Novel T-cell membrane protein (TIRC7), peptides and antibodies derived therefrom and uses thereof

Abstract

Described are generally a T cell immune response cDNA 7 (TIRC7) encoding a novel T-cell transmembrane protein as well as peptides und polypeptides derived therefrom and antibodies recognizing said (poly)peptides. More particularly, peptide and polypeptide as well as antibodies being capable of inhibiting T-cell stimulation through the T-cell membrane protein (TIRC7) are provided. Furthermore, vectors comprising the aforementioned polynucleotides and host cells transformed therewith as well as their use in the production of the above-defined proteins, peptides or polypeptides are described. Additionally, pharmaceutical and diagnostic compositions are provided comprising any one of the afore described polynucleotide, vector, protein, peptide, polypeptide, or antibody. Furthermore, methods and uses for modulating immune responses through the novel TIRC7 membrane protein as well as pharmaceutical compositions comprising agents which act on the TIRC7 membrane protein or its ligand are described. Also, the use of said polynucleotide, vector, protein, peptide, polypeptide, or antibody for the preparation of pharmaceutical compositions for use in organ transplantation, for the treatment of autoimmune, allergic or infectious diseases, or for treatment of tumors is provided. Furthermore, methods for modulating (antigen-specific) T cell unresponsiveness inducing maintaining or reversing T cell unresponsiveness by inhibiting or stimulating an (unresponsive) T cell through the novel TIRC7 membrane protein are encompassed herein.

What is claimed is:  
     
         1 . A polynucleotide encoding a TIRC7 membrane protein or a biologically active fragment thereof comprising a DNA sequence selected from the group consisting of 
 (i) DNA sequences comprising a nucleotide sequence encoding the amino acid sequence depicted in SEQ ID NO. 2 or SEQ ID NO. 13 from amino acid position 1 to 614 or from amino acid position 1 to 601;    (ii) DNA sequences comprising the nucleotide sequence depicted in SEQ ID NO. 1 or SEQ ID NO. 12;    (ii) DNA sequences comprising a nucleotide sequence encoding a fragment or derivative of the protein encoded by the DNA sequence of (i) or (ii); and    (iii) DNA sequences the complementary strand of which hybridizes with and which is at least 70% identical to the polynucleotide as defined in any one of (i) to (iii).    
     
     
         2 . A nucleic acid molecule of at least 15 nucleotides in length hybridizing specifically with a polynucleotide of  claim 1  or with a complementary strand thereof.  
     
     
         3 . A vector comprising the polynucleotide of  claim 1 .  
     
     
         4 . The vector of  claim 3 , wherein said polynucleotide is operably linked to regulatory sequences allowing for the transcription and optionaly expression of said nucleic acid molecule.  
     
     
         5 . A host cell comprising a polynucleotide of  claim 1  or the vector of  claim 3  or  4 .  
     
     
         6 . A method for the production of a TIRC7 membrane protein or a biologically active fragment thereof comprising: 
 (a) culturing the host of  claim 5  under conditions allowing for the expression of the protein; or    (b) in vitro translation of the polynucleotide of  claim 1;     and recovering the protein produced in (a) or (b).    
     
     
         7 . A TIRC7 membrane protein or biologically active fragment thereof encoded by the nucleic molecule of  claim 1  or produced by the method of  claim 6 .  
     
     
         8 . An antibody specifically recognizing the protein of  claim 7 .  
     
     
         9 . A normal cell that has been modified to express the protein of  claim 7  or the antibody of  claim 8 .  
     
     
         10 . A pharmaceutical composition comprising a peptide or polypeptide being capable of inhibiting T-cell stimulation through the TIRC7 membrane protein and/or being recognized by an antibody capable of inhibiting T-cell stimulation through the TIRC7 membrane protein encoded by a fragment of the polynucleotide of  claim 1  or an antibody specifically recognizing said peptide or polypeptide, and optionally a pharmaceutically acceptable carrier.  
     
     
         11 . The pharmaceutical composition of  claim 10 , wherein said peptide or polypeptide is in a soluble form.  
     
