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T cell regulatory genes and methods of use thereof

Title: T cell regulatory genes and methods of use thereof.
Abstract: A genetic locus and corresponding family of proteins associated with regulation of immune function and cell survival are provided. These genes encode cell surface molecules with conserved IgV and mucin domains. The locus comprising the TIM family is genetically associated with immune dysfunction, including asthma. Furthermore, the TIM gene family is located within a region of human chromosome 5 that is commonly deleted in malignancies and myelodysplastic syndrome. Polymorphisms in the gene sequences are associated with the development of airway hyperreactivity and allergic inflammation, and T cell production of IL-4 and IL-13. The proteins include the human hepatitis A cellular receptor, hHAVcr-1. ...
USPTO Applicaton #: #20090252737
Inventors: Jennifer Jones Mcintire, Rosemarie Dekruyee, Dale T. Limetsu, Gordon J. Freeman, Vliay Klichroo

The Patent Description & Claims data below is from USPTO Patent Application 20090252737, T cell regulatory genes and methods of use thereof.


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The astonishing complexity of the immune system is its greatest strength. The 1012-1014 possible antibody specificities, the delicate interplay between the various regulatory and effector cells, the restriction of T cell responses according to MHC antigens; all these contribute to the ability of the host to effectively react against infectious agents and other antigens perceived as foreign. But this diversity has its drawbacks. Mistakes happen: the target of a response may turn out to be a normal self protein; inflammatory responses are misregulated; and normal responses are undesirably directed against grafts and transplanted cells. Under these circumstances, the complexity of the system makes diagnosis and therapy extremely difficult.

The profile of cytokines produced by CD4+ T cells during an immune response determines the nature of effector functions which develop and regulates the outcome of an immune response. Production of IL-2 and IFN-γ during Th1-dominated responses is associated with vigorous cell-mediated immunity, the induction of IgG2a and inhibition of IgE synthesis, and with resistance to intracellular pathogens. In contrast, the production of IL-4, IL-5 and IL-10 during Th2-dominated responses is associated with humoral immunity and protection from autoimmune pathology. Overproduction of Th2-cytokines by allergen-specific CD4+ T cells can result in the development of allergic disease and asthma, while Th1 cells have been associated with a variety of pro-inflammatory diseases.

One approach to immune associated diseases is immunotherapy. Immunotherapy has proven to be effective when used properly, and it is hoped that advances in immunologic intervention will further improve the efficacy. Alternative approaches have attempted to use cytokines to shift the immune response. IL-12, a heterodimeric cytokine produced by macrophages and dendritic cells, is potent in driving the development of Th1 cytokine synthesis in naive and memory CD4+ T cells. Other cytokines, such as IL-13 and IL-4, have been associated with the differentiation of T cells to a Th2 type.

Atopy, which includes asthma, allergic rhinitis, and atopic dermatitis, is a complex trait that arises as a result of environmentally induced immune responses in genetically susceptible individuals. The prevalence of all atopic diseases has dramatically increased in industrialized countries over the past two decades. Asthma is the most common chronic disease of childhood and affects more than 15 million individuals in the United States, leading to direct treatment costs exceeding $11 billion per annum. Epidemiological studies have suggested that the increase in asthma prevalence results from changes in hygiene and from reduced frequency of infections (e.g., tuberculosis or hepatitis A) within industrialized society. However, the specific molecular pathways that result in the increased asthma prevalence, and the genetic polymorphisms that confer asthma susceptibility are poorly understood.

Expression of asthma is influenced by multiple environmental and genetic factors that interact with each other in non-additive ways, complicating the identification of asthma susceptibility genes. Asthma susceptibility has been linked to several chromosomal regions, but with resolution no better than 5-10 cM, in which there are usually hundreds of candidate genes. Moreover, because the effects of genetic variation in any single gene are likely to have only modest effects in the overall pathogenesis of asthma, and because gene-gene and gene-environment interactions confound the analysis, the location of putative susceptibility genes to regions amenable to positional cloning has proven difficult to refine. Nevertheless, asthma susceptibility has been linked to chromosomes 5, 6, 11, 14, and 12. Of these, chromosome 5q23-35 has received the greatest attention because it contains a large number of candidate genes (11, 12, 13, 14, 15, 16, 17, 18), including IL-9, IL-12p40, the β-adrenergic receptor, and the IL4 cytokine cluster, which contains the genes for IL-4, IL-5, and IL-13. However, the large size of the linked region of 5q complicates its analysis, and a gene for asthma from this site has not yet been conclusively identified.

