EP0400077A1 - Use of synthetic peptides to generate and manipulate cellular immunity - Google Patents
Use of synthetic peptides to generate and manipulate cellular immunityInfo
- Publication number
- EP0400077A1 EP0400077A1 EP19890903393 EP89903393A EP0400077A1 EP 0400077 A1 EP0400077 A1 EP 0400077A1 EP 19890903393 EP19890903393 EP 19890903393 EP 89903393 A EP89903393 A EP 89903393A EP 0400077 A1 EP0400077 A1 EP 0400077A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- antigen
- class
- amino acids
- peptide
- sequence
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
- C12N2760/00011—Details
- C12N2760/16011—Orthomyxoviridae
- C12N2760/16022—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
Definitions
- the Class I transplantation antigens, H-2D, K, and L in the mouse and HLA-A, B, and C in the human, encoded within the major histocompatibility complex are polymorphic cell surface glycoproteins which play a central role in the regulation and function of the immune system. These molecules act as antigen presen- tation structures or "restriction elements" directing the attack of cytotoxic T-lymphocytes (CTL) against virally infected or non-self target cells. CTL gener ⁇ ally show a requirement for the co-recognition of foreign antigens in the context of specific self MHC Class I products. Therefore, CTL recognition is said to be "MHC-restricted.”
- the immune system is a major determinant of the health and welfare of the mammalian host.
- mammalian hosts still remain susceptible to a wide variety of diseases as a result of infection by microorganism and viral pathogens and of the occurrence of aberrant cells, such as neo-plastic cells. While for the most part, the mammalian host is able to over- come most diseases, not infrequently a significant period of debilitating illness with varied consequences to the mammalian host may result.
- the protection afforded is related to the various mechanisms of invasion and regulation of the pathogen, to the nature of the diseased cell, and to the partic ⁇ ular susceptibility of various individuals to diseases.
- compositions for modulating the immune response of a host to a foreign antigen by providing a peptide comprising at least one of the helices of the polymorphic region of a foreign Class I antigen.
- the compositions may be employed to enhance the immune response in relation to a foreign MHC or other antigen or to tolerize the host to a foreign MHC.
- DESCRIPTION OF THE SPECIFIC EMBODIMENTS Methods and compositions are provided for modulating the immune system in relation to Class I restricted elements. Peptides which bind to the native MHC providing an epitope of interest may be employed.
- the subject peptides are characterized by having at least a partially non-contiguous sequence which is primarily hydrophobic and binds to the ⁇ - pleated sheet of a designated host Class I major histo ⁇ compatibility antigen (MHC).
- MHC major histo ⁇ compatibility antigen
- the sequence may be the same as or substantially similar to the ⁇ -sheet binding sequence of an ⁇ -helix of the designated Class I antigen itself.
- the intervening amino acids between the binding sequence may be the sequence of an o-helix of a Class I antigen other than the designated Class I antigen or the same sequence. Where different, the sequence will be chosen to stimulate or tolerize T-cells to an antigen of interest.
- compositions are characterized by having a sequence of at least 10 amino acids which are naturally in an ⁇ -helix conformation or may be induced into such conformation by binding to a ⁇ -sheet of the cleft of a Class I MHC.
- the sequence will be further character ⁇ ized by having hydrophobic residues spaced from 2 to 3 amino acids apart, where the hydrophobic residues are conserved, (that is, are the same amino acid or may be substituted by a conservative substitution), which sequence is referred to as the agretope.
- amino acids may be divided into groups which are non-polar and polar, and further divided into low and high polarity, where the low polarity amino acids may be readily substituted for the non-polar amino acids.
- the non-polar aliphatic amino acids are: G, A, P, V, L, I; the non-polar aromatic amino acids are: F, W, Y; the low polarity amino acids are: H, C, M, S, T; and the high polarity amino acids are: D, E, K, R, N, Q.
- the amino acid sequence associated with and binding to the ⁇ -sheet will be referred to as the binding domain.
- the binding domain will be comprised of two parts, the amino acid residues associated with binding to the ⁇ -sheet and occupying a region of the MHC cleft ("binding sequence") and the amino acid residues interspersed between the binding residues ("epitope"), where amino acids of one group may participate to varying degrees in the handling of the other group to a complementary region.
