Monoclonal antibody to the HLA class I alpha 3 domain inhibits T cell activation and prolongs cardiac allograft survival in HLA-transgenic mice.
Antibodies recognizing MHC class I molecules expressed on the surface of T cells have been shown to inhibit T cell responses in vitro. These findings suggested that therapy with such an antibody may prevent rejection and promote graft acceptance. We therefore tested the effect of an anti-HLA class I alpha 3 domain antibody (TP25.99) in vivo using transgenic C57BL/6 mice expressing HLA-B2705. Flow cytometric analysis confirmed the binding of TP25.99 to normal human peripheral blood lymphocytes and to mouse spleen cells, bone marrow cells and thymocytes isolated from hemizygous (+/-) transgenic littermates but not from homozygous (-/-) littermates. TP25.99 inhibited OKT-3-induced, but not PMA+ionomycin-induced, proliferation of human peripheral blood lymphocyte as well as anti-CD3 or Con A-induced proliferation of HLA+ mouse T cells. Both intact monoclonal antibody TP25.99 and TP25.99 Fab inhibited T cell proliferation. Reduced proliferation was associated with suppressed production of interleukin-2 as measured by ELISA. The efficacy of TP25.99 Fab in vivo was evaluated in a heart allograft model. Antibody therapy of (H-2h, B2705+) transgenic recipients of allogeneic Balb/c (H-2d) heart grafts prolonged graft survival significantly (MST = 19.8 +/- 6.4, p = 0.003) compared to treated (H-2b, B2705-) (MST = 9.17 +/- 2.2) or untreated (H-2b, B2705+) (MST = 10.0 +/- 2.8) transgenic recipients. This demonstrates that immunomodulation through anti-HLA class I antibody therapy can lead to prolongation of graft survival.
Woo
J
J
Sangstat Medical Corporation, Menlo Park, California 94025, USA.
Cornejo
M C
MC
Gao
L
L
Taurog
J D
JD
Hammer
R E
RE
Buelow
R
R
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D004306:Dose-Response Relationship, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005805:Genes, MHC Class I / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology; D006649:Histocompatibility Antigens / Q000032:analysis / Q000276:immunology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D007518:Isoantibodies / Q000096:biosynthesis; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016685:Mitomycin / Q000494:pharmacology; D013154:Spleen / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000502:physiology; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D006649:Histocompatibility Antigens; D018960:Hyaluronan Receptors; D007518:Isoantibodies; D016685:Mitomycin