Classifications

• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F02—COMBUSTION ENGINES; HOT-GAS OR COMBUSTION-PRODUCT ENGINE PLANTS
  • F02D—CONTROLLING COMBUSTION ENGINES
  • F02D11/00—Arrangements for, or adaptations to, non-automatic engine control initiation means, e.g. operator initiated
  • F02D11/06—Arrangements for, or adaptations to, non-automatic engine control initiation means, e.g. operator initiated characterised by non-mechanical control linkages, e.g. fluid control linkages or by control linkages with power drive or assistance
  • F02D11/10—Arrangements for, or adaptations to, non-automatic engine control initiation means, e.g. operator initiated characterised by non-mechanical control linkages, e.g. fluid control linkages or by control linkages with power drive or assistance of the electric type
  • F02D11/106—Detection of demand or actuation
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F02—COMBUSTION ENGINES; HOT-GAS OR COMBUSTION-PRODUCT ENGINE PLANTS
  • F02D—CONTROLLING COMBUSTION ENGINES
  • F02D11/00—Arrangements for, or adaptations to, non-automatic engine control initiation means, e.g. operator initiated
  • F02D11/06—Arrangements for, or adaptations to, non-automatic engine control initiation means, e.g. operator initiated characterised by non-mechanical control linkages, e.g. fluid control linkages or by control linkages with power drive or assistance
  • F02D11/10—Arrangements for, or adaptations to, non-automatic engine control initiation means, e.g. operator initiated characterised by non-mechanical control linkages, e.g. fluid control linkages or by control linkages with power drive or assistance of the electric type
  • F02D11/107—Safety-related aspects
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2319/00—Fusion polypeptide

Definitions

• the present invention relates to compositions and methods for affecting mammalian physiology, including morphogenesis or immune system function.
• it provides nucleic acids, proteins, and antibodies which regulate development and/or the immune system. Diagnostic and therapeutic uses of these materials are also disclosed.
• Recombinant DNA technology refers generally to techniques of integrating genetic information from a donor source into vectors for subsequent processing, such as through introduction into a host, whereby the transferred genetic information is copied and/or expressed in the new environment.
• the genetic information exists in the form of complementary DNA (cDNA) derived from messenger RNA (mRNA) coding for a desired protein product .
• cDNA complementary DNA
• mRNA messenger RNA
• the carrier is frequently a plasmid having the capacity to incorporate cDNA for later replication in a host and, in some cases, actually to control expression of the cDNA and thereby direct synthesis of the encoded product in the host .
• cDNA complementary DNA
• mRNA messenger RNA
• the carrier is frequently a plasmid having the capacity to incorporate cDNA for later replication in a host and, in some cases, actually to control expression of the cDNA and thereby direct synthesis of the encoded product in the host .
• the mammalian immune response is based on a series of complex
• Lymphokines apparently mediate cellular activities in a variety of ways. They have been shown to support the proliferation, growth, and/or differentiation of pluripotential hematopoietic stem cells into vast numbers of progenitors comprising diverse cellular lineages which make up a complex immune system. Proper and balanced interactions between the cellular components are necessary for a healthy immune response. The different cellular lineages often respond in a different manner when lymphokines are administered in conjunction with other agents .
• B-cells which can produce and secrete immunoglobulins (proteins with the capability of recognizing and binding to foreign matter to effect its removal)
• T-cells of various subsets that secrete lymphokines and induce or suppress the B-cells and various other cells (including other T- cells) making up the immune network.
• B-cells can produce and secrete immunoglobulins (proteins with the capability of recognizing and binding to foreign matter to effect its removal)
• T-cells of various subsets that secrete lymphokines and induce or suppress the B-cells and various other cells (including other T- cells) making up the immune network.
• mast cell which has not been positively identified in all mammalian species
• mast cell which is a granule-containing connective tissue cell located proximal to capillaries throughout the body. These cells are found in especially high concentrations in the lungs, skin, and gastrointestinal and genitourinary tracts.
