TIRC7 pathway as a target for preventing allograft rejection.
A number of leukocyte surface molecules play an essential role during immune activation. Targeting of these molecules utilizing antibodies serves as a specific therapeutic approach for the treatment of a variety of human diseases. Antibodies targeting a number of leukocyte surface molecules were shown to induce tolerance to transplants in several animal models. A novel membrane molecule, T-cell immune response cDNA 7 (TIRC7), has been shown to be an essential protein in the regulation of lymphocyte activation. TIRC7 does not share any homology with other known membrane proteins expressed during the course of lymphocyte activation and does not belong to any of the known costimulatory, cytokine, chemokine or receptor families. TIRC7, a highly conserved protein across species, is expressed in immune tissues such as spleen, lymph nodes, and T and B lymphocytes. Antibodies against extracellular domains of TIRC7 prolong allograft survival in rat and mouse transplantation models. The prevention of rejection is mediated at least partially via induction of cytotoxic T lymphocyte antigen 4 (CTLA4) in T cells. Functional cellular assays utilizing TIRC7-deficient mice splenocytes show that TIRC7 does have an impact not only on T-cell, but also on B-cell response. Subtherapeutic amounts of FK506 and anti-TIRC7 monoclonal antibody prolong graft survival, suggesting synergistic effects with calcineurin inhibitors. Targeting TIRC7 with monoclonal antibody might serve as a promising therapeutic strategy for preventing allograft rejection in humans and treatment of other immune-related diseases. Acutely rejected human kidney allografts show strong expression of TIRC7 despite treatment with calcineurin inhibitors. Therefore, monitoring TIRC7 expression may facilitate an early diagnostic tool of acute rejection. TIRC7 seems to belong to a group of targets with dual roles in disease pathogenesis, so-called theranostics, which can be utilized to treat and diagnose diseases.
Tamura
Akihiko
A
Institute of Medical Immunology, Campus Mitte, Charite, Humboldt-University of Berlin, Schumannstrasse 20/21, Berlin, Germany. nalan.utku@charite.de
Milford
Edgar L
EL
Utku
Nalân
N
D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D007165:Immunosuppression Therapy; D021122:Protein Subunits / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D025262:Vacuolar Proton-Translocating ATPases / Q000276:immunology / Q000378:metabolism / Q000502:physiology
D000906:Antibodies; D021122:Protein Subunits; C472421:TCIRG1 protein, human; D025262:Vacuolar Proton-Translocating ATPases