathered from animals injected with clone 6, clone 7, wild type, or uncloned D22139AX-expressing cells are presented in Table 8. The tumors that developed from uncloned D22139AX-expressing Ad9-101 cells were on average somewhat smaller than the tumors that developed from wild type Ad9-101 cells, consistent with the results of the experiment shown in Table 7, while the tumors that developed from clones 6 and 7 were substantially smaller. In addition, clones 1, 2, 3, 5, and 9 showed essentially no tumor outgrowth through day 35 (data from clone 2 is shown in Table 8) .

Table 8 : Estimated Volume (mm³) of Palpated Tumor

Day Uncloned Clone 6 Clone 7 Wild Type Clone 2

0 0 0 0 0 0

7 0 0 0 0 0

15 18 27 0 139 0

19 77 59 3 289 0

26 692 131 88 906 0

30 1455 447 128 2376 0

^{3 5} 2575 901 301 6973 1 Example 9 : Expression of IL-7 has No Effect on Tumor Growth

In order to demonstrate that the immunomodulatory effect observed in the experimental paradigms described above is due to the expression of nucleic acid molecules that encode peptides conforming to Formula I, II, III, IV, or V, a nucleic acid molecule encoding a peptide that does not conform to any of these formulas was studied according to the paradigm described in Example 1. Approximately 10,000 SPMWl cells transduced with IL-7 (interleukin 7) were subcutaneously injected into the hindlimbs of each of 7 rats. As a control, an equivalent group of rats was similarly injected with approximately 10,000 wild type (i.e., non-transduced) SPMWl cells. The size of the tumor that developed in vivo was estimated in both groups for up to seventeen days following injection. As shown in Table 9, expression of IL-7 had no effect on tumor growth, and therefore presumably no effect on the animals' immune response.

Table 9: Estimated Volume (mm³) of Palpated Tumor

Day Wild Type IL-7 Infected

0 0 0

6 65 85

13 925 1543

17 2574 2380 Additional Assays for Identifying Immunostimulants

The following assays can be used to identify immunostimulatory peptides that can be delivered by gene therapy in accordance with the invention. Delayed Type Hypersensitivity (DTH) Test

The ability of a DNA molecule to. encode a peptide that modulates the immune response can be determined using the delayed type hypersensitivity (DTH) test in mice. The detailed protocol for this assay can be found, for example, in Carlsten et al . (1986, Int. Arch. Allergy Appl. Immunol. 81:322) . Briefly, male or female mice, such as Balb/c mice, are sensitized by exposure to 4-ethoxymethylene-2-phenyloxazolin-5- one (OXA; Sigma Chemical Co. ) . On Day 0, 150 μl of an absolute ethanol-acetone (3:1) solution containing 3% OXA is applied to the animal's shaved abdomen. Treatment with the immunoactive peptide itself (e.g., by topical or IV administration), or with gene therapy using a nucleic acid encoding the peptide, is then begun (methods of administration are discussed below) . Approximately one week after sensitization, the thickness of the animal's ears is measured with an Oditest spring caliper before both ears are challenged by topical application of 20 μl of 1% OXA dissolved in an oil, such as peanut oil. Ear thickness is measured again 24 and 48 hours after the challenge. To minimize discomfort, challenges and measurements are performed under light anesthesia.

The intensity of the DTH reaction is measured as described by van Loveren et al. (1984, J. Immunol. Methods 67:311), and expressed according to the formula: Tt24/48 - TtO (in mm units) where tO, t24, and t48 represent ear thickness before, 24 hours after, and 48 hours after the challenge, respectively. The ability of the peptide or gene therapy to modulate ear thickness is an indication of its ability to modulate the immune response: a relative increase in thickness indicates a heightened response, while a relative decrease in thickness indicates immune suppression. Inhibition of Tumor Growth

Nucleic acids encoding peptides that stimulate the immune response can be identified using any model system analogous to the mammary carcinoma models described above. These additional model systems could be developed with immortalized cells from an established cell line or an induced or spontaneous tumor of an animal. Other cell lines that would be amenable to an assay for tumor growth are readily available from the American Type Culture Collection (A.T.C.C.) , which maintains cell lines established from a wide variety of tumors that developed in many different species. Transgenic animals that develop tumors due to, for example, overexpression of an oncogene or inhibition of a tumor suppressor gene provide a second source of tumor cells suitable for tumor growth assays. Alternatively, a spontaneous or induced tumor from an animal (e.g., a spontaneous tumor from a human) could be used. Cells from any of these sources could be placed in culture, transduced with a nucleic acid encoding a candidate immunoactive peptide, and transplanted into a test animal.

Cells cultured in parallel, but untransduced or transduced only with the "empty" vector or a vector encoding a non-immunoactive peptide, would be transplanted into control animals. If the transplanted cells that expressed the candidate peptide failed to produce a tumor, or produced a tumor that was significantly smaller than that found in control animals, the encoded peptide would be deemed an effective immunostimulant. In a variation on this assay, the transduced cells could be irradiated and mixed with non-irradiated wild type cells prior to injection, so that the effect of the secreted peptide on growth of wild type tumor cells in vivo would be measured. Model systems developed from different sources of immortalized cells may provide the means to determine whether peptides are broadly effective or particularly effective in treating a certain type of cancer. Immunization Assay

Genes encoding peptides that stimulate the immune response can also be identified in various model systems by the "immunization" procedure described in Example 6. Immortalized cells obtained from the A.T.C.C. or established from primary tumor tissue as described above, would be transduced with the gene of interest, lethally irradiated, and injected into animals. As a control, animals could be injected with irradiated wild type tumor cells. Subsequently, both groups of animals would be challenged with wild type tumor cells and examined for tumor formation. If the peptide is an immunostimulant with therapeutic potential, the growth of the tumor following the challenge with wild type cells would be impeded in animals that had been immunized with peptide- expressing cells. By performing the analysis of a given gene in model systems that employ immortalized cells from an array of tumors, it should be possible to determine whether the gene encodes a peptide that could serve as a broad-based vaccine, or whether it is primarily effective against a particular form of cancer. In a variation on this method, one could use as the test animals transgenic animals (e.g., mice) that spontaneously develop tumors. Transduced, irradiated tumor cells from such an animal can be used to immunize other animals of the same line, before they begin to develop any tumors . Subsequent spontaneous or induced tumor formation and growth are then assessed in the immunized animals.

Assay for Tumor Regression

Another way to assay a peptide-encoding gene is to administer it to an animal after a tumor has formed. The animal can be one that is a transgenic model for tumor formation, or one which has developed a tumor following injection of wild type tumor cells. When a tumor of a given size has formed in a test animal, the animal is injected with the peptide-encoding vector or with peptide-expressing cells, which could either be viable or lethally irradiated. A reduction in tumor size or number compared to control, or an extended time to death, would provide very strong evidence for the utility of genes encoding immunostimulatory peptides in the treatment of cancer.

In each of the assays described above, it would be possible to show that the immune system was suppressed by the gene product in question by performing the experiment presented in Example 5. This experiment would demonstrate that the gene product exerted its influence by stimulating the activity of T lymphocytes, rather than by a mechanism that is independent of the immune system. Peptides that are ineffective in impeding tumor outgrowth, or that enhance tumor outgrowth, could be tested further, as described below, in order to determine whether they would be useful immunosuppressants. Assays for Identifying Immunosuppressants

The following procedures could be employed in order to determine whether a given peptide is an immunosuppressant that could be usefully delivered by genetic therapy. Transplantation Paradigms

In order to determine whether a peptide is capable of functioning as an immunosuppressant, it can be administered, directly or by genetic therapy, in the context of well- established transplantation paradigms. A putative immunosuppressing peptide, or a nucleic acid molecule encoding it, could be systemically or locally administered by standard means to any conventional laboratory animal, such as a rat, mouse, rabbit, guinea pig, or dog, before an allogeneic or xenogeneic skin graft, organ transplant, or cell implantation is performed on the animal. Alternatively, the graft itself could be transduced with the nucleic acid of the invention. Strains of mice such as C57B1-10, B10.BR, and B10.AKM (Jackson Laboratory, Bar Harbor, ME) , which have the same genetic background but are mismatched for the H-2 locus, are well suited for assessing various organ grafts .

A method for performing cardiac grafts by anastomosis of the donor heart to the great vessels in the abdomen of the host was first published by Ono et al . (1969, J. Thorac. Cardiovasc. Surg. 57:225; see also Corry et al . , 1973, Transplantation

16:343) . According to this surgical procedure, the aorta of a donor heart is anastomosed to the abdominal aorta of the host, and the pulmonary artery of the donor heart is anastomosed to the adjacent vena cava using standard microvascular techniques. Once the heart is grafted in place, and warmed to 37°C with Ringer's lactate solution, normal sinus rhythm will resume. Function of the transplanted heart can be assessed frequently by palpation of ventricular contractions through the abdominal wall. Rejection is defined as the cessation of myocardial contractions. With regard to the current invention, a given peptide would be considered a successful immunosuppressant if it prolonged the time the grafted organ was tolerated by the host . The effectiveness of an immunoactive peptide can also be assessed following a skin graft. To perform skin grafts on a rodent, a donor animal is anesthetized and the full thickness skin is removed from a part of the tail. The recipient animal is also anesthetized, and a graft bed is prepared by removing a portion of skin from the shaved flank. Generally, the patch is approximately 0.5 x 0.5 cm. The skin from the donor is shaped to fit the graft bed, positioned, covered with gauze, and bandaged. The grafts can be inspected daily beginning on the sixth post-operative day, and are considered rejected when more than half of the transplanted epithelium appears non-viable.

Another technique for assaying immunosuppression is with cells that have been tranduced with a nucleic acid of the invention, then implanted into an allogeneic or xenogeneic animal . If the transduced implanted cells survive longer than control implanted cells which have not been transduced, then the nucleic acid molecule presumably encodes an immunosuppressive peptide. Models of Autoimmune Disease

Models of autoimmune disease provide another means to assess peptides in vivo . These models are well known to skilled artisans and can be used to determine whether a given peptide is an immunosuppressant that would be therapeutically useful in treating a specific autoimmune disease when delivered via genetic therapy.

Autoimmune diseases that have been modeled in animals include rheumatic diseases, such as rheumatoid arthritis and systemic lupus erythematosis (SLE) , type I diabetes, and autoimmune diseases of the thyroid and central nervous system. For example, animal models of SLE include MRL mice, BXSB mice, and NZB mice and their FI hybrids. These animals can be crossed in order to study particular aspects of the rheumatic disease process; the NZB strain develops severe lupus glomerulonephritis when crossed with NZW mice (Bielschowsky et al., 1959, Proc. Univ. Otago Med. Sch. 37:9; see also Fundamental Immunology, 1989, Paul, Ed., Raven Press, New York, NY) . Similarly, a shift to lethal nephritis is seen in the progeny of NBZ X SWR matings (Data et al . , 1976, Nature

263:412) . The histological appearance of renal lesions in SNFl mice has been well characterized (Eastcott et al . , 1983, J. Immunol. 131:2232; Paul, supra) . Therefore, the general health of the animal as well as the histological appearance of renal tissue can be used to determine whether the administration of genes encoding immunoactive peptides can effectively suppress the immune response in an animal model of SLE.