Related Publications

The genetic sequence of the human hepatitis virus A cellular receptor may be found in Genbank, accession number XM—011327. A related sequence is provided in Genbank, accession number BAB55044. Monney et al. (2002) Nature 415:436 describe cell surface molecules expressed on Th1 cells. U.S. Pat. No. 5,721,351, U.S. Pat. No. 6,204,371, U.S. Pat. No. 6,288,218 relate to sequences corresponding to a mouse TIM-3 allele.


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Genetic sequences of a gene family encoding polypeptides associated with immune function and cell survival are provided. These genes encode cell surface molecules with conserved IgV and mucin domains, herein referred to as T cell Immunoglobulin domain and Mucin domain (TIM) proteins. The locus comprising the TIM family is genetically associated with immune dysfunction, including asthma. Furthermore, the TIM gene family is located within a region of human chromosome 5 that is commonly deleted in malignancies and myelodysplastic syndrome. Polymorphisms are identified in TIM-1, TIM-3 and TIM-4, which can be associated with Th1/Th2 differentiation and airway hyperresponsiveness (AHR).

The nucleic acid compositions are used to produce the encoded proteins, which may be employed for functional studies, as a therapeutic, and in studying associated physiological pathways. TIM specific binding agents, including nucleic acids, antibodies, and the like, are useful as diagnostics for determining genetic susceptibility to atopy and asthma and as diagnostics for assessing tumor resistance to cancer therapy. TIM blocking agents find use as therapeutics in the treatment of immune dysfunction and disorders of cell survival, including malignancies.


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FIG. 1a, HBA mice produce significantly less IL-4 than do BALB/c mice. Lymph node cells of mice immunized with 150 μg of KLH were harvested, B-cell depleted, and cultured in cDME with 10 μg/ml KLH. Supernatants were harvested after 96 hours and assessed for IL-4 levels by ELISA. Shown is a box plot of IL-4 levels (n=10 in each group), representing the full range of data, with the boxes encompassing the upper and lower quartiles, with the median of the data set shown inside each box. IL-4 levels produced by BALB/c cells and by (BALB/c×HBA) F1 cells are significantly higher than HBA IL-4 levels P<0.0001 (student's t-test). b, HBA mice produce significantly less IL-13 and IL-10 than do BALB/c mice. Data shown are the average values of cytokines produced by lymph node cell cultures from ten individual mice in each experimental group, ±S.D. HBA IL-13 and IL-10 levels were lower than either the BALB/c or (BALB/c×HBA) F1 values, P<0.0001. HBA IL-5 versus BALB/c, P<0.05. HBA IFN-γ versus BALB/c, P<0.001. c, Allergen-induced airway hyperreactivity is significantly greater in BALB/c than do HBA mice. Pulmonary airflow obstruction was measured, and data shown represent peak enhanced pause (Penh) values averaged among sensitized mice in each group at various methacholine concentrations, +S.E.M. (BALB×HBA) F1 demonstrate BALB/c phenotypes, while (BALB×DBA) F1 mice demonstrate DBA/2-like phenotypes.

FIG. 2. Regions of HBA chromosome 11 were inherited from DBA/2. HBA chromosome 11 contains two regions derived from DBA between hba-α2 and es-3, as delineated by SSLP markers. The regions of HBA chromosome 11 with DBA/2 genotypes are highlighted (in blue) in the diagram to the left. The markers (left) provide 2-5 cM resolution distal to D11Mit230. Where the mouse chromosome 11 has regions of highly conserved synteny with 5q23-35, additional markers were identified with informative polymorphisms between BALB/c and DBA/2, to provide 0.01-2 cM resolution in this region (right column markers). Single-stranded confirmation polymorphisms (SSCP) markers are shown in green to distinguish them from the SSLP markers, and the positions of particular genes of interest, denoted in red, are also shown. Where the arrangement of our marker map differs from the Chromosome Committee Reports and the MIT linkage map, our map concurs with previous linkage and physical maps.