• Mast cells play a central role in allergy-related disorders, particularly anaphylaxis as follows: when selected antigens crosslink one class of immunoglobulins bound to receptors on the mast cell surface, the mast cell degranulates and releases mediators, e.g., histamine, serotonin, heparin, and prostaglandins, which cause allergic reactions, e.g., anaphylaxis.
• the interleukin-1 family of proteins includes the IL-l ⁇ , the IL-l ⁇ , the IL-1RA, and recently the IL-l ⁇ (also designated Interferon-Gamma Inducing Factor, IGIF) .
• This related family of genes have been implicated in a broad range of biological functions. See Dinarello (1994) FASEB ⁇ 8:1314-1325; Dinarello (1991) Blood 77:1627-1652; and Okamura, et al. (1995) Nature 378:88-91.
• various growth and regulatory factors exist which modulate morphogenetic development.
• lymphokines soluble proteins and their receptors
• new therapies for a wide range of degenerative or abnormal conditions which directly or indirectly involve development, differentiation, or function, e.g., of the immune system and/or hematopoietic cells.
• novel receptors for lymphokine-like molecules which enhance or potentiate the beneficial activities of other lymphokines would be highly advantageous.
• the present invention provides new receptors for ligands exhibiting similarity to interleukin-1 like compositions and related compounds, and methods for their use.
• FIG. 1 shows a schematic comparison of the protein architectures of Drosophila, Caenorabditis, and human DTLRs, and their relationship to vertebrate IL-1 receptors and plant disease resistance proteins.
• Three Drosophila (Dm) DTLRs Toll, 18w, and the Mst ORF fragment) (Morisato and Anderson (1995) Ann. Rev. Genet. 29:371-399; Chiang and Beachy (1994) Mech. Develop. 47:225-239; Mitcham, et al. (1996) J. Biol. Chem. 271:5777-5783; and Eldon, et al. (1994) Develop.
• the loss of the internal Cys-rich region in DTLRs 1-5 largely accounts for their smaller ectodomains (558, 570, 690, and 652 aa, respectively) when compared to the 784 and 977 aa extensions of Toll and 18w.
• the incomplete chains of DmMst and HuDTLR5 (about 519 and 153 aa ectodomains, respectively) are represented by dashed lines.
• the intracellular signaling module common to DTLRs, IL-1-type receptors (IL-lRs), the intracellular protein Myd88, and the tobacco disease resistance gene N product (DRgN) is indicated below the membrane. See, e.g., Hardiman, et al.
• Additional domains include the trio of Ig-like modules in IL-lRs (disulfide-linked loops) ; the DRgN protein features an NTPase domain (box) and Myd88 has a death domain (black oval) .
• Figures 2A-2C show conserved structural patterns in the signaling domains of Toll- and IL-1-like cytokine receptors, and two divergent modular proteins.
• Figures 2A-2B show a sequence alignment of the common TH domain.
• DTLRs are labeled as in Figure 1; the human (Hu) or mouse (Mo) IL-1 family receptors (IL-1R1-6) are sequentially numbered as earlier proposed (Hardiman, et al. (1996) Oncogene 13:2467-2475); Myd88 and the sequences from tobacco (To) and flax, L. usitatissimum (Lu) , represent C- and N-terminal domains, respectively, of larger, multidomain molecules.
• the parallel ⁇ -sheet (with ⁇ -strands A-E as yellow triangles) is seen at its C- terminal end; ⁇ -helices (circles labeled 1-5) link the ⁇ - strands; chain connections are to the front (visible) or back (hidden) .
• conserveed, charged residues at the C-end of the ⁇ -sheet are noted in gray (Asp) or as a lone black (Arg) residue (see text) .
• Figure 3 shows evolution of a signaling domain superfa ily.
• the multiple TH module alignment of Figures 2A-2B was used to derive a phylogenetic tree by the Neighbor-Joining method (Thompson, et al. (1994) Nucleic Acids Res. 22:4673-4680) . Proteins labeled as in the alignment; the tree was rendered with TreeView.
• FIGS 4A-4D depict FISH chromosomal mapping of human DTLR genes.