     
         12 . The pharmaceutical composition of  claim 10  or  11 , wherein said peptide or polypeptide comprises the amino acid sequence depicted in any one of SEQ ID NOS 3 to 9.  
     
     
         13 . The pharmaceutical composition of any one of  claims 10  to  12  further comprising a second agent which inhibits T-cell stimulation.  
     
     
         14 . The pharmaceutical composition of  claim 13 , wherein the second agent is an antibody to a receptor or ligand involved in T-cell stimulation or is a soluble form of said receptor.  
     
     
         15 . The pharmaceutical composition of  claim 14 , wherein said second agent blocks interaction of the CD2, CD28, CTLA4 or CD40 surface receptor with a CD2, CD28, CTLA4 or CD40 ligand.  
     
     
         16 . The pharmaceutical composition of any one of  claims 10  to  15  for use in cell or organ transplantation, for the treatment of autoimmune, allergic or infectious diseases, or for the treatment of tumors.  
     
     
         17 . A diagnostic composition comprising a polynucleotide of  claim 1 , the vector of  claim 3  or  4 , the cell of  claim 5  or  9 , the protein of  claim 7 , or the antibody of  claim 8  or a (poly)peptide or antibody as defined in any one of  claims 10  to  12 ; and optionally suitable means for detection.  
     
     
         18 . An in vitro method for inducing or maintaining unresponsiveness of a T-cell to an antigen comprising contacting the T-cell with an agent which inhibits stimulation of the T-cell through a TIRC7 membrane protein.  
     
     
         19 . Use of an agent which inhibits T-cell stimulation through a TIRC7 membrane protein for the preparation of a pharmaceutical composition for inducing or maintaining T-cell unresponsiveness to an antigen in a subject.  
     
     
         20 . The method of  claim 18  or the use of  claim 19 , wherein the agent blocks an interaction of the TIRC7 membrane protein with its ligand.  
     
     
         21 . The method or the use of  claim 20 , wherein the agent is a peptide or polypeptide being capable of inhibiting T-cell stimulation through the TIRC7 membrane protein and/or being recognized by an antibody capable of inhibiting T-cell stimulation through the TIRC7 membrane protein encoded by a fragment of the polynucleotide of  claim 1  or an antibody specifically recognizing said peptide or polypeptide.  
     
     
         22 . The method of any one of claims  18 ,  20  or  22  or the use of any one of  claims 19  to  21 , further comprising the use of a second agent as defined in any one of  claims 13  to  16 .  
     
     
         23 . A pharmaceutical composition comprising a first agent which stimulates a T-cell through a TIRC7 membrane protein and optionally a pharmaceutically acceptable carrier.  
     
     
         24 . The pharmaceutical composition of  claim 23 , wherein said agent is a ligand of the TIRC7 membrane protein or is at least one anti-TIRC7 membrane protein antibody.  
     
     
         25 . The pharmaceutical composition of  claim 23  to  24  further comprising a second agent which stimulates T-cell proliferation.  
     
     
         26 . The pharmaceutical composition of  claim 25 , wherein said agent is IL-2, IL-4 or an agent which stimulates a T-cell through a CD2, CD28, CD40 or CTLA4 surface receptor.  
     
     
         27 . An in vitro method for restoring responsiveness to an antigen by a T-cell which is unresponsive to the antigen, comprising contacting the T-cell in the presence of the antigen with a first agent which stimulates the T-cell through a TIRC7 membrane protein.  
     
     
         28 . The method of  claim 27 , wherein the TIRC7 ligand is expressed on a cell surface by introducing to the cell a nucleic acid molecule encoding the TIRC7 ligand in a suitable form for expression of the TIRC7 ligand on the cell surface.  
     
     
         29 . The method of  claim 28 , wherein the cell is a tumor cell.  
     
     
         30 . The method of any one of  claims 27  to  29 , further comprising contacting the T-cell with a second agent as defined in  claim 25  or  26 .  
     
     
         31 . The method of  claim 30 , wherein the T-cell is contacted with the second agent prior to being contacted with the first agent.  
     