- the individual interspersed residues will be referred to as the epi- topic residues, which in varying degrees participate in and define the epitope of the binding domain. These residues will be varied widely depending upon the func ⁇ tion and purpose of the binding domain.
- the epitopic residues will be involved in the recognition by the T-cell receptor of the MHC antigen to which the binding domain is bound.
- the epitope will include at least 1, usually 2, hydrophilic residues, frequently charged.
- the amino acids involved in defining the epitope may be identi ⁇ fied. These may be substituted with amino acids asso ⁇ ciated with an epitopic site of an antigen of interest. In this way novel peptides are designed to provide a T- cell response to a particular epitopic site.
- the peptide which is employed will have at least 10 amino acids, usually at least about 12 amino acids, preferably at least 14 amino acids. It may have 200 amino acids or more, usually having not more than about 60 amino acids, more usually having not more than about 36 amino acids.
- the binding domain will usually occupy at least 10, usually 14, amino acids, will usually be not more than about 20 amino acids, more usually not more than about 18 amino acids, among these, at least 3 being binding residues.
- the remaining amino acids of the peptide may be present for a variety of reasons. Included among the remaining amino acids, particularly those amino acids contiguous with the binding domain, may be amino acids providing for a second epitope common to an antigen of interest which may be involved in T-cell stimulation. Alter ⁇ natively or in addition, the additional sequence or extended sequence may provide for stability of the peptide, direction of the peptide to a particular cellular compartment, ease of administration, or the like.
- peptides of fewer than about 60 amino acids will be preferred, since these can be synthesized employing automated synthesizers. How- ever, peptides of about 35 or more amino acids, can be obtained employing recombinant DNA technology, by devising DNA sequences encoding the desired peptide, inserting the sequence into an expression vector. These vectors are now generally available or can be readily made, and can be transformed into an appro ⁇ priate host for expression and isolation of the desired peptide. In devising peptides different from the natural sequence of the Class I antigen, a pattern is defined in a helix domain, either the ⁇ -1 or ⁇ -2 helix domain.
- a turn of the helix is something greater than 3 amino acids, approximately 3.2-3.6 amino acids, and one can define those amino acids which will likely be on the upper portion or top of the helix and those which will likely be at the lower portion or bottom of the helix.
- the lower amino acids will be involved in non-covalent binding to the ⁇ -sheet, whereas the upper amino acids will be involved in defining the epitope and binding to the T-cell receptor, in varying degrees.
- the epitopic sequence will be primarily a hydrophilic sequence, while the agretopic sequence will primarily be hydrophobic.
- the sequence employed would be a T-cell stimulating sequence of the antigen as the epitope of interest.
- the T-cell stimulating sequence of the antigen may be one which is restricted by the haplotype of the T-cells to be stimulated.
- the hydrophobic sequence may be common to a number of different Class I antigens although this will have to be verified as to each haplotype. That is, one would normally select a binding sequence similar to or the same as the binding sequence of a helix of the haplotype of the host. Otherwise, one would use the particular sequence of the ⁇ -helix of the haplotype of the host cells. Since the host will normally be heterozygous for each Class I antigen, one could choose to stimulate only one subset of T-cells restricted by one haplotype or have two or more ⁇ -helices for the different haplotypes. In some instances, one helix could be chosen over another due to greater or lesser homology between the host Class I ⁇ -helix and the ⁇ -helix of the foreign antigenic sequence.
- the Class I antigen employed is H-2L d
- the epitope of interest will be an epitope of influenza virus.
- the following is the sequence of the ⁇ -1 domain of the H-2L" Class I antigen.
- underlined letters are those which are likely to be involved with the epitope.
- an epitope of interest will be a sequence of the influenza virus.
- the hybrids By employing the hybrids in conjunction with cells of an allogeneic host and T-cells restricted by the cells of the allogeneic host, one would stimulate a subset of T-cells recognizing the epitope displayed by the hybrid peptide. At least one of the stimulated T-cell subsets would be active toward a cell infected with influenza virus.
- the peptide need not be limited to a single modified sequence, but a string of such sequences may be joined together, either directly or through linking or spacing sequences, usually short sequences of no more than about 30 amino acids. With viruses or other microorganisms, one may encounter a large number of sequences which would be presented to T-cells. Each of the epitopes of these sequences could be substituted for the epitope of the Class I ⁇ -helix sequence.