One of the MRL strains of mice that develops SLE, MRL- lpr/lpr, also develops a form of arthritis that resembles rheumatoid arthritis in humans (Theofilopoulos et al . , 1985, Adv. Immunol. 37:269) . Alternatively, an experimental arthritis can be induced in rodents by injecting rat type II collagen (2 mg/ml) mixed 1:1 in Freund's complete adjuvant (100 μl total) into the base of the tail. Arthritis develops 2-3 weeks after immunization.

The ability of genes encoding immunoactive peptides to combat the arthritic condition can be assessed by targeting the genes to T lymphocytes and/or to synovial cells of the joint. One way to target T lymphocytes is the following: spleen cell suspensions are prepared 2-3 days after the onset of arthritis and incubated with collagen (100 μg/ml) for 48 hours to induce proliferation of collagen-activated T lymphocytes. During this time, the cells are transduced with a vector encoding the peptide of interest. As a control, parallel cultures are untransduced or transduced with the "empty" vector. The cells are then injected intraperiotoneally (5 x IO⁷ cells/animal) . The effectiveness of the treatment is assessed by following the disease symptoms during the subsequent 2 weeks, as described by Chernajovsky et al . (1995, Gene Therapy 2:731-735) . A decrease in symptoms compared to control indicates that the peptide of interest, and the gene encoding it, function as an immunosuppressant potentially useful in treating autoimmune disease.

Alternatively, one could introduce the peptide-encoding vector, e.g., an adenoviral vector, directly into the cells of the joint synovium. An effective control in this instance would entail injecting a joint on the opposite side of the same animal or the joint of a second animal, with an adenovirus that carries the vector sequence only (Evans et al . , 1995, Trends in Mol. Med. 27:543-546) . The ability of genes encoding immunoactive peptides to suppress the immune response in the case of Type I diabetes can be tested in the BB rat strain, which was developed from a commercial colony of Wistar rats at the Bio-Breeding Laboratories in Ottawa. These rats spontaneously develop autoantibodies against pancreatic islet cells and insulin, just as occurs in human Type I diabetes. Prior to development of full-scale diabetes in these animals, the vector of the invention could be targeted to their T lymphocytes, as discussed above, or to islet cells. Human Therapy

The application of peptide-encoding genes to the treatment of cancer, infection, autoimmune disease, or graft rejection in humans can utilize either in vivo or ex vivo based therapeutic approaches.

Ex vivo-based Human Therapies

This approach would entail harvesting cells (e.g., tumor cells, synovial cells, or T lymphocytes) from a patient, establishing them in culture, and transducing them with a nucleic acid of the invention. The transduction step could be accomplished by any standard means used for ex vivo gene therapy, including calcium phosphate, lipofection, electroporation, viral infection, and biolistic gene transfer. Cells that have been successfully transduced are then selected, for example via a drug resistance gene. The cells may then be lethally irradiated if desired (e.g., for tumor cells) and injected or implanted into the patient.

For treatment of rheumatoid arthritis, T lymphocytes obtained from the synovial fluid of an affected joint are stimulated ex vivo with IL-2 or anti-human CD3 monoclonal antibody and simultaneously infected with a relevant gene construct. The cells are reintroduced into the patient, e.g., by intravenous administration, where they should home to the diseased joints and produce the peptide at the site of the inflammation. A retroviral or adeno-associated viral vector would be appropriate for this ex vivo infection procedure. In vivo-based Human Therapies

The in vivo approach requires delivery of the construct of the invention directly into the patient, targeting it to the cells or tissue of interest. For example, after surgical removal of a primary tumor, residual cells may be targeted by treating the vicinity of the tumor with a composition containing a retroviral vector encoding an immunostimulatory peptide. Instead of surgery, the primary tumor could be treated by in si tu injection of the vector directly into the tumor.

Malignant cells distal to the primary tumor site may be reached by delivering the vector intravenously. Targeting of tumor cells can be accomplished by the use of a retrovirus, which targets proliferating cells. Alternatively, one could utilize an engineered cell attachment ligand on the vector or the viral particle to accomplish preferential targeting of specific cells in accordance with standard methods .

An example of a non-viral vector system is a molecular conjugate composed of a plasmid attached to poly-L-lysine by electrostatic forces. Poly-L-lysine covalently binds to a ligand that can bind to a receptor on tumor cells (Cristiano et al., 1995, J. Mol. Med 73:479-486) . A promoter inducing relatively tumor-specific expression can be used to achieve a further level of targeting: for example, α-fetoprotein promoter for hepatocellular carcinoma (Huber et al . , 1991, Proc. Natl. Acad. Sci. USA 88:8039-8043) or the tyrosinase promoter for melanoma (Hart et al . , 1995, Br. Med. Bull. 51 (3) : 647-655) . Alternatively, a constitutively active promoter could be used, e.g., the SV40 promoter or CMV promoter. One could treat rheumatoid arthritis via direct inoculation of the vector into the affected joint in order to infect the synovial cells in si tu . Adeno-associated viral vectors may be used if long-term expression is desired, or an adenoviral vector for shorter-term expression. Both of these vectors are known to infect synovial cells in rabbits (Evans et al . Gene therapy for arthritis. In Wolff, J.A. Ed. Therapeutics: Methods and Applications of Direct Gene Transfer. Birkhauser, Boston, MA, 1994 320-343) .

Other embodiments are within the following claims.

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(ii) TITLE OF INVENTION: EXPRESSION OF RECOMBINANT PEPTIDES

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Gly Pro Cys He

1 (2) INFORMATION FOR SEQ ID NO:34:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO:34:

Leu Leu Phe Gly Pro Cys He 1 5

(2) INFORMATION FOR SEQ ID NO:35:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:35:

Leu Leu Phe Ala Pro Cys He

1 5 (2) INFORMATION FOR SEQ ID NO:36:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:36:

Leu Leu Phe Arg Pro Cys He 1 5

(2) INFORMATION FOR SEQ ID NO:37:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:37:

Leu Leu Phe He Pro Cys He

1 5 (2) INFORMATION FOR SEQ ID NO:38:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO:38:

Leu Leu Phe Asp Pro Cys He 1 5

(2) INFORMATION FOR SEQ ID NO:39:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO:39

Ala Val Trp Thr Pro Cys Tyr 1 5 (2) INFORMATION FOR SEQ ID NO:40:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO:40:

Phe Val Met Ala Pro Cys Phe 1 5

(2) INFORMATION FOR SEQ ID NO:41:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID Nθ:41;

Leu Leu Tyr Ser Pro Cys Phe 1 5 (2) INFORMATION FOR SEQ ID NO:42:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 2:

He Ser Gly Pro Cys Pro Lys 1 5

(2) INFORMATION FOR SEQ ID NO:43:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

( i) SEQUENCE DESCRIPTION: SEQ ID NO: 43

Phe Leu Phe Gly Pro Cys He 1 5 (2) INFORMATION FOR SEQ ID NO:44:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

( i) SEQUENCE DESCRIPTION: SEQ ID NO:44:

Leu Phe Gly Pro Cys He Leu

1 5

(2) INFORMATION FOR SEQ ID NO:45:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:45:

Glu Lys Gly Pro Cys Tyr Arg

1 5 (2) INFORMATION FOR SEQ ID NO:46:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:46:

Phe Cys Leu Gly Pro Cys Pro 1 5

(2) INFORMATION FOR SEQ ID NO:47:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:47 ;

Phe Gly Pro Cys He

1 5 (2) INFORMATION FOR SEQ ID NO:48:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 9 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:48:

Phe Leu Phe Gly Pro Cys He Leu Asn 1 5

(2) INFORMATION FOR SEQ ID NO: 9:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:49:

Gly Pro Cys He Leu Asn Arg

1 5 (2) INFORMATION FOR SEQ ID NO:50:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:50:

Leu Leu Phe Trp Pro Cys He

1 5

(2) INFORMATION FOR SEQ ID NO:51:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:51:

Leu Leu Phe Gly He Cys He 1 5 (2) INFORMATION FOR SEQ ID NO: 52:

(1) SEQUENCE CHARACTERISTICS: (A) LENGTH: 9 ammo acids (B) TYPE: ammo acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(11) MOLECULE TYPE: peptide

(XI) SEQUENCE DESCRIPTION: SEQ ID NO:52:

Leu Leu Phe Gly Pro Cys He Leu Asn 1 5

(2) INFORMATION FOR SEQ ID NO: 53:

(l) SEQUENCE CHARACTERISTICS: (A) LENGTH: 10 am o acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

( n ) MOLECULE TYPE : peptide

(Xl ) SEQUENCE DESCRIPTION : SEQ ID NO : 53 :

Leu Leu Phe Gly Pro Cys He Leu Asn Arg 1 5 10 (2) INFORMATION FOR SEQ ID NO:54:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 12 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:54:

Trp Cys Gly Pro Cys Lys Met He Lys Pro Phe Phe 1 5 10

(2) INFORMATION FOR SEQ ID NO:55:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 13 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

( i i ) MOLECULE TYPE : pept ide

(xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 55 :

Leu Leu Phe Gly Pro Cys He Leu Asn Arg Leu Met Glu 1 5 10 (2) INFORMATION FOR SEQ ID NO:56:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 13 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 56:

Phe Leu Phe Gly Pro Cys He Leu Asn Arg Leu Met Glu 1 5 10

(2) INFORMATION FOR SEQ ID NO:57:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 32 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 57:

Met Lys Phe Leu Ser Ala Arg Asp Phe His Pro Val Ala Phe Leu Gly

1 5 10 15 Leu Met Leu Val Thr Thr Thr Ala Phe Gly Pro Cys He Leu Asn Arg 20 25 30

(2) INFORMATION FOR SEQ ID NO: 58:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 31 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 58

Met Arg Leu Arg Leu Leu Val Ser Ala Gly Met Leu Leu Val Ala Leu 1 5 10 15

Ser Pro Cys Leu Pro Cys Arg Ala Leu Leu Phe Gly Pro Cys He 20 25 30

(2) INFORMATION FOR SEQ ID NO: 59:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 31 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide (XI) SEQUENCE DESCRIPTION: SEQ ID NO:59:

Met Arg Leu Arg Leu Leu Val Ser Ala Gly Met Leu Leu Val Ala Leu 1 5 10 15

Ser Pro Cys Leu Pro Cys Arg Ala Leu Leu Tyr Ser Pro Cys Phe 20 25 30

(2) INFORMATION FOR SEQ ID NO:60:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 24 amino acids

(B) TYPE: am o acid (C) STRANDEDNESS: not relevant (D) TOPOLOGY: linear

(li) MOLECULE TYPE: peptide

(XI) SEQUENCE DESCRIPTION: SEQ ID NO:60:

Met Trp Phe Leu He Leu Phe Leu Ala Leu Ser Leu Gly Gin He Asp

1 5 10 15

Ala Ala Pro Gly Cys Cys Pro Gly 20

(2) INFORMATION FOR SEQ ID NO:61:

(1) SEQUENCE CHARACTERISTICS: (A) LENGTH: 31 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:61:

Met Lys Phe Leu Ser Ala Arg Asp Phe His Pro Val Ala Phe Leu Gly 1 5 10 15

Leu Met Leu Val Thr Thr Thr Ala Phe Cys Leu Gly Pro Cys Pro 20 25 30

(2) INFORMATION FOR SEQ ID NO:62:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 24 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

( ii ) MOLECULE TYPE : peptide

(xi ) SEQUENCE DESCRIPTION: SEQ ID NO : 62 :

Met Trp Phe Leu He Leu Phe Leu Ala Leu Ser Leu Gly Gin He Asp 1 5 10 15 Ala Ala Pro Gly Cys Cys Gly Pro 20

(2) INFORMATION FOR SEQ ID NO: 63:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 24 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO:63 :

Met Lys Val Ala He He Phe Leu Leu Ser Ala Leu Ala Leu Leu Ser 1 5 10 15

Leu Ala Gly Pro Cys Cys Pro Gly 20

(2) INFORMATION FOR SEQ ID NO:64:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 31 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 64:

Met Arg Leu Arg Leu Leu Val Ser Ala Gly Met Leu Leu Val Ala Leu 1 5 10 15

Ser Pro Cys Leu Pro Cys Arg Ala Leu Leu Phe Ala Pro Cys He 20 25 30

(2) INFORMATION FOR SEQ ID NO: 65:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 31 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

( i i ) MOLECULE TYPE : peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 65:

Met Gly Phe Leu Lys Phe Ser Pro Phe Leu Val Val Ser He Leu Leu 1 5 10 15

Leu Tyr Gin Ala Cys Gly Leu Gin Ala Val He Cys Cys Leu Thr 20 25 30 (2) INFORMATION FOR SEQ ID NO:66:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 32 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 66:

Met Arg Leu Arg Leu Leu Val Ser Ala Gly Met Leu Leu Val Ala Leu 1 5 10 15

Ser Pro Cys Leu Pro Cys Arg Ala Leu Leu Phe Gly Pro Cys He Leu 20 25 30

(2) INFORMATION FOR SEQ ID NO: 67 :

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 24 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 67: Met Trp Phe Leu He Leu Phe Leu Ala Leu Ser Leu Gly Gin He Asp 1 5 10 15

Ala Ala Pro Asp Cys Cys He Pro 20

(2) INFORMATION FOR SEQ ID NO:68:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 31 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 68:

Met Arg Leu Arg Leu Leu Val Ser Ala Gly Met Leu Leu Val Ala Leu 1 5 10 15

Ser Pro Cys Leu Pro Cys Arg Ala Leu Leu Phe Asp Pro Cys He 20 25 30 (2) INFORMATION FOR SEQ ID NO: 69:

(1) SEQUENCE CHARACTERISTICS: (A) LENGTH: 96 base pairs (B) TYPE: nucl'- _ c acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 69:

ATGAAGTTCC TCTCTGCAAG AGACTTCCAT CCAGTTGCCT TCTTGGGACT GATGCTGGTG 60

ACAACCACGG CCTTCGGACC CTGCATTCTT AATCGA 96

(2) INFORMATION FOR SEQ ID NO:70:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 93 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO:70:

ATGCGGCTGC GGCTGCTGGT GTCCGCGGGC ATGCTGCTGG TGGCTCTGTC GCCCTGTCTG 60

CCTTGCAGGG CCCTGCTGTT CGGACCGTGC ATT 93

(2) INFORMATION FOR SEQ ID NO:71: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 90 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single (D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:71:

ATGCGGCTGC GGCTGCTGGT GTCCGCGGGC ATGCTGCTGG TGGCTCTGTC GCCCTGTCTG 60

CCTTGCAGGG CCCTGCTGTA TTCCCCGTGC 90

(2) INFORMATION FOR SEQ ID NO:72:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 72 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:72:

ATGTGGTTCC TGATCCTGTT CCTCGCCCTG TCCCTGGGAC AGATTGATGC TGCACCTGGC 60

TGCTGCCCTG GC 72 (2) INFORMATION FOR SEQ ID N0:73:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 90 base pairs (B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO:73:

ATGAAGTTCC TCTCTGCAAG AGACTTCCAT CCAGTTGCCT TCTTGGGACT GATGCTGGTG 60

ACAACCACGG CCTTCTGCCT CGGACCATGC 90

(2) INFORMATION FOR SEQ ID NO:74:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 72 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:74:

ATGTGGTTCC TGATCCTGTT CCTCGCCCTG TCCCTGGGAC AGATTGATGC TGCACCAGGA 60

TGCTGCGGAC CA 72

(2) INFORMATION FOR SEQ ID NO:75: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 72 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single (D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:75:

ATGAAAGTGG CCATCATCTT CCTGCTGTCC GCACTGGCAC TGCTGTCCCT GGCAGGACCA 60

TGCTGCCCAG GA 72

(2) INFORMATION FOR SEQ ID NO:76:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 90 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: 1inear

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO:76:

ATGCGGCTGC GGCTGCTGGT GTCCGCGGGC ATGCTGCTGG TGGCTCTGTC GCCCTGTCTG 60

CCTTGCAGGG CCCTGCTGTT CGCGCCATGC 90 (2) INFORMATION FOR SEQ ID NO:77:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 90 base pairs (B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

( i) SEQUENCE DESCRIPTION: SEQ ID NO:77:

ATGGGCTTCC TGAAATTCTC CCCTTTCCTG GTGGTGTCCA TCCTGCTGCT GTATCAAGCG 60

TGTGGCCTGC AAGCGGTGAT CTGCTGCCTG 90

(2) INFORMATION FOR SEQ ID NO:78:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 96 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear

(Xl) SEQUENCE DESCRIPTION: SEQ ID NO:78:

ATGCGGCTGC GGCTGCTGGT GTCCGCGGGC ATGCTGCTGG TGGCTCTGTC GCCCTGTCTG 60

CCTTGCAGGG CCCTGCTGTT CGGACCGTGC ATTCTG 96

(2) INFORMATION FOR SEQ ID NO:79: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 72 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single (D) TOPOLOGY: linear

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO:79:

ATGTGGTTCC TGATCCTGTT CCTCGCCCTG TCCCTGGGAC AGATTGATGC TGCACCAGAC 60

TGCTGCATCC CA 72

(2) INFORMATION FOR SEQ ID NO:80:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 93 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:80:

ATGCGGCTGC GGCTGCTGGT GTCCGCGGGC ATGCTGCTGG TGGCTCTGTC GCCCTGTCTG 60

CCTTGCAAGG CCCTGCTGTT CGACCCGTGC ATT 93 (2) INFORMATION FOR SEQ ID NO:81:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 ammo acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(n) MOLECULE TYPE: peptide

(XI) SEQUENCE DESCRIPTION: SEQ ID NO:81:

Gin Cys Ala Leu Cys Arg

1 5

(2) INFORMATION FOR SEQ ID NO:82:

(l) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(n) MOLECULE TYPE: peptide

(Xl) SEQUENCE DESCRIPTION: SEQ ID NO:82:

Val Ala Leu Ser Cys Gin

1 5 (2) INFORMATION FOR SEQ ID NO:83:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:83:

He Val Lys Ser Cys Lys 1 5

(2) INFORMATION FOR SEQ ID NO:84:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:84:

Leu Ala Phe Glu Pro Cys Met

1 5 (2) INFORMATION FOR SEQ ID NO:85:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO:85:

Leu Leu Pro Gly Pro Cys Met 1 5

(2) INFORMATION FOR SEQ ID NO:86:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

( i) SEQUENCE DESCRIPTION: SEQ ID NO:86:

Met Ala Pro Ala Pro Cys Trp 1 5 (2) INFORMATION FOR SEQ ID NO:87:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:87

Ala Leu Tyr Ala Pro Cys Met 1 5

(2) INFORMATION FOR SEQ ID NO:88:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:88:

Val Leu Trp Glu Pro Cys Trp 1 5 (2) INFORMATION FOR SEQ ID NO:89:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO:89:

Met Leu Phe Ser Pro Cys Trp

1 5

(2) INFORMATION FOR SEQ ID NO:90:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO:90:

Leu Leu Cys Gly Pro Ala He

1 5 (2) INFORMATION FOR SEQ ID NO:91:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO:91:

Leu Cys Phe Gly Pro Ala He 1 5

(2) INFORMATION FOR SEQ ID NO:92:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:92:

Val Met Pro Ser Pro Cys Tyr 1 5 (2) INFORMATION FOR SEQ ID NO:93:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO:93:

Val Val Phe Ala Pro Cys Tyr

1 5

(2) INFORMATION FOR SEQ ID NO:94:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO:94:

Ala Val Pro Glu Pro Cys Phe

1 5 (2) INFORMATION FOR SEQ ID NO:95:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO:95:

Met Met Tyr Glu Pro Cys Tyr 1 5

(2) INFORMATION FOR SEQ ID NO:96:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:96:

Ala Ala Trp Ser Pro Cys Met

1 5 (2) INFORMATION FOR SEQ ID NO:97:

(1) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(XI) SEQUENCE DESCRIPTION: SEQ ID NO:97:

Val Ala Tyr Gly Pro Cys Trp

1 5

(2) INFORMATION FOR SEQ ID NO:98:

(1) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: ammo acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(il) MOLECULE TYPE: peptide

(Xl) SEQUENCE DESCRIPTION: SEQ ID NO:98:

Leu Arg Pro Arg Cys Arg Pro He

1 5 (2) INFORMATION FOR SEQ ID NO:99:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:99:

Ala Gly Tyr Cys Pro Thr Met Thr 1 5

(2) INFORMATION FOR SEQ ID NO: 100:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:100:

Pro Gin Val Val Cys Asn Tyr Arg

1 5 (2) INFORMATION FOR SEQ ID NO:101:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 12 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 101:

Ala Asn Phe Cys Ala Gly Ala Cys Pro Tyr Leu Trp 1 5 10

(2) INFORMATION FOR SEQ ID NO: 102:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 31 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

( i i ) MOLECULE TYPE : pept ide

(xi ) SEQUENCE DESCRI PTION : SEQ ID NO : 102 :

Met Arg Leu Arg Leu Leu Val Ser Ala Gly Met Leu Leu Val Ala Leu 1 5 10 15 Ser Pro Cys Leu Pro Cys Arg Ala Leu Ala Phe Glu Pro Cys Met 20 25 30

(2) INFORMATION FOR SEQ ID NO:103:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 38 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO:103:

Met His Leu Ser Leu Ser His Gin Trp Ser Ser Trp Thr Val Leu Leu 1 5 10 15

Leu Leu Val Ser Asn Leu Leu Leu Trp Glu Asn Thr Ala Ser Ala Met 20 25 30

Ala Pro Ala Pro Cys Trp 35

(2) INFORMATION FOR SEQ ID NO:104:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 32 amino acids

(B) TYPE: amino acid (C) STRANDEDNESS: not relevant (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 104:

Met Gly Phe Leu Lys Phe Ser Pro Phe Leu Val Val Ser He Leu Leu 1 5 10 15

Leu Tyr Gin Ala Cys Gly Leu Gin Ala Val Leu Trp Glu Pro Cys Trp 20 25 30

(2) INFORMATION FOR SEQ ID NO:105:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 32 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:105:

Met Gly Phe Leu Lys Phe Ser Pro Phe Leu Val Val Ser He Leu Leu

1 5 10 15

Leu Tyr Gin Ala Cys Gly Leu Gin Ala Val Met Pro Ser Pro Cys Tyr 20 25 30 (2) INFORMATION FOR SEQ ID NO:106:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 38 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 106:

Met His Leu Ser Leu Ser His Gin Trp Ser Ser Trp Thr Val Leu Leu 1 5 10 15

Leu Leu Val Ser Asn Leu Leu Leu Trp Glu Asn Thr Ala Ser Ala Met 20 25 30

Leu Phe Ser Pro Cys Trp 35

(2) INFORMATION FOR SEQ ID NO:107:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 32 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 107:

Met Gly Phe Leu Lys Phe Ser Pro Phe Leu Val Val Ser He Leu Leu 1 5 10 15

Leu Tyr Gin Ala Cys Gly Leu Gin Ala Val Val Phe Ala Pro Cys Tyr 20 25 30

(2) INFORMATION FOR SEQ ID NO:108:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 93 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:108:

ATGCGGCTGC GGCTGCTGGT GTCCGCGGGC ATGCTGCTGG TGGCTCTGTC GCCCTGTCTG 60

CCTTGCAGGG CCCTGGCCTT CGAACCGTGC ATG 93

(2) INFORMATION FOR SEQ ID NO:109:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 114 base pairs (B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:109:

ATGCACCTGA GCCTGAGCCA CCAATGGAGC AGCTGGACAG TACTGCTGCT GCTGGTAAGC 60

AACTTATTAT TATGGGAAAA CACAGCAAGC GCAATGGCAC CAGCACCATG CTGG 114

(2) INFORMATION FOR SEQ ID NO:110:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 96 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:110:

ATGGGCTTCC TGAAATTCTC CCCTTTCCTG GTGGTGTCCA TCCTGCTGCT GTATCAAGCG 60

TGTGGCCTGC CAGCGGTATT ATGGGAACCA TGCTGG 96

(2) INFORMATION FOR SEQ ID NO:111: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 96 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single (D) TOPOLOGY: linear

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 111:

ATGGGCTTCC TGAAATTCTC CCCTTTCCTG GTGGTGTCCA TCCTGCTGCT GTATCAAGCG 60

TGTGGCCTGC AAGCGGTAAT GCCTTCCCCT TGCTAC 96

(2) INFORMATION FOR SEQ ID NO: 112:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 115 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 112:

ATGCACCTGA GCCTGAGCCA CCAATGGAGC AGCTGGACAG TACTACTGCT GCTGGTAAGC 60

AACTTATTAT TATGGGAAAA CACAGCAAGC AGCAATGTTA TTCAGCCCAT GCTGG 115 (2) INFORMATION FOR SEQ ID NO: 113:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 96 base pairs (B) TYPE: nucleic acid

(C) STRANDEDNESS: Single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:113:

ATGGGCTTCC TGAAATTCTC CCCTTTCCTG GTGGTGTCCA TCCTGCTGCT GTATCAAGCG 60

TGTGGCCTGC AAGCGGTAGT ATTCGCGCCT TGCTAC 96

(2) INFORMATION FOR SEQ ID NO:114:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 4 ammo acids

(B) TYPE: am o acid (C) STRANDEDNESS: not relevant (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:114:

Gly Pro Met He 1

(2) INFORMATION FOR SEQ ID NO:115: (1) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 5 ammo acids

(B) TYPE: amino acid (C) STRANDEDNESS: not relevant (D) TOPOLOGY: linear

(n) MOLECULE TYPE: peptide

(Xl) SEQUENCE DESCRIPTION: SEQ ID NO:115:

Lys Met Arg Met Lys 1 5

(2) INFORMATION FOR SEQ ID NO:116:

(1) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 5 amino acids

(B) TYPE: ammo acid (C) STRANDEDNESS: not relevant (D) TOPOLOGY: linear

(il) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:116:

Phe Met He Met Lys 1 5

(2) INFORMATION FOR SEQ ID NO:117: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 5 amino acids

(B) TYPE: amino acid (C) STRANDEDNESS: not relevant (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:117:

He Cys Thr Met Glu 1 5

(2) INFORMATION FOR SEQ ID NO: 118:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 5 amino acids

(B) TYPE: amino acid (C) STRANDEDNESS: not relevant (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:118:

Leu Met Ala Met Val 1 5

(2) INFORMATION FOR SEQ ID NO: 119: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 5 amino acids

(B) TYPE: amino acid (C) STRANDEDNESS: not relevant (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO:119:

He Met Tyr Met Glu 1 5

(2) INFORMATION FOR SEQ ID NO: 120:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 6 amino acids

(B) TYPE: amino acid (C) STRANDEDNESS: not relevant (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:120:

Ala Pro Met Met Val Pro

1 5

(2) INFORMATION FOR SEQ ID NO:121: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 6 amino acids

(B) TYPE: amino acid (C) STRANDEDNESS: not relevant (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 121:

Gly Pro Met Met Pro Gly 1 5

(2) INFORMATION FOR SEQ ID NO:122:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 6 amino acids

(B) TYPE: amino acid (C) STRANDEDNESS: not relevant (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:122:

Gly Pro Cys Met Pro Gly 1 5

(2) INFORMATION FOR SEQ ID NO: 123: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 6 amino acids

(B) TYPE: amino acid (C) STRANDEDNESS: not relevant (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xl) SEQUENCE DESCRIPTION: SEQ ID NO:123:

Gly Pro Met Cys Pro Gly

1 5

(2) INFORMATION FOR SEQ ID NO: 124:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 6 amino acids

(B) TYPE: amino acid (C) STRANDEDNESS: not relevant (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 124:

Pro Gly Met Met Gly Pro

1 5

(2) INFORMATION FOR SEQ ID NO: 125: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 6 amino acids

(B) TYPE: amino acid (C) STRANDEDNESS: not relevant (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 125:

Val He Met Met Leu Thr

1 5

(2) INFORMATION FOR SEQ ID NO: 126:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 7 amino acids

(B) TYPE: amino acid (C) STRANDEDNESS: not relevant (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 126:

Leu Ala Phe Glu Pro Met Met 1 5

(2) INFORMATION FOR SEQ ID NO: 127: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 7 amino acids

(B) TYPE: amino acid (C) STRANDEDNESS: not relevant (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 127:

Met Leu Phe Ser Pro Met Trp 1 5

(2) INFORMATION FOR SEQ ID NO: 128:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 7 amino acids

(B) TYPE: amino acid (C) STRANDEDNESS: not relevant (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 128:

Val Val Phe Ala Pro Met Tyr 1 5

(2) INFORMATION FOR SEQ ID NO: 129: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 7 amino acids

(B) TYPE: amino acid (C) STRANDEDNESS: not relevant (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO:129:

Leu Leu Phe Gly Pro Met He 1 5

(2) INFORMATION FOR SEQ ID NO: 130:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 7 amino acids

(B) TYPE: amino acid (C) STRANDEDNESS: not relevant (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:130:

Leu Leu Tyr Ser Pro Met Phe

1 5

(2) INFORMATION FOR SEQ ID NO:131: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 7 amino acids

(B) TYPE: amino acid (C) STRANDEDNESS: not relevant (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 131:

Leu Leu Phe Asp Pro Met He

1 5

(2) INFORMATION FOR SEQ ID NO: 132:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 7 amino acids

(B) TYPE: amino acid (C) STRANDEDNESS: not relevant (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO:132:

Leu Leu Phe Trp Pro Met He 1 5

(2) INFORMATION FOR SEQ ID NO: 133: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 7 amino acids

(B) TYPE: amino acid (C) STRANDEDNESS: not relevant (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 133:

Leu Leu Phe Arg Pro Met He 1 5

(2) INFORMATION FOR SEQ ID NO: 134:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 7 amino acids

(B) TYPE: amino acid (C) STRANDEDNESS: not relevant (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:134:

Leu Leu Phe Ala Pro Met He

1 5 (2) INFORMATION FOR SEQ ID NO:135:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO:135:

Leu Leu Phe Gly He Met He

1 5

(2) INFORMATION FOR SEQ ID NO:136:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 136:

Phe Met Leu Gly Pro Met Pro

1 5 (2) INFORMATION FOR SEQ ID NO:137:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 31 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:137:

Met Arg Leu Arg Leu Leu Val Ser Ala Gly Met Leu Leu Val Ala Leu 1 5 10 15

Ser Pro Cys Leu Pro Cys Arg Ala Leu Leu Phe Gly Pro Met He 20 25 30

(2) INFORMATION FOR SEQ ID NO-.138:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 93 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:138:

ATGCGGCTGC GGCTGCTGGT GTCCGCGGGC ATGCTGCTGG TGGCTCTGTC GCCCTGTCTG 60

CCTTGCAGGG CCCTGCTGTT CGGACCGATG ATT 93

(2) INFORMATION FOR SEQ ID NO:139:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 18 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO:139:

Arg Asn Arg Cys Lys Gly Thr Asp Val Gin Ala Trp He Arg Gly Cys 1 5 10 15

Arg Leu

(2) INFORMATION FOR SEQ ID NO:140:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 16 amino acids

(B) TYPE: amino acid (C) STRANDEDNESS: not relevant (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:140:

He Asn Thr Lys Cys Tyr Lys Leu Glu His Pro Val Thr Gly Cys Gly 1 5 10 15

(2) INFORMATION FOR SEQ ID NO:141:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 23 amino acids

(B) TYPE: amino acid (C) STRANDEDNESS: not relevant (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:141:

Asp Asn Tyr Arg Gly Tyr Ser Leu Gly Asn Trp Val Cys Ala Ala Lys 1 5 10 15

Phe Glu Ser Asn Phe Thr Gin 20 (2) INFORMATION FOR SEQ ID NO:142:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO:142:

Ala Pro Ser Pro Leu Pro Glu Thr Thr Glu Asn Val Val Cys Ala Leu 1 5 10 15

Gly Leu Thr Val 20

(2) INFORMATION FOR SEQ ID NO: 143:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 25 amino acids

(B) TYPE: amino acid (C) STRANDEDNESS: not relevant (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:143: Gly Asp Met Tyr Pro Lys Thr Trp Ser Gly Met Leu Val Gly Ala Leu 1 5 10 15

Cys Ala Leu Ala Gly Val Leu Thr He 20 25

(2) INFORMATION FOR SEQ ID NO:144:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 14 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:144:

Val Pro Gly Leu Tyr Ser Pro Cys Arg Ala Phe Phe Asn Lys 1 5 10

(2) INFORMATION FOR SEQ ID NO: 145:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 18 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO:145:

Val Pro Gly Leu Tyr Ser Pro Cys Arg Ala Phe Phe Asn Lys Glu Glu 1 5 10 15

Leu Leu

(2) INFORMATION FOR SEQ ID NO: 146:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:146:

Val Pro Gly Leu Tyr Ser Pro Cys Arg Ala Phe Phe Asn Lys 1 5 10

(2) INFORMATION FOR SEQ ID NO:147;

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 17 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

( ii ) MOLECULE TYPE : peptide

(Xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 147 :

