title: Monoclonal antibody specific for TIRC7 induces donor-specific anergy and prevents rejection of cardiac allografts in mice.
abstract: T cell immune response c-DNA (TIRC7) is up-regulated during the early stages of T-cell activation in response to alloantigens. In this study, we analyzed the effects of newly developed monoclonal antibodies (mAb) against TIRC7 in acute cardiac allograft rejection. Fully vascularized heterotopic allogeneic heart transplantation was performed in mice across a full-mismatch barrier (C57Bl/10 into CBA). Recipients received seven injections (day 0-7) of a novel anti-TIRC7 mAb or remained untreated. Graft survival, histology and ex vivo lymphocyte functions were tested. Targeting of TIRC7 with an anti-TIRC7 mAb diminishes lymphocyte infiltration into grafts resulting in delay of morphological graft damage and prolongation of allograft survival. The lymphocytes from anti-TIRC7 mAb-treated animals exhibit hypo-responsiveness without evidence of lymphocyte depletion against the donor allo-antigens. Proliferation and expression of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) were down-regulated while interleukin-4 (IL-4) and IL-10 expression were spared. Moreover, anti-TIRC7 mAb enhanced up-regulation of CTLA-4 expression but suppressed up-regulation of CD25 on stimulated lymphocytes in vitro and in vivo. Ligation of TIRC7 has important effects on the regulation of co-stimulatory signaling pathways associated with suppressing of T-cell activation. Targeting of TIRC7 may therefore provide a novel therapeutic approach for modulating T cell immune responses during organ transplantation.
authors.affiliation: Institute of Medical Immunology, Humboldt-University of Berlin, Germany.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kumamoto
authors.forename: Antje
authors.initials: A
authors.lastname: Tomschegg
authors.forename: Fatima
authors.initials: F
authors.lastname: Bennai-Sanfourche
authors.forename: Anke
authors.initials: A
authors.lastname: Boerner
authors.forename: Arthur
authors.initials: A
authors.lastname: Kaser
authors.forename: Isabella
authors.initials: I
authors.lastname: Schmidt-Knosalla
authors.forename: Thomas
authors.initials: T
authors.lastname: Heinemann
authors.forename: Mirko
authors.initials: M
authors.lastname: Schlawinsky
authors.forename: Richard S
authors.initials: RS
authors.lastname: Blumberg
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Volk
authors.forename: Nalan
authors.initials: N
authors.lastname: Utku
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002455:Cell Division; D002462:Cell Membrane / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival; D016027:Heart Transplantation / Q000379:methods*; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D009206:Myocardium / Q000378:metabolism; D021122:Protein Subunits / Q000276:immunology*; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D013154:Spleen / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D025262:Vacuolar Proton-Translocating ATPases / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D018076:DNA, Complementary; D021122:Protein Subunits; D015375:Receptors, Interleukin-2; C472421:TCIRG1 protein, human; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma; D025262:Vacuolar Proton-Translocating ATPases