Lack of cognate help by CD4+ T cells and anergy of CD8+ T cells are the principal mechanisms for anti-leukocyte function-associated antigen-1/intercellular adhesion molecule-1-induced cardiac allograft tolerance.
Combined treatment with anti-leukocyte function-associated antigen-1 (LFA-1) and anti-intercellular adhesion molecule-1 (ICAM-1) monoclonal antibodies leads to allograft tolerance in murine cardiac transplantation. In the present study, we analyzed the mechanisms for this tolerance induction. In the tolerant mice, proliferative response of splenic T cells against donor-type cardiac myocytes and of CD8+ T cells against donor-type alloantigens was impaired as compared with responses in naive or rejected mice, but was completely restored with exogenous interleukin 2. This suggests that class I-restricted CD8+ T cells of tolerant mice were rendered anergic against donor-type alloantigens in the periphery. In contrast, proliferative response of CD4+ T cells against donor-type alloantigens in vitro was comparable between tolerant and naive mice. When heart and skin grafts from the same donor (BALB/c [H2d]) were simultaneously transplanted to C3H mice (H2k), both were rejected within 29 days, even though the mice were similarly treated with anti-LFA-1 and anti-ICAM-1 monoclonal antibodies. In contrast, when heart graft from BALB/c and skin graft from third-party donor (C57BL/6 [H2b]) were simultaneously transplanted to C3H mice under the same condition, the heart graft was accepted indefinitely and the skin graft was rejected. These findings suggest that the peripheral tolerance against cardiac allografts could be induced by selective inactivation of alloreactive CD8+ T cells resulting from the lack of cognate help by CD4+ T cells.
Bashuda
H
H
Department of Immunology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan.
Seino
K
K
Ra
C
C
Yagita
H
H
Okumura
K
K
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology*; D007108:Immune Tolerance; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology*; D007519:Isoantigens / Q000276:immunology; D008213:Lymphocyte Activation; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016038:Skin Transplantation; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology
D007519:Isoantigens; D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1