FIG. 3a. IL-4 production by N2 mice is bimodal, with peaks corresponding to F1 and HBA phenotypes. As a means of evaluating the relative phenotypes of recombinant N2 mice in multiple experiments, we utilized an indexing function that allowed us to consolidate data from multiple experiments. A histogram shows a bimodal distribution of IL-4 index values for N2 mice with (BALB×HBA) F1, HBA homozygous, and recombinant haplotypes indicated. Distributions associated with the F1 and HBA haplotypes are distinct (P<0.0001, paired Student's t-test)-b. IL-4 regulation segregates with Kim1sscp. Recombinant N2 haplotypes were sorted by IL-4 index values into groups associated with high IL-4 phenotypes (index<0.35) and low IL-4 phenotypes (index>0.65). Each column of boxes represents a recombinant haplotype. Alleles for these haplotypes at loci between D11Mit269 to D11Mit154 are shaded according to genotype (dark=F1; pale ═HBA). High IL-4 production segregates with four haplotypes (left), and low IL-4 production segregates with four haplotypes (right). The IL4 phenotype is linked to Kim1sscp. c. AHR of N2 mice is bimodal, with peaks corresponding to F1 and HBA phenotypes. Index values calculated from Penh values are shown. The histogram shows a bimodal distribution of AHR index values for N2 mice. (BALB×HBA) F1, HBA homozygous, and recombinant haplotypes are indicated. Distributions associated with the F1 and HBA haplotypes are distinct (P<0.0001, paired student's t-test). d. AHR Regulatory Locus cosegregates with the IL-4 Regulatory Locus between D11Mit22 and D11Mit271. Recombinant N2 haplotypes were sorted by AHR index values into groups associated with high AHR phenotypes (index<0.35) and low AHR phenotypes (index>0.65). Each column of boxes represents a recombinant haplotype. Alleles for these haplotypes at loci between D11Mit269 to D11Mit154 are shaded according to genotype (dark=F1; pale=HBA). High AHR segregates with four haplotypes (left), and low IL-4 production segregates with three haplotypes (right). The AHR regulatory locus is linked to Kim1sscp, between D11Mit271 and D11Mit22.

FIG. 4 Mouse chromosome 11 interval containing Tapr is highly homologous to 5q33. In order to construct a composite map around the Tapr locus, we integrated available information from the mouse linkage, backcross, and radiation hybrid maps and identified a region of highly conserved synteny in current maps of the human genome (Human Genome Browser v3, UCSC, March 2001). ESTs located on a physical map of mouse chromosome 11 (left) are denoted by their accession numbers and aligned by homology to genes (center), which correspond to ESTs on human chromosome 5 (right). All known genes between KIAA0171 and Sgd are shown.

FIG. 5a,b,c. Identification novel TIM gene family and major polymorphisms in TIM-1 and TIM-3. Cloning of mouse TIM-1 and mouse TIM-2. Members of a gene family. Sequences of the mouse TIM gene family members are shown. Shaded boxes illustrate identity between two of the mouse TIM genes. Total RNA from conA-stimulated splenocytes was reverse transcribed using Gibco Superscript II. PCR products of full length Tim-3 cDNA were amplified, purified with Qiagen QIAquick PCR Purification reagents, and sequenced directly by Biotech Core (Mountain View, Calif.). PCR products for Tim-1 and Tim-2 cDNA were cloned into electrocompetent TOP10 cells with TOPO-XL cloning reagents (Invitrogen). Plasmids were purified with a standard alkaline lysis protocol. BALB/c and HBA plasmids were sequenced, as described. Homology of mouse TIM-1, rat KIM-1, and HAVcr-1. Identity with mouse TIM-1 is denoted by the shaded boxes. The approximate signal site is denoted by an open, inverted triangle and the Ig domain/mucin domain boundary is shown with a filled diamond. The predicted transmembrane domains are underlined. TIM-1 and TIM-3 sequences with major polymorphisms between BALB/c and HBA TIM-1 and TIM-3 shown.