• Denatured chromosomes from synchronous cultures of human lymphocytes were hybridized to biotinylated DT ⁇ .R cDNA probes for localization.
• the assignment of the FISH mapping data (left, Figures 4A, DTLR2; 4B, DTLR3; 4C, DTLR ; D, DTLR5) with chromosomal bands was achieved by superimposing FISH signals with DAPI banded chromosomes (center panels) .
• Analyses are summarized in the form of human chromosome ideograms (right panels) .
• Figures 5A-5F depict mRNA blot analyses of Human DTLRs.
• Human multiple tissue blots He, heart; Br, brain; PI, placenta; Lu, lung; Li, liver; Mu, muscle; Ki, kidney; Pn, Pancreas; Sp, spleen; Th, thymus; Pr, prostate; Te, testis; Ov, ovary, SI, small intestine; Co, colon; PBL, peripheral blood lymphocytes
• cancer cell line promyelocytic leukemia, HL60; cervical cancer, HELAS3; chronic myelogenous leukemia, K562; lymphoblastic leukemia, Molt4; colorectal adenocarcinoma, SW480; melanoma, G361; Burkitt ' s Lymphoma Raji, Burkitt's; colorectal adenocarcinoma, SW480; lung carcinoma, A549) containing approximately 2 ⁇ g of poly (A) +
• the present invention is directed to nine novel related mammalian receptors, e.g., primate, human, DNAX Toll receptor like molecular structures, designated DTLR2, DTLR3, DTLR4, DTLR5, DTLR7, DTLR8 , DTLR9, and DTLR10, and their biological activities. It includes nucleic acids coding for the polypeptides themselves and methods for their production and use. The nucleic acids of the invention are characterized, in part, by their homology to cloned complementary DNA (cDNA) sequences enclosed herein.
• cDNA cloned complementary DNA
• the invention provides a composition of matter selected from the group of: a substantially pure or recombinant DTLR2 protein or peptide exhibiting identity over a length of at least about 12 amino acids to SEQ ID NO: 4; a natural sequence DTLR2 of SEQ ID NO: 4; a fusion protein comprising DTLR2 sequence; a substantially pure or recombinant DTLR3 protein or peptide exhibiting identity over a length of at least about 12 amino acids to SEQ ID NO: 6; a natural sequence DTLR3 of SEQ ID NO: 6; a fusion protein comprising DTLR3 sequence; a substantially pure or recombinant DTLR4 protein or peptide exhibiting identity over a length of at least about 12 amino acids to SEQ ID NO: 26; a natural sequence DTLR4 of SEQ ID NO: 26; a fusion protein comprising DTLR4 sequence; a substantially pure or recombinant DTLR5 protein or peptide exhibiting identity over a length of at least about
• the composition of matter is DTLR2, which comprises a mature sequence of Table 2; or lacks a post-translational modification; is DTLR3, which comprises a mature sequence of Table 3; or ⁇ lacks a post-translational modification; is DTLR4, which: comprises a mature sequence of Table 4; or lacks a post- translational modification; is DTLR5, which: comprises the complete sequence of Table 5; or lacks a post- translational; is DTLR6, which comprises a mature sequence of Table 6; or lacks a post-translational modification; is DTLR7, which comprises a mature sequence of Table 7; or lacks a post-translational modification; is DTLR8, which: comprises a mature sequence of Table 8; or lacks a post
• DTLRIO further exhibits at least two non-overlapping epitopes which are specific for a primate DTLR2, DTLR3, DTLR4, DTLR5, DTLR6, DTLR7, DTLR8, DTLR9, or DTLRIO; exhibits identity over a length of at least about 20 amino acids to a rodent DTLR6; is glycosylated; has a molecular weight of at least 100 kD with natural glycosylation; is a synthetic polypeptide; is attached to a solid substrate; is conjugated to another chemical moiety; is a 5-fold or less substitution from natural sequence; or is a deletion or insertion variant from a natural sequence.