- the subject peptides could be used in the case of autoimmunity. Autoimmunity may be associated with cross-reactivity between an antigen to which the host has mounted an immune response ("pathogenic antigen") and a native surface antigen, e.g. a transplantation antigen.
- the epitope of the pathogenic antigen will not be identical to the epitope of the native antigen.
- the peptide may be used as a vaccine.
- One stimu ⁇ lates the immune response to mount a more effective response to the pathogenic antigen to result in stimu ⁇ lated T-cells which are less stimulated by the native antigen than the pathogenic antigen.
- the change in response would serve to protect a host from an auto ⁇ immune disease to which the host might be susceptible, due to cross-reactivity between a native antigen and a foreign antigen.
- Cellular microorganisms may include myco- plasma, or viruses including DNA or RNA viruses, such as retroviruses, rhinoviruses, picornaviruses, FeLV, influenza virus, visna viruses, paramyxoviruses ortho- myxoviruses, hepatitus virus, papovavirus, reovirus, parvovirus, herpesvirus, rhabdovirus, etc.
- DNA or RNA viruses such as retroviruses, rhinoviruses, picornaviruses, FeLV, influenza virus, visna viruses, paramyxoviruses ortho- myxoviruses, hepatitus virus, papovavirus, reovirus, parvovirus, herpesvirus, rhabdovirus, etc.
- the binding domain of the Class I antigen may be bound to additional peptide sequences, particularly immunodominant sequences, normally foreign, for a variety of purposes.
- the Class I binding domain may be bound to one or more immunodominant sequences which are restricted by the Class I haplotype of the host. This will have the effect of greatly enhancing the binding of the foreign domain to the Class I antigen providing for a stronger immune response.
- the foreign antigen and the epitope of the binding domain are associated with the same entity, two different subsets of T-cells will be stimulated. Thus, when either of the epitopes are presented upon infection, there will be enhanced popu ⁇ lations of previously stimulated T-cells.
- Class I antigens may be known for specific entities, e.g. viruses or other pathogens, or may be readily determined. These domains will fit the constraints described above for the Class I ⁇ -helix. Namely, based on the helical conformation, there will be a hydro- phobic face and a hydrophilic face. Also, there may be some conservation between the hydrophobic face of a helix of the Class I antigen and the hydrophobic face of the domain of the foreign antigen. In any event, where the sequence is not known, there will be rela ⁇ tively few partial sequence candidates among the antigen sequence to be tested for T-cell response.
- the immunodominant sequence refers to a sequence of an antigen which binds to the Class I antigen haplotype of interest.
- the immunodominant sequence refers to a sequence of an antigen which binds to the Class I antigen haplotype of interest.
- Rothbard algorithm which requires a sequence in either the N-C or C-N direction of the first amino acid being glycine or charged, the next two amino acids, being non-charged, usually non- or low-polarity, and one of the next two amino acids being polar. Sequences including this algorithm are likely candidates for an immunodominant sequences.
- binding domain and additional peptide sequence(s) need not be joined directly together, but may be bridged with up to about 30 amino acids to space the sequences apart.
- the particular number of amino acids is not critical and will usually be primarily one of convenience.
- the foreign sequences may be associated with the same entity, e.g. antigen of the same virus, or with different entities, e.g. antigens of different viruses.
- compositions may also be used in case of neoplasia, where the neoplastic cells produce a surface protein which occurs either infrequently or at very low concentration on normal cells of the host.
- neoplasia where the neoplastic cells produce a surface protein which occurs either infrequently or at very low concentration on normal cells of the host.
- compositions may be administered as a single peptide or a mixture of peptides, depending upon the purpose and function of the composition.
- a single compound may suffice.
- a substantially universal binding domain or at least a binding domain which can bind to Class I MHC's of the major population groups would suffice joined to an antigenic epitope cross- reactive to a particular pathogen in providing for a T-cell immune response to the pathogen.
- the subject invention may find use with any vertebrate, particularly domestic animals, pets, animals in zoos, or the like.
- the different binding sequences of the Class I antigens will be determined and employed.
- the formulations will be affected by the manner in which the formulation is administered, the particular nature of the peptide, the intended lifetime of the peptide, or the like.