FIG. 6. Tapr Regulates CD4 T cell IL-4 and IL-13 Responses. T cells from BALB/c DO11.10 mice produce higher levels of IL-4 and IL-13 in response to antigen than do T cells from HBA DO11.10 mice. Splenic CD4+ cells were isolated by positive selection with anti-CD4 magnetic beads and then cocultured with bone marrow-derived DCs and OVA. After seven days, the cells were restimulated. Supernatants were harvested after 18-24 hours of the secondary culture. Data represent mean cytokine levels detected at increasing concentrations of OVA, ±S.D. Detection of expression of TIM-1 mRNA in purified CD 4 T cells during priming and differentiation.

FIG. 7. Sequence alignment of Human and Mouse TIM protein sequences.

FIG. 8. Polymorphisms in human TIM-1

FIG. 9. SSCP polymorphism analysis of human TIM-1.


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Genetic sequences associated with immune function, including susceptibility to asthma, are provided. The sequences of murine Tim-1, Tim-2, Tim-3, and Tim-4, and the human counterpart sequences, are provided herein. The sequence of major polymorphisms are also provided. Genomic sequences demonstrate that these polymorphisms, including a deletion, are true polymorphisms, not splicing variants. Variants of the TIM-1 and TIM-3 sequences are associated with susceptibility to airway hyperreactivity and allergic T cell responses, and other variants associated with protection against these responses.

The extracellular domain of TIM gene family members contains two domains, an IgV domain and a mucin domain. This Ig/mucin structure is also found in MAdCAM (mucosal addressin cell adhesion molecule), which contains two Ig domains and a mucin domain; however, there is only a low level of homology between TIMs and MAdCAM. A similar degree of homology is also present between TIM-1 and TOSO (NP—005440.1 GI:4885641), a protein which, like TIM-1 is expressed on activated T cells, and which protects T cells from Fas-mediated apoptosis.

T cells express the TIM family of genes, which critically regulates CD4 T cell differentiation. Th1 cells preferentially express the TIM-3 protein, while Th2 cells preferentially express the TIM-1 protein. TIM-1 has been linked to airway hyperreactivity and TIM-3 to autoimmune disease, therefore the expression pattern on differentiating lymphoid cells and the kinetics of expression of TIM-1 on lymphoid cells reflect the function of these molecules.

In another aspect of the invention, methods are provided for determining susceptibility of an individual to developing asthma and atopic diseases, by determining the genotype at the Tim locus. Screening may analyze, for example, polymorphisms in any one of the TIM-1, TIM-3 or TIM-4 alleles provided herein, or otherwise determined. Methods are provided for screening such polymorphisms, e.g. SSCP analysis, size polymorphisms, and the like.

In another aspect of the invention, a method of screening for biologically active agents that modulate Tim gene or polypeptide function is provided, where the method comprises combining a candidate biologically active agent with any one of: (a) a Tim polypeptide; (b) a cell comprising a nucleic acid encoding a Tim polypeptide; or (c) a non-human transgenic animal model for Tim gene function comprising one of: (i) a knockout of an Tim gene; (ii) an exogenous and stably transmitted Tim gene sequence; or (iii) a Tim promoter sequence operably linked to a reporter gene; and determining the effect of said agent on Tim function.

The activity of TIM polypeptides may be modulated in order to direct immune function. TIM-1 is preferentially expressed in Th2 cells, and agents that modulate TIM-1 activity find use in the treatment of Th2 related disorders, including allergies, asthma, and the like. TIM-3 is preferentially expressed in Th1 cells, and agents that modulate TIM-3 activity find use in the treatment of pro-inflammatory immune diseases, including autoimmune diseases, graft rejection and the like.