Glu Ala He Tyr Asp He Cys Arg Arg Asn Leu Asp He Glu Arg Pro 1 5 10 15

Thr

(2) INFORMATION FOR SEQ ID NO: 148:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 13 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO:148:

Glu Ala He Tyr Asp He Cys Arg Arg Asn Leu Asp He 1 5 10

(2) INFORMATION FOR SEQ ID NO: 149: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 25 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 149:

Asp Leu Leu Glu Gin Arg Arg Ala Ala Val Asp Thr Tyr Cys Arg His 1 5 10 15

Asn Tyr Gly Val Gly Glu Ser Phe Thr 20 25

(2) INFORMATION FOR SEQ ID NO: 150:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 13 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 150:

Thr Ser He Leu Cys Tyr Arg Lys Arg Glu Trp He Lys 1 5 10 (2) INFORMATION FOR SEQ ID NO: 151:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 151:

Leu Pro Phe Phe Leu Phe Arg Gin Ala Tyr His Pro Asn Asn Ser Ser 1 5 10 15

Pro Val Cys Tyr 20

(2) INFORMATION FOR SEQ ID NO: 152:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 28 amino acids

(B) TYPE: amino acid (C) STRANDEDNESS: not relevant (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 152: Gin Ala Lys Phe Phe Ala Cys He Lys Arg Ser Asp Gly Ser Cys Ala 1 5 10 15

Trp Tyr Arg Gly Ala Ala Pro Pro Lys Gin Glu Phe 20 25

(2) INFORMATION FOR SEQ ID NO:153:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 19 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 153:

Gin Ala Lys Phe Phe Ala Cys He Lys Arg Ser Asp Gly Ser Cys Ala

1 5 10 15

Trp Tyr Arg

(2) INFORMATION FOR SEQ ID NO:154:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 18 amino acids (B) TYPE: ammo acid (C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:154:

Lys Val Phe Gly Arg Cys Glu Leu Ala Ala Ala Met Lys Arg His Gly 1 5 10 15

Leu Asp

(2) INFORMATION FOR SEQ ID NO:155:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO:155:

Ala Glu Ala Leu Glu Arg Met Phe Leu Ser Phe Thr Thr Lys Thr 1 5 10 15

(2) INFORMATION FOR SEQ ID NO:156: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 20 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:156:

Lys Asn He Phe His Phe Lys Val Asn Gin Glu Gly Leu Lys Leu Ser 1 5 10 15

Asn Asp Met Met 20

(2) INFORMATION FOR SEQ ID NO:157:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO:157:

Leu Glu Cys Gly Pro Cys Phe Leu 1 5 (2) INFORMATION FOR SEQ ID NO: 158:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 158:

Leu Cys Ala Gly Pro Cys Phe Leu 1 5

(2) INFORMATION FOR SEQ ID NO:159:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 159:

Tyr He Pro Cys Phe Pro Ser Ser Leu Lys Arg Leu Leu He 1 5 10 (2) INFORMATION FOR SEQ ID NO: 160:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 13 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 160:

Tyr He Pro Cys Phe Pro Ser Ser Leu Lys Arg Leu He 1 5 10

(2) INFORMATION FOR SEQ ID NO:161:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 161:

Ser Gly Pro Cys Pro Lys Asp Gly Gin Pro Ser 1 5 10 (2) INFORMATION FOR SEQ ID NO: 162:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO:162:

Thr Pro Pro Thr Pro Cys Pro Ser 1 5

(2) INFORMATION FOR SEQ ID NO: 163:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:163

Asp Pro Cys He He 1 5 (2) INFORMATION FOR SEQ ID NO: 164:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO:164:

Cys Gly Gly He Cys He Ala Arg 1 5

(2) INFORMATION FOR SEQ ID NO:165:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:165:

Ser Gly Pro Cys Pro Lys Asp Gly Gin Pro Ser 1 5 10 (2) INFORMATION FOR SEQ ID NO: 166:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 166:

Cys His Gly Ser Asp Pro cys 1 5

(2) INFORMATION FOR SEQ ID NO: 167:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:167:

Ser Gly Pro Cys Pro Lys Asp Gly Gin Pro Ser 1 5 10 (2) INFORMATION FOR SEQ ID NO:168:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 13 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 168:

Tyr Arg Arg Gly Arg Cys Gly Gly Leu Cys Leu Ala Arg 1 5 10

(2) INFORMATION FOR SEQ ID NO: 169:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 16 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:169:

Tyr Arg Arg Gly Arg Ala Ala Ala Cys Gly Gly Leu Cys Leu Ala Arg 1 5 10 15

(2) INFORMATION FOR SEQ ID NO:170:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO:170:

Tyr Arg Arg Gly Arg Cys Gly Gly Gly Leu Cys Leu Ala Arg 1 5 10

(2) INFORMATION FOR SEQ ID NO:171:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 17 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 171:

Tyr Arg Arg Gly Arg Ala Ala Ala Cys Gly Gly Gly Leu Cys Leu Ala 1 5 10 15

Arg

(2) INFORMATION FOR SEQ ID NO:172:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

( i) SEQUENCE DESCRIPTION: SEQ ID NO: 172:

Tyr Arg Arg Gly Arg Cys Gly Gly Gly Gly Leu Cys Leu Ala Arg 1 5 10 15

(2) INFORMATION FOR SEQ ID NO:173:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 18 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:173:

Tyr Arg Arg Gly Arg Ala Ala Ala Cys Gly Gly Gly Gly Leu Cys Leu 1 5 10 15

Ala Arg

(2) INFORMATION FOR SEQ ID NO: 174:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 7 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY-, linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO:174:

Cys Gly Gly Leu Cys Ala Arg (2) INFORMATION FOR SEQ ID NO:175:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 6 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO:175:

Ser Pro Tyr Met Glu Ala

1 5

(2) INFORMATION FOR SEQ ID NO:176:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 17 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide (Xi) SEQUENCE DESCRIPTION: SEQ ID NO:176:

Ala Pro Ser Pro Leu Pro Glu Thr Thr Glu Asn Val Val Cys Ala Leu

1 5 10 15

Gly

Claims

1. A nucleic acid molecule comprising a coding sequence encoding an immunoactive peptide of Formula I : A_n-X-Cys-Cys-Y-B_π, (I) where each A and each B is independently selected from any of the 20 common, naturally occurring amino acids;

Y is selected from the group consisting Ala, Val, Leu, lie, Gly, Ser, Thr, Asp, Glu, Asn, Gin, Tyr, Phe, and Pro; n and are whole integers chosen with the proviso that the sum of n and m is zero to twenty-six, inclusive; provided that SEQ ID NOs . 139 through 156 are excluded from Formula I; the coding sequence optionally further encoding a mammalian signal peptide linked to the amino terminal of the immunoactive peptide.

2. The nucleic acid molecule of claim 1, wherein X is selected from the group consisting of Gly, Pro, lie, Val, Asp, Leu, Glu, Gin, and Ala; Y is selected from the group consisting of Gly, Pro, lie, Val, Asp, Leu, Glu, Ser, Phe, Tyr, and Thr; and the sum of n and is zero to eleven, inclusive.

3. The nucleic acid molecule of claim 1, wherein X is Gly and Y is Pro, X is Gly and Y is Gly, X is Pro and Y is Pro,

X is Pro and Y is Val,

X is lie and Y is Leu,

X is Pro and Y is Glu, X is Glu and Y is Tyr,

X is Pro and Y is Phe,

X is Glu and Y is Phe,

X is Ala and Y is Val,

X is Val and Y is lie, X is Gin and Y is Ser,

X is lie and Y is Thr,

X is Leu and Y is Asp, or

X is Asp and Y is lie; and the sum of n and m is zero to eleven, inclusive.

4. The nucleic acid molecule of claim 1, wherein said immunoactive peptide is selected from the group consisting of Glu-Glu-Cys-Cys-Phe-Tyr (SEQ ID N0..1; D22041AX) , Pro-Gly-Cys-Cys-Gly-Pro (SEQ ID NO. :2) , Pro-Gly-Cys-Cys-Pro-Gly (SEQ ID NO. :3 ; D22139AA), Gly-Pro-Cys-Cys-Pro-Gly (SEQ ID N0..4) , Ala-Pro-Cys-Cys-Val-Pro (SEQ ID NO.:5; D22037AX) , Val-Ile-Cys-Cys-Leu-Thr (SEQ ID N0..6), Lys-Pro-Cys-Cys-Glu-Arg (SEQ ID NO.:7), Lys-Glu-Cys-Cys-Tyr-Val (SEQ ID NO. :8),

Thr-Pro-Cys-Cys-Phe-Ala (SEQ ID NO. :9; D22040AX) , Leu-Ala-Cys-Cys-Val-Val (SEQ ID NO. :10), Pro-Val-Cys-Cys-Ile-Gly (SEQ ID N0..11), Ser-Gln-Cys-Cys-Ser-Leu (SEQ ID N0..12), Ser-Ile-Cys-Cys-Thr-Lys (SEQ ID N0..13), Lys-Leu-Cys-Cys-Asp-Ile (SEQ ID NO.:14), Pro-Ala-Cys-Cys-Gly-Pro (SEQ ID NO.:15), Pro-Asp-Cys-Cys-Ile-Pro (SEQ ID NO.:16), and Arg-Cys-Ser-Gly-Cys-Cys-Asn (SEQ ID NO.:17) .

5. A nucleic acid molecule comprising a coding sequence encoding an immunoactive peptide of Formula II :

A_n-X-Cys-Z-Cys-Y-B_m (II) where each A and each B is independently selected from any of the 20 common, naturally occurring amino acids;

X is selected from the group consisting of Ala, Val, Leu, lie, Gly, Asp, Glu, Asn, Gin, His, Lys, Phe, and Pro; Z is selected from the group consisting of Ala, Val, Leu, lie, Gly, Ser, Thr, Lys, and Arg;

Y is selected from the group consisting of Ala, Val, Leu, lie, Gly, Asp, Glu, Lys, Arg, Gin, Tyr, Phe, Ser, Thr, and Pro; and n and m are whole integers chosen with the proviso that the sum of n and m is zero to twenty-five, inclusive; provided that SEQ ID NOs . 139 through 156 are excluded from Formula II; the coding sequence optionally further encoding a mammalian signal peptide linked to the amino terminal of the immunoactive peptide.

6. The nucleic acid molecule of claim 5, wherein X is selected from the group consisting of Gly, Pro, lie, Val, Asp, Leu, Glu, Gin, and Ala; Y is selected from the group consisting of Gly, Glu, Val, Gin, Arg, Leu, Tyr, Phe, lie, Ser, Thr, Asp, and Pro; Z is selected from the group consisting of lie, Gly, Thr, Ala, Arg, and Lys; and the sum of n and m is zero to ten, inclusive.

7. The nucleic acid molecule of claim 5, wherein

X is Gly and Y is Gly,

X is Pro and Y is Pro,

X is Pro and Y is Val,

X is lie and Y is Leu, X is Pro and Y is Glu,

X is Glu and Y is Tyr,

X is Pro and Y is Phe,

X is Glu and Y is Phe,

X is Ala and Y is Val, X is Val and Y is lie,

X is Gin and Y is Ser,

X is lie and Y is Thr,

X is Leu and Y is Asp, or

X is Asp and Y is lie; Z is lie, Gly, Thr, Ala, or Lys; and the sum of n and m is zero to ten, inclusive.