- the formulations may include lyophilized powders, dispersions in aqueous or alkanolic media, e.g. saline and phosphate buffered saline, in liposomes, as aerosols, etc.
- the concentra ⁇ tion and amount administered may vary widely, depending upon the particular composition, the manner of admini ⁇ stration, and the host response. Normally, at least about 0.01 ⁇ g/kg of host, more usually about 0.05 ⁇ g/kg of host, will be employed, and not more than about 10 ⁇ g/kg of host, more usually not more than about 5 yg/kg of host.
- the concentration will generally be from about 10 ⁇ g/ml to 1 mg/ml.
- the amount used will vary with the size of the host, the upper range being used with smaller hosts.
- the manner of administration may be subcuta ⁇ neous, intravascular, intraperitoneally, intramuscular, by inhalation, orally, or the like.
- One or more admin- istrations may be made, and when used as a vaccine, particularly at at least two week intervals and up to bi-annual intervals, although random repetitive admin ⁇ istrations may be called for, particularly as a special need arises.
- C3H mice were immunized by i.p. injection of 10' 1591 cells expressing the A149 antigen as well as the A216 and A166 antigens (Linsk, e_t al., J. Exp. Med. (1986) 164:794-813) .
- Spleens were harvested 4 weeks later and a secondary culture of 1591-tumor specific CTL was established by using mitomycin c treated 1591 tumor cells in complete medium (RPMI medium containing 10% FCS and 10 "6 M 2-mercaptoethanol) . After 1 week of growth, effector populations were transferred to L-cell stimulator cells transfected with either H-2L° or H-2L 149 to enrich for specific CTL populations.
- Cultures are maintained with L-cell transfectant stimu ⁇ lators or with L-cells in presence of 61-85 H-2L pep- tide (lO ⁇ g/ml) in CTL medium (complete medium with 15% rat ConA supernatant).
- Allospecific CTL clone L3 was derived from a C57BL/6 anti-DBA/2 mixed lymphocyte culture (MLC) Glasebrook and Fitch, Nature (1979) 278:171-173 (received from Dr. 0. Kanagawa,, Scripps Institute, La Jolla, CA) . Allospecific CTL clones L9.4, L13.D4 and L.13.D.8 have been previously described (Linsk, et-. al. , supra) and were received from Dr. J. Forman, University of Texas, Health Sciences Center, Dallas, TX.
- MLC mixed lymphocyte culture
- L9.4 was derived from a (C3Hxdm2)Fl anti-BALB/c culture while L13.4 and L13.D8 was derived from a CBA anti-A.AL culture. All clones have been shown to be reactive to H-2L d and are maintained in CTL medium with mitomycin treated BALB/c splenocytes as stimulators.
- Murine tumor cell lines P815 (H-2 d ), EL4(H-2 b ) and C3H Ltk ⁇ cell (H-2 k ) were used as target cells.
- K2a-7 and H23-12.1 are L-cell transfectants of H-2L d or H-2L 1 "" genes, respectively.
- mice are available from Jackson Laboratory (Bar Harbor, ME): C3H/HeJ(K k D k ), BALB/cJ(K d D d L d ), BALB/c H-2 dm2 (K d D d ) , BUB/BnJtK-W), A.CA/SnJ(K f D f ), RIIIS/J(K r D r ) , ASW/SnJ(K s D s ). B10.RKR.l(K D r ), and B10.ASR2(K k D s ) mice were received from Dr. Chella David, Mayo Clinic, Rochester, Minnesota.
- Splenocytes were Concanavalin A induced for 48h and used as targets.
- Peptides were synthesized by using an Applied Biosystems model 430A automatic peptide synthesizer, then cleaved from resin and deprotected by using hydrogen fluoride (Penninsular Lab Inc., Belmont, CA and Applied Biosystems Inc., Foster City, CA) . They were chromatographed on Sephadex G-10 using 10% acetic acid following lyophilization. The peptide was then purified by reversed phase HPLC at room temperature on a Brownlee 20 micron, 300A, 25 x 1 cm Aquaphoroctyl Prep-10 cartridge column using 0.1% trifluoroacetic acid with a gradient of acetonitrile. Peptides were resuspended in 30% propanol at a concentration of 2mg/ml and further diluted to appropriate concentra ⁇ tions with assay medium. 51 Cr Release Assay
- the 51 Cr labelled target cells were trans ⁇ ferred to 96 well microtiter plate along with appro ⁇ priate aliquots of peptides and brought to a total volume of lOO ⁇ l with CTL medium. After 30 min. of incubation at room temperature, cells were washed 3X and resuspended in lOO ⁇ l of CTL medium. CTL at various effector to target ratios were tested in a 4 hr assay.