Conditions of Interest

Atopic diseases are complex genetic traits that develop as a result of environmentally induced immune responses in genetically predisposed individuals. Both atopic and non-atopic individuals are exposed to the same environmental factors, but genetic differences that distinguish atopic from non-atopic individuals result in atopic disease in some individuals, manifested by allergic inflammation in the respiratory tract, skin or gastrointestinal tract, as well as by elevated serum IgE, eosinophilia and the symptoms of wheezing, sneezing or hives. In addition, allergic inflammatory responses are characterized by the presence of Th2 lymphocytes producing high levels of IL-4, IL-5, IL-9 and IL-13, which enhance the growth, differentiation and/or recruitment of eosinophils, mast cells, basophils and B cells producing IgE.

Allergens of interest include antigens found in food, such as strawberries, peanuts, milk proteins, egg whites, etc. Other allergens of interest include various airborne antigens, such as grass pollens, animal danders, house mite feces, etc. Molecularly cloned allergens include Dermatophagoides pteryonyssinus (Der P1); Lol pl-V from rye grass pollen; a number of insect venoms, including venom from jumper ant Myrmecia pilosula; Apis mellifera bee venom phospholipase A2 (PLA2 and antigen 5S; phospholipases from the yellow jacket Vespula maculifrons and white faced hornet Dolichovespula maculata; a large number of pollen proteins, including birch pollen, ragweed pollen, Parol (the major allergen of Parietaria officinalis) and the cross-reactive allergen Parjl (from Parietaria judaica), and other atmospheric pollens including Olea europaea, Artemisia sp., gramineae, etc. Other allergens of interest are those responsible for allergic dermatitis caused by blood sucking arthropods, e.g. Diptera, including mosquitos (Anopheles sp., Aedes sp., Culiseta sp., Culex sp.); flies (Phlebotomus sp., Culicoides sp.) particularly black flies, deer flies and biting midges; ticks (Dermacenter sp., Ornithodoros sp., Otobius sp.); fleas, e.g. the order Siphonaptera, including the genera Xenopsylla, Pulex and Ctenocephalides felis felis. The specific allergen may be a polysaccharide, fatty acid moiety, protein, etc.

Polymorphisms in a number of interacting/epistatic atopy genes are thought to result in enhanced susceptibility to allergic disorders. Genome wide scans have sought to identify the responsible genes by linking various parameters of allergy and asthma with polymorphic DNA markers of specific genes, usually repeat sequences of DNA (microsatellites that contain di- tri- and tetra-nucleotide repeats). These studies have identified several chromosomal regions as likely to be involved in the pathogenesis of atopy, but with resolution no better than 5-10 cM in which there are typically hundreds of candidate genes. Nevertheless, asthma susceptibility has been linked to chromosomes 5q23-31, chromosome 6p21, chromosome 11q13, and chromosome 12q (9-13) by two or more of these genome wide scanning studies.

Asthma, as defined herein, is reversible airflow limitation in an individual over a period of time. Asthma is characterized by the presence of cells such as eosinophils, mast cells, basophils, and CD25+ T lymphocytes in the airway walls. There is a close interaction between these cells, because of the activity of cytokines which have a variety of communication and biological effector properties. Chemokines attract cells to the site of inflammation and cytokines activate them, resulting in inflammation and damage to the mucosa. With chronicity of the process, secondary changes occur, such as thickening of basement membranes and fibrosis. The disease is characterized by increased airway hyperresponsiveness to a variety of stimuli, and airway inflammation. A patient diagnosed as asthmatic will generally have multiple indications over time, including wheezing, asthmatic attacks, and a positive response to methacholine challenge, i.e., a PC20 on methacholine challenge of less than about 4 mg/ml. Guidelines for diagnosis may be found, for example, in the National Asthma Education Program Expert Panel Guidelines for Diagnosis and Management of Asthma, National Institutes of Health, 1991, Pub. No. 91-3042.