8. The nucleic acid molecule of claim 5, wherein said immunoactive peptide is selected from the group consisting of

Val-Cys-Ile-Cys-Gln (SEQ ID N0. :18), Val-Cys-Gly-Cys-Arg (SEQ ID NO.:19) ,

Lys-Cys-Arg-Cys-Lys (SEQ ID NO.-.20) ,

Asp-Cys-Ile-Cys-Gln (SEQ ID N0.:21),

Ile-Cys-Thr-Cys-Glu (SEQ ID NO. :22) ,

Ile-Cys-Thr-Cys-Arg (SEQ ID N0..23) , Leu-Cys-Ala-Cys-Val (SEQ ID NO. :24) , Phe-Cys -Ile-Cys -Lys ( SEQ ID N0 . : 25 ) , Ala-Cys -Lys-Cys -Gln ( SEQ ID N0 . . 26 ) , and Gly-Pro-Cys-Ile-Cys-Pro-Gly (SEQ ID NO.:27).

9. A nucleic acid molecule comprising a coding sequence encoding an immunoactive peptide of Formula III:

A_n-X-Y-Cys-Z-B_m (III) where each A and each B is independently selected from any of the 20 common, naturally occurring amino acids;

Y is selected from the group consisting of Ala, Val, Leu, lie, Gly and Pro;

Z is selected from the group consisting of Ala, Val, Leu, lie, Gly, Ser, Thr, Lys, His, Phe, Tyr, Arg, and Pro; and n and m are whole integers chosen with the proviso that the sum of n and m is zero to twenty-six, inclusive; provided that SEQ ID NOs . 139 through 156 are excluded from Formula III; the coding sequence optionally further encoding a mammalian signal peptide linked to the amino terminal of the immunoactive peptide.

10. The nucleic acid molecule of claim 9, wherein X is selected from the group consisting of Gly, Ala, lie, Asp, Thr, Ser, Arg, and Trp; Y is selected from the group consisting of lie, Gly, and Pro; Z is selected from the group consisting of Lys, lie, Phe, Pro, Ala, Tyr, and Gly; and the sum of n and is zero to eleven, inclusive.

11 The nucleic acid molecule of claim 9, wherein

X is Gly, Y is Pro and Z is He,

X is Gly, Y is Pro and Z is Gly,

X is Ala, Y is Pro and Z is Ala,

X is He, Y is Pro and Z is Tyr,

X is Ala, Y is Pro and Z is He,

X is Arg, Y is Pro and Z is He,

X is He, Y is Pro and Z is He,

X is Asp, Y is Pro and Z is He,

X is Trp, Y is Pro and Z is He,

X is Trp, Y is Pro and Z is Gly,

X is Gly, Y is He and Z is He,

X is Thr, Y is Pro and Z is Tyr,

X is Ala, Y is Pro and Z is Phe,

X is Ser, Y is Pro and Z is Phe,

X is Gly, Y is Pro and Z is Pro,

X is Gly, Y is Pro and Z is Tyr.

12. The nucleic acid molecule of claim 9, wherein said immunoactive peptide is selected from the group consisting of Gly-Pro-Cys-Gly (SEQ ID NO.:28), Ala-Pro-Cys-Ala (SEQ ID N0..29), Ile-Pro-Cys-Tyr (SEQ ID NO..30), Trp-Pro-Cys-Gly (SEQ ID N0..31), Gly-Pro-Cys-Ile-Leu-Asn (SEQ ID NO.:32) , Gly-Pro-Cys-He (SEQ ID NO.:33; D22078AX) , Leu-Leu-Phe-Gly-Pro-Cys-He (SEQ ID O. :34), Leu-Leu- Phe- Ala- Pro-Cys -He (SEQ ID NO. :35) Leu-Leu- Phe- Arg- Pro-Cys -He (SEQ ID NO. :36) Leu-Leu- Phe- He- Pro-Cys -He (SEQ ID NO. :37) Leu-Leu- Phe -Asp- Pro-Cys -He (SEQ ID NO. :38) Ala-Val-Trp-Thr-Pro-Cys -Tyr (SEQ ID NO. :39) Phe-Val -Met -Ala- Pro-Cys -Phe (SEQ ID NO. :40) Leu-Leu -Tyr-Ser- Pro -Cys -Phe (SEQ ID NO. :41) He- Ser-Gly- Pro -Cys -Pro-Lys (SEQ ID NO. :42) Phe-Leu- Phe-Gly -Pro-Cys -He (SEQ ID NO. :43) Leu-Phe-Gly-Pro-Cys -He-Leu (SEQ ID NO. :44) Glu-Lys-Gly-Pro-Cys-Tyr-Arg (SEQ ID NO. :45) Phe-Cys-Leu-Gly- Pro-Cys -Pro (SEQ ID NO. :46) Phe-Gly-Pro-Cys-He ( SEQ ID NO. :47; D22077AX) , Phe-Leu- Phe -Gly- Pro-Cys -He -Leu-Asn (SEQ ID N0..48), Gly-Pro-Cys-Ile-Leu-Asn-Arg ( SEQ ID NO . 49; D22087AX) , Leu-Leu- Phe-Trp- Pro-Cys -He ( SEQ ID NO . 50; D22023AX) , Leu-Leu -Phe-Gly- I le-Cys- He ( SEQ ID NO . 51; D22022AX) , Leu-Leu- Phe-Gly-Pro-Cys - He -Leu-Asn

( SEQ ID NO . : 52 ; D22014AX ) , Leu-Leu- Phe-Gly- Pro-Cys - He •Leu-Asn-Arg

( SEQ ID NO . : 53 ; D22087AX) , Trp-Cys -Gly-Pro-Cys-Lys-Met -He-Lys-Pro-Phe-Phe

(SEQ ID NO. :54; D7233) , Leu-Leu-Phe-Gly-Pro-Cys-He ^■Leu-Asn-Arg-Leu-Met -Glu

(SEQ ID NO. :55) , and Phe-Leu-Phe-Gly-Pro-Cys-He -Leu-Asn-Arg-Leu-Met -Glu

(SEQlDNO.:56).

13. A nucleic acid molecule having a coding sequence coding sequence encoding a polypeptide selected from the group consisting of:

D22175AX Met-Lys-Phe-Leu-Ser-Ala-Arg-Asp-Phe-His-Pro-Val- Ala-Phe-Leu-Gly-Leu-Met-Leu-Val-Thr-Thr-Thr-Ala-

Phe-Gly-Pro-Cys-He-Leu-Asn-Arg (SEQ ID NO. :57) ,

D7208 Met-Arg-Leu-Arg-Leu-Leu-Val-Ser-Ala-Gly-Met-Leu- Leu-Val-Ala-Leu-Ser-Pro-Cys-Leu-Pro-Cys-Arg-Ala-

Leu-Leu-Phe-Gly-Pro-Cys-He (SEQ ID NO. :58) ,

D22069AX Met-Arg-Leu-Arg-Leu-Leu-Val-Ser-Ala-Gly-Met-

Leu-Leu-Val-Ala-Leu-Ser-Pro-Cys-Leu-Pro-Cys-Arg- Ala-Leu-Leu-Tyr-Ser-Pro-Cys-Phe (SEQ ID NO. :59),

D22139AA Met-Trp-Phe-Leu-Ile-Leu-Phe-Leu-Ala-Leu-Ser-

Leu-Gly-Gln-Ile-Asp-Ala-Ala-Pro-Gly-Cys-Cys-Pro- Gly (SEQ ID NO. :60) ,

D22075AX Met-Lys-Phe-Leu-Ser-Ala-Arg-Asp-Phe-His-Pro-

Val-Ala-Phe-Leu-Gly-Leu-Met-Leu-Val-Thr-Thr-Thr- Ala-Phe-Cys-Leu-Gly-Pro-Cys-Pro (SEQ ID NO.:61) ,

D22009AX Met-Trp-Phe-Leu-Ile-Leu-Phe-Leu-Ala-Leu-Ser-

Leu- Gly-Gln-He-Asp-Ala-Ala-Pro-Gly-Cys-Cys- Gly-Pro (SEQ ID NO. :62) ,

D22004AX Met-Lys-Val-Ala-He-He-Phe-Leu-Leu-Ser-Ala- Leu-Ala-Leu-Leu-Ser-Leu-Ala-Gly-Pro-Cys-Cys-Pro- Gly (SEQ ID NO. :63) ,

D22021AX Met-Arg-Leu-Arg-Leu-Leu-Val-Ser-Ala-Gly-Met-

Leu-Leu-Val-Ala-Leu-Ser-Pro-Cys-Leu-Pro-Cys-Arg- Ala-Leu-Leu-Phe-Ala-Pro-Cys-He (SEQ ID NO. :64) ,

D22039AX Met-Gly-Phe-Leu-Lys-Phe-Ser-Pro-Phe-Leu-Val-

Val-Ser-He-Leu-Leu-Leu-Tyr-Gln-Ala-Cys-Gly-Leu- Gln-Ala-Val-He-Cys-Cys-Leu-Thr (SEQ ID NO. :65) ,

D22045AX Met-Arg-Leu-Arg-Leu-Leu-Val-Ser-Ala-Gly-Met-

Leu-Leu-Val-Ala-Leu-Ser-Pro-Cys-Leu-Pro-Cys-Arg- Ala-Leu-Leu-Phe-Gly-Pro-Cys-He-Leu (SEQ ID NO. :66) ,

D22121AX Met-Trp-Phe-Leu-He-Leu-Phe-Leu-Ala-Leu-Ser-

Leu-Gly-Gln-He-Asp-Ala-Ala-Pro-Asp-Cys-Cys-He- Pro (SEQ ID NO.: 67), and

D22050AX Met-Arg-Leu-Arg-Leu-Leu-Val-Ser-Ala-Gly-Met-Leu-

Leu-Val-Ala-Leu-Ser-Pro-Cys-Leu-Pro-Cys-Arg-Ala- Leu-Leu-Phe-Asp-Pro-Cys-He (SEQ ID NO. :68) .