- the specific percent ⁇ 1 Cr released was determined as follows: (ER-SR)/(FR-SR) X 100, where ER is the average experimental CTL mediated release; SR is the average spontaneous release; and FR is the average full release from the target cells lysed in 150 ⁇ l of RPMI containing 50 ⁇ l of 1% NP-40.
- 1591 is a UV induced C3H fibrosarcoma which expresses several novel Class I epitopes not normally found on C3H tissue in addition to normal H-2 k products (Phillips et al., Proc. Natl. Acad. Sci. USA (1985) 8 ⁇ :5140-5144).
- three novel Class I genes from the 1591 genome were cloned, whose products account for the expression of these epitopes and the recognition of these products by several CTL clones as well as viral-specific and alloreactive CTL cultures was examined (Linsk, e_t al., supra; Strauss, e_t a_l., J. Immunogenics (1986) 3 ⁇ :101-111).
- H-2L 149 One of the novel genes, designated A149, is highly homologous to the H-2L d gene derived from BALB/c and encodes a distinct product which is recognized by a subset of H-2L d reac ⁇ tive CTL clones.
- the product of this gene is referred to as H-2L 149 .
- the H-2L 149 molecule is identical to the H-2L antigen in the ⁇ l domain and differs by only 6 amino acid substitutions in the ⁇ 2 domain. Function ⁇ ally, this product can be distinguished from H-2L by the lack of reactivity with two H-2L d -reactive mAb and by its inability to serve as a target for several other H-2L d -specific CTL clones.
- H-2L reactive CTL was gener- ated, which are specific for the ⁇ l domain of H-2L , by taking advantage of the identity between H-2L d and H-2L 149 in this region.
- spleen cells from 1591-immunized C3H mice were cultured ⁇ i vitro in the presence of mitomycin c treated 1591 tumor cells expressing H-2L 149 .
- cultures were stimulated with C3H L-cell transfectants expressing H-2L . Since CTL require specific antigenic stimulation in order to grow in the presence of interleukin-2 containing medium, only those cells reac- tive with the H-2L d stimulator cells would be expected to grow out under these conditions.
- H-2L d transfectants stimulate stimulation of the anti-1591 CTL by H-2L d transfectants enrich for CTL which preferentially recognize struc ⁇ tural features shared between the H-2L 149 and H-2L d products, namely CTL epitopes encoded within the ⁇ l domain.
- CTL generated in this manner exhibited anti-H-2L specific reactivity, lysing both the H-2L and A149 transfectants, while showing no lysis of syngeneic L-cells.
- H-2L Peptide Recognition of an H-2L Peptide by Cross Reactive CTL Since the CTL were selected on the basis of the cross-reactivity between H-2L d and H-2L 149 products expressed on an H-2 k haplotype cells, these CTL are capable of recognizing a peptide from the region common to both H-2L molecules and as shown below in associa ⁇ tion with H-2 k restriction element. A peptide was synthesized corresponding to amino acids 61-85 form the ⁇ l domain of H-2L . This peptide was chosen because it is derived from a region shared by the two H-2L mole ⁇ cules which is highly polymorphic among several other H-2 products.
- This region corresponds to the ⁇ helical region predicted for Class I antigen (Novotny and Auffray, Nucleic Acids Res. (1984) 12:243-255) and recently confirmed by the crystal structure of the HLA- A2 molecule (Bjorkman et al.. Nature (1987) 329:506- 512; 512-518).
- a population of anti-1591 CTL selected in parallel for growth on an H-2L 149 L-cell transfectant instead of H-2L d exhibited comparable anti-H-2L specific reactivity, lysing both the H-2L and A149 transfectants, but exhibiting no reactivity with the H-2L peptide. Therefore, selection for growth on H-2L d appears to be important in order to enrich for the presumably small percentage of anti-H-2L CTL cells exhibiting peptide reactivity.