Asthma, allergic rhinitis (hay fever), atopic dermatitis (eczema) and food allergy are diseases that occur in the same families, implying common genetic mechanisms. These atopic diseases are exceedingly prevalent, affecting 20-40% of the general population and constitute a major public health problem. The economic costs for these disorders are enormous. For asthma alone, the estimated health care costs in 1996 were $14 billion. In addition, the prevalence of all of the atopic diseases has increased dramatically in industrialized countries over the past two decades for reasons that are not yet clear. The prevalence of asthma in industrialized countries, for which the numbers are the most accurate, has doubled since 1982, and is projected to double again in prevalence by the year 2020.

Pro-inflammatory diseases associated with Th1 type T cells include autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, type I diabetes mellitus, etc. (RA) is a chronic autoimmune inflammatory synovitis affecting 0.8% of the world population. Current therapy for RA utilizes therapeutic agents that non-specifically suppress or modulate immune function. Such therapeutics, including the recently developed TNFα antagonists, are not fundamentally curative, and disease activity rapidly returns following discontinuation of therapy. Tremendous clinical need exists for fundamentally curative therapies that do not cause systemic immune suppression or modulation.

A quantitative increase in myelin-autoreactive T cells with the capacity to secrete IFN-gamma is associated with the pathogenesis of MS and EAE, suggesting that autoimmune inducer/helper T lymphocytes in the peripheral blood of MS patients may initiate and/or regulate the demyelination process in patients with MS. The overt disease is associated with muscle weakness, loss of abdominal reflexes, visual defects and paresthesias. During the presymptomatic period there is infiltration of leukocytes into the cerebrospinal fluid, inflammation and demyelination.

IDDM is a cell-mediated autoimmune disorder leading to destruction of insulin-secreting beta cells and overt hyperglycemia. T lymphocytes invade the islets of Langerhans, and specifically destroy insulin-producing β-cells. The depletion of p cells results in an inability to regulate levels of glucose in the blood. The disease progression may be monitored in individuals diagnosed by family history and genetic analysis as being susceptible. The most important genetic effect is seen with genes of the major histocompatibility locus (IDDM1), although other loci, including the insulin gene region (IDDM2) also show linkage to the disease (see Davies et al., supra and Kennedy et al., (1995) Nature Genetics 9:293-298).

TIM Gene Family

The provided TIM family genes and fragments thereof, encoded proteins, genomic regulatory regions, and specific antibodies are useful in the identification of individuals predisposed to development or resistance to asthma, and for the modulation of gene activity in vivo for prophylactic and therapeutic purposes. The encoded proteins are useful as an immunogen to raise specific antibodies, in drug screening for compositions that mimic or modulate activity or expression, including altered forms of the proteins, and as a therapeutic.

The TIM family genes are immediately adjacent to each other on human chromosome 5, in the order TIM-4, TIM-1, TIM-3, with no intervening genes. This segment of human chromosome 5 is commonly deleted in malignancies and dysplastic cell populations, as in myeolodysplastic syndrome (see Boultwood, et al, (1997) Genomics 45:88-96). There are TIM pseudogenes on chromosomes 5, 12, and 19. Each TIM protein, except TIM-4, contains a distinct predicted tyrosine signaling motif. The cytoplasmic region of TIM-1 contains two tyrosine residues and includes a highly conserved tyrosine kinase phosphorylation motif, RAEDNIY. The expanded region, SRAEDNIYIVEDRP, contains a predicted site for Itk phosphorylation and for EGF-receptor phosphorylation.

The mouse Tim1 gene encodes a 305 amino acid membrane protein. The cytoplasmic region of TIM-1 contains two tyrosine residues and includes a highly conserved tyrosine kinase phosphorylation motif, RAEDNIY. The mucin domain of TIM-1 has multiple sites for O-linked glycosylation, and there two sites for N-linked glycosylation found in the immunoglobulin domain.

Mouse TIM-2, a similar 305 amino acid membrane protein, has 64% identity to mouse TIM-1, 60% identity to rat KIM-1, and 32% identity to hHAVcr-1. Like TIM-1, TIM-2 has two extracellular N-linked glycosylation sites and a serine, threonine-rich mucin domain with many O-linked glycosylation sites. TIM-2 also has an intracellular tyrosine kinase phosphorylation motif, RTRCEDQVY.