14. The nucleic acid molecule of claim 13, wherein the coding sequence is selected from the group consisting of:

D22175AX ATGAAGTTCCTCTCTGCAAGAGACTTCCATCCAGTTGCCTTCTTG GGACTGATGCTGGTGACAACCACGGCCTTCGGACCCTGCATTCTT AATCGA (SEQ ID NO.: 69), D7208 ATGCGGCTGCGGCTGCTGGTGTCCGCGGGCATGCTGCTGGTGGCT CTGTCGCCCTGTCTGCCTTGCAGGGCCCTGCTGTTCGGACCGTGC ATT (SEQ ID NO. :70) ,

D22069AX ATGCGGCTGCGGCTGCTGGTGTCCGCGGGCATGCTGCTGGTGGCT

CTGTCGCCCTGTCTGCCTTGCAGGGCCCTGCTGTATTCCCCGTGC TTC (SEQ ID NO. :71) ,

D22139AA ATGTGGTTCCTGATCCTGTTCCTCGCCCTGTCCCTGGGACAGATT GATGCTGCACCTGGCTGCTGCCCTGGC (SEQ ID NO. :72) ,

D22075AX ATGAAGTTCCTCTCTGCAAGAGACTTCCATCCAGTTGCCTTCTTG GGACTGATGCTGGTGACAACCACGGCCTTCTGCCTCGGACCATGC CCA (SEQ ID NO. :73) ,

D22009AX ATGTGGTTCCTGATCCTGTTCCTCGCCCTGTCCCTGGGACAGATT GATGCTGCACCAGGATGCTGCGGACCA (SEQ ID NO.:74) ,

D22004AX ATGAAAGTGGCCATCATCTTCCTGCTGTCCGCACTGGCACTGCTG TCCCTGGCAGGACCATGCTGCCCAGGA (SEQ ID NO. :75) ,

D22021AX ATGCGGCTGCGGCTGCTGGTGTCCGCGGGCATGCTGCTGGTGGCT

CTGTCGCCCTGTCTGCCTTGCAGGGCCCTGCTGTTCGCGCCATGC

TC (SEQ ID NO. :76) ,

D22039AX ATGGGCTTCCTGAAATTCTCCCCTTTCCTGGTGGTGTCCATCCTG

CTGCTGTATCAAGCGTGTGGCCTGCAAGCGGTGATCTGCTGCCTG

ACA (SEQ ID NO. :77) , D22045AX ATGCGGCTGCGGCTGCTGGTGTCCGCGGGCATGCTGCTGGTGGCT CTGTCGCCCTGTCTGCCTTGCAGGGCCCTGCTGTTCGGACCGTGC ATTCTG (SEQ ID NO. :78) ,

D22121AX ATGTGGTTCCTGATCCTGTTCCTCGCCCTGTCCCTGGGACAGATT

GATGCTGCACCAGACTGCTGCATCCCA (SEQ ID NO. :79) , and

D2205OAX ATGCGGCTGCGGCTGCTGGTGTCCGCGGGCATGCTGCTGGTGGCT CTGTCGCCCTGTCTGCCTTGCAAGGCCCTGCTGTTCGACCCGTGC ATT (SEQ ID NO. :80) .

15. The nucleic acid molecule of claim 13, wherein said molecule additionally comprises a mammalian expression control sequence.

16. A nucleic acid molecule comprising a coding sequence encoding an immunoactive peptide of Formula IV:

A_n-X_p-Y-Cys-Z_q-B_m (IV) where each A and each B is independently selected from any of the 20 common, naturally occurring amino acids;

X is selected from the group consisting of Ser, Glu, Gly, Ala, Leu, Pro, Thr, Val, Asn, and Lys;

Y is selected from the group consisting of Leu, Arg, Pro, Tyr, He, Val, Ser, Ala, and Phe;

Z is selected from the group consisting of Met, Trp, Tyr, Phe, Gly, Pro, Arg, Asn, Gin, Ala, and Lys; n, m, p, and q are whole integers chosen with the following provisos: p and q are independently zero or 1 but are not both simultaneously zero; when q is zero, m is zero; and the sum of n, m, p, and q is 1 to 28, inclusive; provided that SEQ ID NOs. 139 through 156 are excluded from Formula IV; the coding sequence optionally further encoding a mammalian signal peptide linked to the amino terminal of the immunoactive peptide.

17. The nucleic acid molecule of claim 16, wherein both p and q are 1, and the sum of n and m is zero to 16, inclusive.

18. The nucleic acid molecule of claim 16, wherein both p and q are 1, and the sum of n and m is zero to 11, inclusive.

19. The nucleic acid molecule of claim 16, wherein both p and q are 1, and the sum of n and m is zero to 3, inclusive.

20. The nucleic acid molecule of claim 16, wherein

X is Glu, Y is Pro, and Z is Met, X is Gly, Y is Pro, and Z is Met,

X is Ala, Y is Pro, and Z is Trp,

X is Ala, Y is Pro, and Z is Met,

X is Glu, Y is Pro, and Z is Trp,

X is Ser, Y is Pro, and Z is Trp, X is Leu, Y is Leu, and Z is Gly,

X is Pro, Y is Arg, and Z is Arg,

X is Gly, Y is Tyr, and Z is Pro,

X is Val, Y is Val, and Z is Asn,

X is Leu, Y is Ser, and Z is Gin, X is Ser, Y is Pro, and Z is Tyr, X is Ala, Y is Leu, and Z is Arg,

X is Ala, Y is Pro, and Z is Tyr,

X is Gly, Y is Ala, and Z is Pro,

X is Lys, Y is Ser, and Z is Lys,

X is Glu, Y is Pro, and Z is Phe,

X is Glu, Y is Pro, and Z is Tyr,

X is Ser, Y is Pro, and Z is Met,

X is Ala, Y is Pro, and Z is Tyr,

X is absent, Y is Leu, and Z is Phe, or

X is Gly, Y is Pro, and Z is Trp.

21. The nucleic acid molecule of claim 16, wherein said immunoactive peptide is selected from the group consisting of

Gln-Cys-Ala-Leu-Cys-Arg (SEQ ID N0. :81) ,

Val-Ala-Leu-Ser-Cys-Gln (SEQ ID N0..82) ,

He-Val-Lys-Ser-Cys-Lys (SEQ ID NO. :83) ,

Leu-Ala- Phe- ^■Glu- Pro- ^■Cys-Met SEQ ID NO. :84) Leu-Leu- Pro- Gly- Pro- ^•Cys -Met SEQ ID NO. :85) Met-Ala- Pro- ^■Ala- Pro- ^■Cys -Trp SEQ ID NO. :86) Ala-Leu- Tyr- ^■Ala- Pro- ^■Cys -Met SEQ ID NO. :87) Val-Leu- Trp- Glu- Pro- Cys -Trp SEQ ID NO. :88) Met-Leu- Phe- ^■Ser- Pro- ^•Cys -Trp SEQ ID NO. :89) Leu-Leu- Cys- ^■Gly- Pro- Ala-He SEQ ID NO. :90) Leu-Cys- Phe- ^■Gly- Pro- Ala-He SEQ ID NO. :91) Val-Met- Pro- Ser- Pro- Cys-Tyr SEQ ID NO. :92) Val-Val- Phe- ^•Ala- Pro- ^■Cys -Tyr SEQ ID NO. :93) Ala-Val- Pro- Glu- Pro- Cys -Phe SEQ ID NO. :94) Met-Met- Tyr- Glu- Pro- Cys-Tyr SEQ ID NO. :95) Ala-Ala- Trp- ^■Ser- Pro- Cys -Met SEQ ID NO. : 96) Val-Ala- Tyr- Gly- Pro- Cys -Trp SEQ ID NO. :97) Leu-Arg-Pro-Arg-Cys-Arg-Pro-He (SEQ ID NO. :98) , Ala-Gly-Tyr-Cys-Pro-Thr-Met-Thr (SEQ ID NO.:99) , Pro-Gln-Val-Val-Cys-Asn-Tyr-Arg (SEQ ID NO.:100) , or Ala-Asn-Phe-Cys-Ala-Gly-Ala-Cys-Pro-Tyr-Leu-Trp (SEQ ID NO. :101) .

22. A nucleic acid molecule having a coding sequence encoding a polypeptide selected from the group consisting of D22184AA Met-Arg-Leu-Arg-Leu-Leu-Val-Ser-Ala-Gly-Met-Leu- Leu-Val-Ala-Leu-Ser-Pro-Cys-Leu-Pro-Cys-Arg-Ala-

Leu-Ala-Phe-Glu-Pro-Cys-Met (SEQ ID O..102),

D22183AA Met-His-Leu-Ser-Leu-Ser-His-Gln-Trp-Ser-Ser-Trp-

Thr-Val-Leu-Leu-Leu-Leu-Val-Ser-Asn-Leu-Leu-Leu- Trp-Glu-Asn-Thr-Ala-Ser-Ala-Met-Ala-Pro-Ala-Pro-

Cys-Trp (SEQ ID NO.:103),

D22196AA Met-Gly-Phe-Leu-Lys-Phe-Ser-Pro-Phe-Leu-Val-Val- Ser-He-Leu-Leu-Leu-Tyr-Gln-Ala-Cys-Gly-Leu-Gln- Ala-Val-Leu-Trp-Glu-Pro-Cys-Trp (SEQ ID

NO. :104) ,

D22197AA Met-Gly-Phe-Leu-Lys-Phe-Ser-Pro-Phe-Leu-Val-Val- Ser-He-Leu-Leu-Leu-Tyr-Gln-Ala-Cys-Gly-Leu-Gln- Ala-Val-Met-Pro-Ser-Pro-Cys-Tyr (SEQ ID

NO. :105) ,

D22217AA Met-His-Leu-Ser-Leu-Ser-His-Gln-Trp-Ser-Ser-Trp- Thr-Val-Leu-Leu-Leu-Leu-Val-Ser-Asn-Leu-Leu-Leu- Trp-Glu-Asn-Thr-Ala-Ser-Ala-Met-Leu-Phe-Ser-Pro- Cys-Trp (SEQ ID NO. :106), and

D22215AA Met-Gly-Phe-Leu-Lys-Phe-Ser-Pro-Phe-Leu-Val-Val- Ser-Ile-Leu-Leu-Leu-Tyr-Gln-Ala-Cys-Gly-Leu-Gln-

Ala-Val-Val-Phe-Ala-Pro-Cys-Tyr (SEQ ID NO. :107) .

23. The nucleic acid molecule of claim 16, wherein the coding sequence is selected from the group consisting of D22184AA ATGCGGCTGCGGCTGCTGGTGTCCGCGGGCATGCTGCTGGTGG

CTCTGTCGCCCTGTCTGCCTTGCAGGGCCCTGGCCTTCGAACCGTGCA

TG (SEQ ID NO. :108) ,

D22183AA ATGCACCTGAGCCTGAGCCACCAATGGAGCAGCTGGACAGTAC

TGCTGCTGCTGGTAAGCAACTTATTATTATGGGAAAACACAGC AAGCGCAATGGCACCAGCACCATGCTGG (SEQ ID NO. :109),

D22196AA ATGGGCTTCCTGAAATTCTCCCCTTTCCTGGTGGTGTCCATCC TGCTGCTGTATCAAGCGTGTGGCCTGCCAGCGGTATTATGGGA

ACCATGCTGG (SEQ ID NO.:110),

D22197AA ATGGGCTTCCTGAAATTCTCCCCTTTCCTGGTGGTGTCCATCC TGCTGCTGTATCAAGCGTGTGGCCTGCAAGCGGTAATGCCTTC CCCTTGCTAC (SEQ ID NO. :Ill),

D2217AA ATGCACCTGAGCCTGAGCCACCAATGGAGCAGCTGGACAGTACT ACTGCTGCTGGTAAGCAACTTATTATTATGGGAAAACACAGCAA GCAGCAATGTTATTCAGCCCATGCTGG (SEQ ID NO.:112) , and D2215AA ATGGGCTTCCTGAAATTCTCCCCTTTCCTGGTGGTGTCCATCCT GCTGCTGTATCAAGCGTGTGGCCTGCAAGCGGTAGTATTCGCGC CTTGCTAC (SEQ ID NO.:113) .