- H-2L d peptide recog ⁇ nition is MHC restricted
- a large panel of tumor cells and spleen cell blasts bearing various MHC haplotypes were examined for the ability to present this peptide to the H-2L reactive anti-1591 CTL.
- H-2 d haplotype cells BALB/c splenic blasts and P815 mastocytoma cells
- no significant lysis was observed for the k, r, s, or f haplotype splenocytes.
- H-2 k haplotype cells C3H splenic blasts and L-cells
- H-2 ⁇ haplotype cells BAB splenic blasts
- This cross-reactivity appears to reflect the strong structural homology which can be observed between two of the novel 1591 tumor antigens and H-2 ⁇ 3 Class I molecules (Linsk, et al ⁇ ., supra; Lillehoj, et al., Proc. Natl. Acad. Sci. USA (1984) 81:2499-2503.
- the antigen presentation activity of the hamster fibroblast line, tk ⁇ ts!3, and the human lympho- blastoid line, WIL 2C 13 were also tested. Neither of these targets were able to present the H-2L peptide to the anti-1591 effectors. It is evident that the anti- 1591 effectors recognize the H-2L peptide in an H-2 k haplotype restricted manner. In addition, haplotype restriction of these CTL appears to be dependent on Class I MHC molecules, since L-cells are known to express no Class II products. Additionally, the anti- 1591 CTL were unable to lyse the Class I negative, H-2 k haplotype thymoma, R1E in the presence of the H-2L peptide.
- H-2 k haplotype restriction element In order to genetically map the H-2 k haplotype restriction element to a specific H-2 k Class I product, the ability of splenic blasts from two H-2 k derived recombinant inbred strains to present antigen to the peptide reactive CTL was examined. Neither H-2 r haplo ⁇ type (RIIIS) nor H-2 S haplotype (A.SW) spleen cells appear to be capable of presenting the H-2L peptide to the H-2L reactive anti-1591 CTL. Therefore, recombi ⁇ nant inbred mice derived from H-2 and H-2 r or H-2 S haplotype progenitors were used to identify the H-2L peptide restriction element.
- RIIIS H-2 r haplo ⁇ type
- A.SW H-2 S haplotype
- anti-1591 CTL populations selected on the H-2L d transfectant appeared to efficiently recognize the H-2L peptide in association with C3H L- cells, it was of interest to determine whether these CTL were also reactive with H-2L d products in the absence of H-2 haplotype restriction elements.
- anti-1591 CTL was grown in the presence of untransfected L-cells with the H-2L d peptide for eight weeks. These effectors were then shown to be able to lyse targets bearing intact H-2L . These cells also efficiently recognized H-2 haplotype P815 as well as BALB/c blast target.
- lysis of BALB/c blasts was entirely dependent on the expression of an intact H-2L d antigen, since BALB/c- H-2 dm2 (K d D d ) splenic blasts which lack the H-2L d product were not lysed by the anti-peptide effectors and appeared to be unable to present the H-2L d peptide. Therefore, the intact H-2L molecule functions either as a distinct antigenic target for the anti-H-2L d effectors or alternatively functions as a restriction element presenting endogenous H-2L d peptide to these CTL.
- H-2L d peptide in association with an H-2 k restriction element mimics an antigenic determinant exhibited by the intact H-2L d molecule.
- this antigenic homology reflects structural conservation which might be detected by other CTL reactive with the H-2L d antigen
- the ability of a panel of H-2L d -reactive CTL clones to recognize the H-2L peptide was examined. Three of the clones tested, L3, L9.4, and L13.D.4 lysed C3H L-cells in the presence of the H-2L d peptide.
- H-2L d reactive clone L13.D.8 appeard to exhibit no reactivity with C3H L-cells plus the H-2L d peptide, indicating that while this peptide appears to be an important antigenic determinant recognized by many H-2L reactive CTL, other H-2L reactive CTL appear to recog- nize distinct structures. These data are especially significant since two CTL, L3 and L9.4, were originally generated against target cells which do not express H-2 k haplotype Class I products (Linsk, ej al, supra; Glasebrook and Fitch, supra (1979). Furthermore, as with the recognition of the H-2L peptide by the anti- 1591 effectors examined above, peptide recognition by the CTL clone, L3, can be mediated by only H-2 k restriction elements.
