Human gene with immunoregulatory and anti-proliferative properties

#The present invention relates generally to the field of immunoregulation and growth inhibition.

#Many human disorders are caused by disregulated activation of the immune system, including but not limited to type 1 diabetes, multiple sclerosis, systemic lupus erythematosus, autoimmune thyroiditis, ulcerative colitis and regional enteritis. Moreover, many human cancers are associated with a generalized immunosuppressive state. Uncovering the molecules responsible for controlling abnormal immunity or the molecules that are aberrantly produced in cancer cells that suppress the immune state would greatly aid in the therapy of these disorders. Such molecules could be used as therapeutic agents to restore normal immunity during states of autoimmunity. Alternatively, such molecules may be used as targets to generate inhibitory antibodies or small molecules that would restore normal immunity in states of immunodeficiency.

#Human Type 1 diabetes mellitus (IDDM) is a disorder caused by an aberrant immune response directed specifically against the insulin producing pancreatic islet beta cells. It is now clear that in patients with IDDM, T lymphocytes recognize self antigens expressed on beta cells such as glutamic acid decarboxylase (GAD), insulin and other proteins as being foreign leading to their destruction. Under normal conditions, such a deviant autoimmune anti-beta cell immune reaction is controlled at several levels. Immune tolerance is usually achieved through “central” or thymic T cell deletion of autoreactive T cells or by peripheral mechanisms designed to silence or “suppress” the reactivity of autoimmune T cells. Several different cell types have been proposed as mediators of peripheral immune suppression including both CD4 and CD8 positive T cells, however, the mechanisms by which these cells modulate an immune response remains enigmatic. By identifying molecules that mediate natural T cell immunosuppression, investigators and physicians may exploit this pathway to treat a variety of autoimmune diseases as well as states of immunodeficiency.

#FIG. 1. Genomic structure of Human G1h. Human G1h (SEQ ID NO:5) is a single exon gene (solid underlining) containing a 5′ consensus TATA box (dashed underlining) required for transcription and a typical 3′ Poly-A signal (waved underlining) for mRNA transcription. G1h has a STAT-1 binding site (dot-dash underline).

#FIG. 2. Genomic similarity between Human G1h and mouse gene G1 (722145) coding regions. Both the human G1h and mouse G1 genes share sequence similarities in the middle portion of the coding region. The human gene with the start site (ATG) underlined in bold and the stop site (TAA) underlined in bold is shown. The mouse G1 sequence homologous region is also shown. The gene identity is depicted in plain underlining. Other than the significant homology within the mid-region of the encoding region, the two genes are generally dissimilar

#FIGS. 3A and 3B. A comparison of the human P1h peptide and mouse peptide P1 (FIG. 3A) and of human P1h peptide and mouse P1B peptide (FIG. 3B).

#This application describes a human gene (G1h) encoding a protein which is regulated during development and T-cell activation. The polynucleotide of the present invention comprises a sequence of SEQ ID NO:1, a degenerate sequence of SEQ ID NO:1 and may also have a sequence which hybridizes to SEQ ID NO:1 under stringent conditions. A portion of the gene encodes for a protein termed herein as the P1h protein.

#By “degenerate sequence” is meant a sequence in which a different codon is used to specify the insertion of the same amino acid in a peptide chain. Degenerate sequence codons are well known to those skilled in the art. Further, sequences which result in conservative substitutions of amino acids such that the function of the protein is not affected are also within the scope of this invention.

#By “stringent conditions” is meant hybridization under conditions of temperature and salt concentration which result in duplex DNA molecules formed only between strands in which greater than 90% of the nucleotide bases are paired.