• compositions comprising: a sterile DTLR2 protein or peptide; or the DTLR2 protein or peptide and a carrier, wherein the carrier is: an aqueous compound, including water, saline, and/or buffer; and/or formulated for oral, rectal, nasal, topical, or parenteral administration; a sterile DTLR3 protein or peptide; or the DTLR3 protein or peptide and a carrier, wherein the carrier is: an aqueous compound, , including water, saline, and/or buffer; and/or formulated for oral, rectal, nasal, topical, or parenteral administration; a sterile DTLR4 protein or peptide; or the DTLR4 protein or peptide and a carrier, wherein the carrier is: an '' aqueous compound, including water, saline, and/or buffer; and/or formulated for oral, rectal, nasal, topical, or parenteral administration; a
• kit embodiments include a kit comprising a DTLR protein or polypeptide, and: a compartment comprising the protein or polypeptide; and/or instructions for use or disposal of reagents in the kit.
• Binding compound embodiments include those comprising an antigen binding site from an antibody, which specifically binds to a natural DTLR2, DTLR3, DTLR4 , DTLR5, DTLR6, DTLR7 , DTLR8 , DTLR9, or DTLRIO protein, wherein: the protein is a primate protein; the binding compound is an Fv, Fab, or Fab2 fragment; the binding compound is conjugated to another chemical moiety; or the antibody: is raised against a peptide sequence of a mature polypeptide of Table 2, 3, 4, 5, 6, 7, 8, 9, or 10; is raised against a mature DTLR2, DTLR3, DTLR4 , DTLR5, DTLR6, DTLR7, DTLR8, DTLR9, or DTLRIO; is raised to a purified human DTLR2, DTLR3, DTLR , DTLR5, DTLR6, DTLR7 , DTLR8, DTLR9, or DTLRIO; is i munoselected; is
• Methods are provided, e.g., of making an antibody, comprising immunizing an immune system with an immunogenic amount of a primate DTLR2, DTLR3, DTLR4, DTLR5, DTLR6, DTLR7, DTLR8, DTLR9, or DTLRIO, thereby causing said antibody to be produced; or producing an antigen: antibody complex, comprising contacting such an antibody with a mammalian DTLR2, DTLR3, DTLR4 , DTLR5, DTLR6, DTLR7, DTLR8 , DTLR9, or DTLRIO protein or peptide, thereby allowing said complex to form.
• compositions include a composition comprising: a sterile binding compound, or the binding compound and a carrier, wherein the carrier is: an aqueous compound, including water, saline, and/or buffer; and/or formulated for oral, rectal, nasal, topical, or parenteral administration.
• Nucleic acid embodiments include an isolated or recombinant nucleic acid encoding a DTLR2-10 protein or peptide or fusion protein, wherein: the DTLR is from a mammal; or the nucleic acid: encodes an antigenic peptide sequence of Table 2, 3, 4, 5, 6, 7, 8, 9, or 10; encodes a plurality of antigenic peptide sequences of Table 2, 3, 4, 5, 6, 7, 8, 9, or 10; comprises at least 17 contiguous nucleotides from Table 2, 3, 4, 5, 6, 7, 8, 9, or 10; exhibits at least about 80% identity to a natural cDNA encoding said segment; is an expression vector; further comprises an origin of replication; is from a natural source; comprises a detectable label; comprises synthetic nucleotide sequence; is less than 6 kb, preferably less than 3 kb; is from a mammal, including a primate; comprises a natural full length coding sequence; is a hybridization probe for a gene encoding said DTLR; or is a
• a cell, tissue, or organ comprising such a recombinant nucleic acid is also provided.
• the cell is: a prokaryotic cell; a eukaryotic cell; a bacterial cell; a yeast cell; an insect cell; a mammalian cell; a mouse cell; a primate cell; or a human cell.
• Kits are provided comprising such nucleic acids, and: a compartment comprising said nucleic acid; a compartment further comprising a primate DTLR2, DTLR3, DTLR4, or DTLR5 protein or polypeptide; and/or instructions for use or disposal of reagents in the kit.
• the kit is capable of making a qualitative or quantitative analysis.