- H-2L d peptide in association with H-2 k restriction element mimics a T-cell eptiope exhibited by the H-2L d mole- cule.
- HLA-A2 the majority of the amino acid residues on the helices which are polymorphic among various Class I molecules are oriented toward the cleft.
- the above data demonstrate that at least some of the polymorphic residues are directly recognized by the T-cell receptor, since a peptide derived from the ⁇ l helix can reconstitute the antigenic structure seen by alloreactive T-cells on the intact molecule.
- the CTL studies not only recognized the peptide antigen in association with MHC, but also exhibited reactivity with allogeneic MHC products alone.
- the above results demonstrate that peptides can be used to, in effect, change the nature of a restriction element of a host, so as to appear allo ⁇ geneic to the CTL.
- an antigen of interest which may be cross-reactive with a patho ⁇ gen, neoplastic cell or the like, a CTL response may be stimulated, so as to protect the host from subsequent exposure or to mount an attack against an infection or tumor. In this way, the host may by holistic effects be better able to respond to the disease and more rapidly recover from the disease.
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Abstract
On a mis au point des procédés et des compositions permettant de traiter un hôte prophylactiquement ou thérapeutiquement, afin de stimuler les CTL (lymphocytes T cytotoxiques) de l'hôte contre la pathologie. On a notamment mis au point un domaine de liaison se liant à un ou plusieurs antigènes MHC (histocompatibilité principale) de classe I, changeant la restriction de l'antigène de classe I, de manière à prévoir une réaction allogénique. Par l'union du domaine de liaison ou spirale alpha à un épitope d'un antigène d'intérêt, on peut stimuler l'hôte afin de provoquer une réaction de CTL dans le cas d'une exposition ultérieure ou d'une pathologie existante.Methods and compositions have been developed for treating a host prophylactically or therapeutically to stimulate CTL (cytotoxic T lymphocytes) of the host against pathology. In particular, a binding domain has been developed which binds to one or more class I MHC (main histocompatibility) antigens, changing the restriction of the class I antigen, so as to provide for an allogenic reaction. By joining the alpha binding domain or spiral to an epitope of an antigen of interest, one can stimulate the host in order to provoke a CTL reaction in the event of a subsequent exposure or of an existing pathology.
Description
Claims
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US15635788A | 1988-02-12 | 1988-02-12 | |
US156357 | 1988-02-12 |
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JP (1) | JPH03504493A (en) |
AU (1) | AU4030989A (en) |
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US6024964A (en) * | 1985-06-24 | 2000-02-15 | Hoechst Aktiengesellschaft | Membrane anchor/active compound conjugate, its preparation and its uses |
DE3937412A1 (en) * | 1989-11-10 | 1991-05-16 | Hoechst Ag | SYNTHETIC VACCINE FOR THE SPECIFIC INDUCTION OF CYTOTOXIC T-LYMPHOZYTES |
US6074650A (en) * | 1985-06-24 | 2000-06-13 | Hoechst Aktiengesellschaft | Membrane anchor/active compound conjugate, its preparation and its uses |
US5723128A (en) * | 1987-01-30 | 1998-03-03 | The Board Of Trustees Of The Leland Stanford Junior University | Cytotoxic T-cell lymphocyte ("CTL") activity regulation by class I MHC peptides |
US5888512A (en) * | 1987-01-30 | 1999-03-30 | Board Of Trustees Of The Leland Stanford Junior University | Lymphocyte activity regulation by HLA peptides |
US7011834B1 (en) | 1987-01-30 | 2006-03-14 | The Board Of Trustees Of Leland Stanford Junior University | Immunomodulating dimers |
US5639458A (en) * | 1987-03-20 | 1997-06-17 | Regents Of The University Of California | Class I MHC modulation of surface receptor activity |
SE8801426D0 (en) * | 1988-04-15 | 1988-04-15 | Ulf Rothman | METHOD AND METHOD OF BLOOD TREATMENT |
IL105503A (en) * | 1992-04-28 | 1999-05-09 | Astra Ab | Peptide-carbohydrate conjugates capable of generating t cell immunity |
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WO1989007448A1 (en) | 1989-08-24 |
AU4030989A (en) | 1989-09-06 |
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