     
         32 . The method of  claim 30  or  31 , wherein a CD2, CD28, CD40 or CTLA4 ligand is expressed on the cell surface by introducing into the cell a nucleic acid molecule encoding the CD2, CD28, CD40 or CTLA4 ligand in a form suitable for expression of said ligand on the cell surface.  
     
     
         33 . Use of a first agent as defined in  claim 23  to  24  for the preparation of a pharmaceutical composition for stimulating a T-cell response to a tumor cell in a subject with a tumor.  
     
     
         34 . The use of  claim 33  wherein the tumor cell is modified to express a TIRC7 ligand and/or a CD2, CD28, CD40 or CTLA4 ligand preferably on the tumor cell surface.  
     
     
         35 . The use of  claim 33  or  34 , wherein the tumor cell is obtained from the subject, modified ex vivo to form a modified tumor cell and said modified tumor cell is used for the preparation of a pharmaceutical composition which is designed for administration to the subject.  
     
     
         36 . The use of any one of  claims 33  to  35 , wherein the T-cells are obtained from a subject, contacted with IL-2 or IL-4 ex vivo and said modified T-cells are used for the preparation of pharmaceutical composition which is designed for the administration to the subject.  
     
     
         37 . The use of any one of  claims 19  to  22  or  33  to  35 , wherein the subject is a recipient of peripheral stem cells or bone marrow transplant.  
     
     
         38 . The use of  claim 37 , wherein the pharmaceutical composition is designed for contacting with peripheral stem cells or bone marrow cell prior to transplantation into the recipient.  
     
     
         39 . The method of any one of claims  18 ,  20  to  22  or any one of  claims 27  to  32  or the use of any one of  claims 19  to  22  or  33  to  36  in organ graft transplantation or for the treatment of auto-immune diseases.  
     
     
         40 . A method for identifying T-cell activating or co-stimulating compounds or for identifying inhibitors of T-cell activation and stimulation comprising 
 (a) culturing T-cells in the presence of the protein of  claim 7 , the antibody of  claim 8 , the cell of  claim 5  or  9  or a peptide or polypeptide being capable of inhibiting T-cell stimulation through the TIRC7 membrane protein and/or being recognized by an antibody capable of inhibiting T-cell stimulation through the TIRC7 membrane protein encoded by a fragment of the polynucleotide of  claim 1  or an antibody specifically recognizing said peptide or polypeptide and, optionally, in the presence of a component capable of providing a detectable signal in response to T-cell activation, with a compound to be screened under conditions permitting interaction of the compound with the (poly)peptide, antibody or cell(s); and    (b) detecting the presence or absence of a signal generated from the interaction of the compound with the cells.    
     
     
         41 . A method for the production of a pharmaceutical compositions comprising the steps of the method of  claim 40  and formulating and optionally synthesizing the compound identified in step (b) in a pharmaceutically acceptable form.  
     
     
         42 . Use of peptide or polypeptide being capable of inhibiting T-cell stimulation through the TIRC7 membrane protein and/or being recognized by an antibody capable of inhibiting T-cell stimulation through the TIRC7 membrane protein encoded by a fragment of the polynucleotide of  claim 1  or an antibody specifically recognizing said peptide or polypeptide the polynucleotide of  claim 1 , the vector of  claim 3  or  4 , the protein of  claim 7 , the antibody of  claim 8 , the cell of  claim 5  or  9  or the compound indentified according to the method of  claim 40  for the preparation of a pharmaceutical composition for the treatment of acute and chronic diseases, involving T-cell activation and Th1 and Th2 immune response, for the treatment of acute and chronic rejection of allo- and xeno organ transplants and bone marrow transplantation, for the treatment of rheumatoid arthritis, lupus erythramatodes, multiple sklerosis, encephalitis, vasculitis, diabetes mellitus, pancreatitis, gastritis, thyroiditis, for the treatment of maligne disorders of T, B or NK cells, for the treatment of asthma, lepramatosis, Helicobacter pylori associated gastritis or for the treatment of skin tumors, adrenal tumors or lung tumors.