24. A nucleic acid molecule comprising a coding sequence encoding an immunoactive peptide of Formula V:

where each A and each B is independently selected from any of the 20 common, naturally occurring amino acids;

X is selected from the group consisting of Cys, Pro, He, Met, Tyr, Thr, and Arg;

Y is selected from the group consisting of Cys and Met; Z is selected from the group consisting of Gly, Phe, Val, He, Pro, Tyr, Trp, Glu, Leu, and Met; , X, and Y are chosen with the proviso that at least one of W, X, or Y is Met, and not more than one of W, X, or Y is Cys; n, , and p are whole integers chosen with the provisos that p is zero or 1; when p is zero, m is zero; and the sum of n, , and p is zero to 27, inclusive; provided that SEQ ID NOs . 139 through 156 are excluded from Formula V;

the coding sequence optionally further encoding a mammalian signal peptide linked to the amino terminal of the immunoactive peptide.

25. The nucleic acid molecule of claim 24, wherein p is one and the sum of n and m is zero to 16, inclusive.

26. The nucleic acid molecule of claim 24, wherein p is one and the sum of n and m is zero to 11, inclusive.

27. The nucleic acid molecule of claim 24, wherein p is one and the sum of n and m is zero to 3, inclusive.

28. The nucleic acid molecule of claim 24, wherein

X is selected from the group consisting of Cys, Pro, He, and Met;

Y is selected from the group consisting of Cys and Met; and

Z is selected from the group consisting of Gly, Phe, Val, He, Pro, and Leu.

29. The nucleic acid molecule of claim 24, wherein at least one of X and Y is Met .

30. The nucleic acid molecule of claim 24, wherein is selected from the group consisting of Gly, Asp, Arg, Ala, Trp, and Ser;

X is selected from the group consisting of Pro and lie;

Y is Met; and

Z is selected from the group consisting of Phe, He, and Pro.

31. The nucleic acid molecule of claim 24, wherein

W is selected from the group consisting of Gly and Ser; X is Pro; Y is Met; and

Z is selected from the group consisting of Phe, He, and Pro.

32. The nucleic acid molecule of claim 24, said immunoactive peptide having a Met and a Cys aligned contiguously.

33. The nucleic acid molecule of claim 24, said immunoactive peptide having a Met and a Cys separated by no more than one amino acid.

34. The nucleic acid molecule of claim 24, wherein said immunoactive peptide is selected from the group consisting of

Gly-Pro-Met-He (SEQ ID NO.:114), Lys-Met-Arg-Met-Lys (SEQ ID NO.:115) Phe-Met-He-Met-Lys (SEQ ID NO. :116), He-Cys-Thr-Met-Glu (SEQ ID NO.:117) , Leu-Met-Ala-Met-Val (SEQ ID NO.-.118), Ile-Met-Tyr-Met-Glu (SEQ ID 0..119) , Ala-Pro-Met-Met-Val-Pro (SEQ ID NO. :120), Gly-Pro-Met-Met-Pro-Gly (SEQ ID N0. :121) , Gly-Pro-Cys-Met-Pro-Gly (SEQ ID NO.:122) , Gly-Pro-Met-Cys-Pro-Gly (SEQ ID NO. :123), Pro-Gly-Met-Met-Gly-Pro (SEQ ID N0..124) , Val-Ile-Met-Met-Leu-Thr (SEQ ID N0..125) , Leu-Ala-Phe- Glu--Pro--Met--Met (SEQ ID NO. :126) , Met -Leu-Phe- Ser- -Pro- -Met- -Trp (SEQ ID NO. :127) , Val -Val -Phe- Ala- -Pro- -Met- -Tyr (SEQ ID NO. :128) , Leu-Leu- Phe- Gly- -Pro- -Met- -He (SEQ ID NO. :129) , Leu-Leu-Tyr- Ser- -Pro- -Met- -Phe (SEQ ID NO. :130) , Leu-Leu-Phe- Asp- -Pro- -Met- -He (SEQ ID NO. :131) , Leu-Leu-Phe- Trp- -Pro- -Met- -He (SEQ ID NO. :132) , Leu-Leu-Phe- Arg- -Pro- -Met- -He (SEQ ID NO. :133) , Leu-Leu-Phe- Ala- -Pro- -Met- -He (SEQ ID NO. :134) , Leu-Leu-Phe- Gly- -He- -Met- -He (SEQ ID NO. :135) , and Phe-Met -Leu- Gly- -Pro- -Met- -Pro (SEQ ID NO. :136) .

35. A nucleic acid molecule having a coding sequence encoding a polypeptide consisting of D22020AX Met-Arg-Leu-Arg-Leu-Leu-Val-Ser-Ala-Gly-Met-Leu-

Leu-Val-Ala-Leu-Ser-Pro-Cys-Leu-Pro-Cys-Arg-Ala- Leu-Leu-Phe-Gly-Pro-Met-He (SEQ ID NO. :137) .

36. The nucleic acid molecule of claim 35, wherein the coding sequence is

D2202OAX ATGCGGCTGCGGCTGCTGGTGTCCGCGGGCATGCTGCTGGTGGCT

CTGTCGCCCTGTCTGCCTTGCAGGGCCCTGCTGTTCGGACCGATGATT (SEQ ID NO. : 138) .

37. The nucleic acid molecule of claim 1, claim 5, claim 9, claim 16, or claim 24, wherein said coding sequence encodes said signal peptide linked to said immunoactive peptide.

38. The nucleic acid molecule of claim 37, wherein said signal peptide (a) directs secretion of said immunoactive peptide from a mammalian cell in which the nucleic acid is expressed, and (b) is enzymatically cleaved from said immunoactive peptide by said cell .

39. The nucleic acid molecule of claim 1, claim 5, claim 9, claim 16, or claim 24, wherein said molecule further comprises a mammalian expression control sequence operatively linked to the coding sequence.

40. The nucleic acid molecule of claim 39, wherein said expression control sequence comprises an inducible promoter.

41. The nucleic acid molecule of claim 39, wherein said expression control sequence comprises a constitutively active promoter.

42. The nucleic acid molecule of claim 39, wherein the expression control sequence directs tissue-specific expression of said immunoactive peptide.

43. The nucleic acid molecule of claim 39, wherein the expression control sequence directs cell-specific expression of said immunoactive peptide.

44. A mammalian expression vector comprising the nucleic acid molecule of claim 1, claim 5, claim 9, claim 16, or claim 24.

45. The expression vector of claim 44, wherein said vector is a viral vector.

46. A viral particle capable of infecting a mammalian cell, said viral particle comprising the expression vector of claim 45.

47. A mammalian cell containing the nucleic acid molecule of claim 39.

48. A method of producing an immunoactive peptide, said method comprising introducing into a mammalian cell the nucleic acid molecule of claim 39, culturing said cell under conditions that permit expression of said immunoactive peptide, and harvesting said immunoactive peptide from said cell or from the medium surrounding said cell.

49. A method of producing an immunoactive peptide in a mammal, said method comprising introducing into a cell of the mammal the nucleic acid molecule of claim 39.

50. A method of producing an immunoactive peptide in a mammal, said method comprising introducing into the mammal the cell of claim 47.

51. A method for modulating the immune response in a patient, said method comprising administering to the patient the nucleic acid molecule of claim 39.

52. The method of claim 51, wherein said administering is carried out by introducing said nucleic acid molecule into the patient's bloodstream.

53. The method of claim 51, wherein said administering is carried out by introducing said nucleic acid molecule into the synovial fluid of the patient.

54. The method of claim 51, wherein said administering is carried out by introducing said nucleic acid molecule into the vicinity of a tumor of the patient.

55. A method for modulating the immune response in a patient, said method comprising administering to said patient the cell of claim 47.

56. The method of claim 55, wherein said cell is a descendant of a cell of said patient, said nucleic acid molecule having been introduced into said descendant cell, or a precursor of said descendant cell, ex vi vo .

57. The method of claim 55, wherein said administering is carried out by introducing said cell into the patient ' s bloodstream.

58. The method of claim 55, wherein said administering is carried out by introducing said cell into the synovial fluid of the patient.

59. The method of claim 55, wherein said administering is carried out by introducing said cell into the vicinity of a tumor of the patient.

60. The nucleic acid molecule of claim 1, claim 5, claim 9, claim 16, or claim 24, wherein said immunoactive peptide is immunosuppressive in a mammal.

61. The nucleic acid molecule of claim 1, claim 5, claim 9, claim 16, or claim 24, wherein said immunoactive peptide is immunostimulatory in a mammal .

62. The method of claim 51, wherein the immunoactive peptide is immunosuppressive in the patient.

63. The method of claim 62, wherein said patient is suspected of having an autoimmune disease.

64. The method of claim 51, wherein the immunoactive peptide is immunostimulatory in the patient.

65. The method of claim 64, wherein the patient is suspected of having cancer.

66. The nucleic acid molecule of claim 37, wherein said signal peptide is a human signal peptide.

67. Use of the nucleic acid molecule of claim 1, claim 5, claim 9, claim 16, or claim 24 in therapy.

68. Use of the nucleic acid molecule of claim 1, claim 5, claim 9 , claim 16, or claim 24 in the manufacture of a medicament for use in modulation of a patient's immune response.

69. Use of claim 68, wherein said patient is suffering from an autoimmune disease or a cancer.

70. Use of claim 68, wherein said patient is suffering from a disease caused by an infectious agent.

71. Use of claim 68, wherein the patient is the recipient of an organ, tissue, or cell transplant.

72. The nucleic acid molecule of claim 2 or 3, wherein A is Gly, Lys, Arg, Cys, Ser, Val, Ala, Thr, Glu, Pro, Trp, Leu, Asp, Phe, or He; B is Leu, Arg, He, Val, Pro, Ala, Tyr, Gly, Trp, Thr, Lys, Met, Asp, Glu, or Phe; and the sum of n and m is two to four, inclusive.

73. The nucleic acid molecule of claim 2 or 3 , wherein A is Pro, Gly, Glu, Ala, Val, Lys, Thr, Leu, or Ser; B is Tyr, Pro, Gly, Thr, Arg, Val, Ala, Leu, Lys, or He; n is one; and m is one.

74. The nucleic acid molecule of claim 6 or 7 , wherein X is Val, Ala, Leu, He, Lys, Asp, Phe or Pro; Y is Glu, Val, Gin, Arg, Lys, or Pro; Z is Gly, Ala, He, Arg, Thr, or Lys; and the sum of n and m is one to three, inclusive.

75. The nucleic acid molecule of claim 10 or 11, wherein X is Gly, Ala, He, Arg, Asp, Trp, Thr, or Ser; Y is Pro, Gly, or He; Z is Gly, Ala, He, Tyr, Phe, or Pro; and the sum of n and m is one to three, inclusive.

76. A therapeutic composition comprising the nucleic acid molecule of claim 1, claim 5, claim 9, claim 16, or claim 24, and a pharmaceutically acceptable carrier

77. The nucleic acid molecule of claim 16, wherein said immunoactive peptide is chosen with the proviso that: when Y is Pro or He, and q is 1, and Z is Tyr, Phe, Gly, Pro, or Ala, then