Tim3 encodes a 281 amino acid membrane protein in mice, and a 301 amino acid protein in humans, that has a similar, integral membrane glycoprotein structure with multiple extracellular glycosylation sites and an intracellular tyrosine phosphorylation motif. Although the mucin domain is not as prominent in TIM-3 as it is in TIM-1 and TIM-2, TIM-3 expressed on T cells interacts with a ligand on APCs and alters APC activation. TIM-3 has four sites for N-linked and five sites for O-linked glycosylation, suggesting that TIM-3, like TIM-1 and TIM-2, is heavily glycosylated and might interact with a ligand present on other cells, such as antigen presenting cells.

Tim4 encodes a 344 amino acid protein in mice, and a 378 amino acid protein in humans. The predicted TIM-4 also shares the general membrane glycoprotein structural motifs of the other TIM proteins, a with an IgV-like domain with highly conserved cysteine residues, a threonine-rich mucin-like domain, and a short intracellular tail.

Polymorphisms in the murine sequences are provided in the sequence listing for the BALB/c and HBA/DBA strains. In TIM-1, these polymorphisms encode three amino acid differences and a fifteen amino acid deletion in HBA/DBA. Seven predicted amino acid differences were identified in TIM-3. The polymorphisms in TIM-1 and TIM-4 are located in the signal and mucin-like domains, while the polymorphisms identified in TIM-3 are clustered in the Ig domain.

Variants in coding regions of human Tim1 are provided in the seqlist and FIG. 8. Variations include an insertion (labeled polymorphism 1), 157insMTTTVP, observed in 65% of the chromosomes, and a deletion (polymorphism 5), 187ΔThr, observed in 65% of the chromosomes. Other polymorphisms are T140A (polymorphism 7); V161A; (polymorphism 2); V1671 (polymorphism 3); T172A (polymorphism 4); N258D (polypmorphism 6). Polymorphism 4 was observed in 40% of the chromosomes, and the other polymorphisms were each observed in <5% of the chromosomes. Most of these variations (2-6) are located within exon 3, the first mucin-encoding exon, and all of the variants occur at the genomic level and are not splice variants. The association between Tim1 and asthma susceptibility is further supported by reports of significant linkage of mite-sensitive childhood asthma to D5S820 (mean LOD score=4.8), a marker which is approximately 0.5 megabases from Tim1.

In human tissues, a 4.4 kb TIM-1 mRNA is present in almost all tissues, though it is faint in most. A 5.5-kb band was observed in colon and liver. A 7.5-kb band was observed in spleen, thymus, and peripheral blood leukocytes, and smaller than 4.4-kb bands were observed in some organs. TIM-1 mRNA is expressed with alternate 5′ untranslated regions, in different cell populations. Hypoxia and ischemia induces TIM-1 expression in epithelial cells, and radiation induces expression of TIM gene family mRNA. The TIM genes are expressed in tumor specimens. Human TIM-4 mRNA is expressed in glioblastoma tissue, and is also detected in mitogen stimulated or irradiated peripheral blood monocytes.

In one aspect, the invention provides for an isolated nucleic acid molecule other than a naturally occurring chromosome comprising a sequence encoding a TIM-1, TIM-2, TIM-3 or TIM-4 protein, or a homolog or variant thereof, which variant may be associated with susceptibility to airway hyperreactivity and allergic T cell responses. The nucleic acid may be operably linked to a vector and/or control sequences for expression in a homologous or heterologous host cell. Such a host cell can find use in the production of the encoded protein. In another aspect of the invention, a purified polypeptide is provided of TIM-1, TIM-2, TIM-3 or TIM4 protein, or a homolog or variant thereof, which variant may be associated with susceptibility to airway hyperreactivity and allergic T cell responses. In another aspect, an antibody or other specific binding member that binds to the TIM-1, TIM-2, TIM-3 or TIM-4 polypeptide is provided.

Sequences of human and murine TIM sequences are provided in the sequence listing, as follows:

SEQ ID NO Name Length Type 1 BALB/c TIM-1 305 Protein 2 BALB/c TIM-1

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