• nucleic acid which: hybridizes under wash conditions of 30° C and less than 2M salt to SEQ ID NO: 3; hybridizes under wash conditions of 30° C and less than 2 M salt to SEQ ID NO: 5; hybridizes under wash conditions of 30° C and less than 2M salt to SEQ ID NO: 7; hybridizes under wash conditions of 30° C and less than 2 M salt to SEQ ID NO: 9; hybridizes under wash conditions of 30° C and less than 2 M salt to SEQ ID NO: 11, 13, 27, or 29; hybridizes under wash conditions of 30° C and less than 2 M salt to SEQ ID NO: 15, 17, or 36; hybridizes under wash conditions of 30° C and less than 2 M salt to SEQ ID NO: 19, 31, or 38; hybridizes under wash conditions of 30° C and less than 2 M salt to SEQ ID NO: 21 or 40; hybridizes under wash conditions of 30° C and less than 2 M salt to SEQ ID NO: 23, 33, 42, or 44; exhibits at least about 85% identity over
• such nucleic acid will have such properties, wherein: wash conditions are at 45° C and/or 500 mM salt; or the identity is at least 90% and/or the stretch is at least 55 nucleotides. More preferably, the wash conditions are at 55° C and/or 150 M salt; or the identity is at least 95% and/or the stretch is at least 75 nucleotides.
• Also provided are methods of producing a ⁇ ligand: receptor complex comprising contacting a substantially pure primate DTLR2, DTLR3, DTLR4 , DTLR5, . DTLR6, DTLR7, DTLR8, DTLR9, or DTLRIO, including a recombinant or synthetically produced protein, with candidate Toll ligand; thereby allowing said complex to form.
• the invention also provides a method of modulating physiology or development of a cell or tissue culture cells comprising contacting the cell with an agonist or antagonist of a " mammalian DTLR2, DTLR3, DTLR4, DTLR5, DTLR6, DTLR7, DTLR8 , DTLR9, or DTLRIO.
• the cell is a pDC2 cell with the agonist or antagonist of DTLRIO.
• the present invention provides the amino acid sequence and DNA sequence of mammalian, herein primate DNAX Toll like receptor molecules (DTLR) having particular defined properties, both structural and biological. These have been designated herein as DTLR2, DTLR3, DTLR4, DTLR5, DTLR6, DTLR7, DTLR8 , DTLR9, and DTLRIO, respectively, and increase the number of members of the human Toll like receptor family from 1 to 10.
• Various cDNAs encoding these molecules were obtained from primate, e.g., human, cDNA sequence libraries. Other primate or other mammalian counterparts would also be desired.
• a complete nucleotide (SEQ ID NO: 3) and corresponding amino acid sequence (SEQ ID NO: 4) of a human DTLR2 coding segment is shown in Table 2.
• a complete nucleotide (SEQ ID NO: 5) and corresponding amino acid sequence (SEQ ID NO: 6) of a human DTLR3 coding segment is shown in Table 3.
• a complete nucleotide (SEQ ID NO: 7) and corresponding amino acid sequence (SEQ ID NO: 8) of a human DTLR4 coding segment is shown in Table 4; see also SEQ ID NO: 25 and 26.
• a partial nucleotide (SEQ ID NO: 9) and corresponding amino acid sequence (SEQ ID NO: 10) of a human DTLR5 coding segment is shown in Table 5.
• a complete nucleotide (SEQ ID NO: 11) and corresponding amino acid sequence (SEQ ID NO: 12) of a human DTLR6 coding segment is shown in Table 6, along with partial sequence of a mouse DTLR6 (SEQ ID NO: 13, 14, 27, 28, 29, and 30).
• Partial nucleotide (SEQ ID NO: 15 and 17) and corresponding amino acid sequence (SEQ ID NO: 16 and 18) of a human DTLR7 coding segment is shown in Table 7; full length sequence is provided in SEQ ID NO: 36 and 37.
• Partial nucleotide (SEQ ID NO: 19) and corresponding amino acid sequence (SEQ ID NO: 20) of a human DTLR8 coding segment is shown in Table 8, with supplementary sequence (SEQ ' ID NO: 31, 32, 38, and 39).
• Partial nucleotide (SEQ ID NO: 21) and corresponding amino acid sequence (SEQ ID NO: 22) of a human DTLR9 coding segment is shown in Table 9; see also SEQ ID NO: 40 and 41.
• Partial nucleotide (SEQ ID NO: 23) and corresponding amino acid sequence (SEQ ID NO: 24) of a human DTLRIO coding segment is shown in Table 10, along with supplementary sequence (SEQ ID NO: 33, 34, 42, and 43) and rodent, e.g., mouse, sequence (SEQ ID NO: 35, 44, and 45) .
• Table 1 Nucleotide and amino acid sequences (see SEQ ID NO: 1 and 2) of a primate, e.g., human, DNAX Toll like receptor 1 (DTLR1) .
• a primate e.g., human, DNAX Toll like receptor 1 (DTLR1) .
• Table 4 Nucleotide and amino acid sequences (see SEQ ID NO: 7 and 8) of a mammalian, e.g., primate, human, DNAX Toll like Receptor 4 (DTLR4).
• GGT TTC CAT AAA AGC CGA AAG GTG ATT GTT GTG GTG TCC CAG CAC TTC 2323
• Table 5 Partial nucleotide and amino acid sequences (see SEQ ID NO: 9 and 10) of a mammalian, e.g., primate, human, DNAX Toll like Receptor 5 (DTLR5) .
• TCT CAC AAT GAT TTA CCT GCT AAT TTA GAG ATC CTG GAC ATA TCC AGG 192
• AGT AAA AAT AGT ATA TTT TTT GTC AAG TCC TCT GAT TTT ' CAG CAT CTT 1536
• AAG TCC AAG TTC CTC CAG CTC CGG AAA AGG CTC TGT GGG AGT TCT GTC 3024 Lys Ser Lys Phe Leu Gin Leu Arg Lys Arg Leu Cys Gly Ser Ser Val 975 980 985
• rodent e.g., mouse sequences: upstream (SEQ ID NO: 27 and 28); nucleotides 186, 196, 217, 276, and 300 designated C, each may be A, C, G, or T:
• nucleotide 1643 designated A may be A or G
• nucleotide 1664 designated C may be A, C, G, or T
• nucleotides 1680 and 1735 designated G may be G or T
• nucle'otide 1719 designated C may be C or T
• nucleotide 1727 designated A may be A, G, or T: TCT CCA GAA ATT CCC TGG AAT TCC TTG CCT CCT GAG GTT TTT GAG GGT 48 Ser Pro Glu He Pro Trp Asn Ser Leu Pro Pro Glu Val Phe Glu Gly 1 5 10 15
• GAATTTTTCC TAACAGTTGT CATGGCTCAG ATTGGTGGGA AATCATCAAT ATATGGCTAA 1322
• Table 7 Nucleotide and amino acid sequences of a mammalian, e.g., primate, human, DNAX Toll like Receptor 7 (DTLR7) . upstream (SEQ ID NO: 15 and 16):
• Trp Asp Pro Gly Leu Ala He He Asp Asn Leu Met Gin Ser He Asn 900 905 910 caa age aag aaa aca gta ttt gtt tta ace aaa aaa tat gca aaa age 2832
• Table 8 Partial nucleotide and amino acid sequences (see SEQ ID NO: 19 and 20) of a mammalian, e.g., primate, human, DNAX Toll like Receptor 8 (DTLR8) .
• DTLR8 DNAX Toll like Receptor 8
• nucleotides 4 and 23 designated C may be A, C, G, or T; nucleotide 845 designated C, may be C or T: C TCC GAT GCC AAG ATT CGG CAC CAG GCA TAT TCA GAG GTC ATG ATG 46
• DTLR8 (SEQ ID NO: 38 and 39): gaatcatcca cgcacctgca gctctgctga gagagtgcaa gccgtggggg ttttgagctc 60 atcttcatca ttcatatgag gaaataagtg gtaaatcct tggaaataca atg aga 116

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