Long-term survival of skin allografts induced by donor splenocytes and anti-CD154 antibody in thymectomized mice requires CD4(+) T cells, interferon-gamma, and CTLA4

• Published in: The Journal of clinical investigation 1998-06, Vol.101 (11), p.2446-2455
• Main Authors: Markees, T G, Phillips, N E, Gordon, E J, Noelle, R J, Shultz, L D, Mordes, J P, Greiner, D L, Rossini, A A
• Format: Article
• Language: English
• Subjects: Abatacept; Animals; Antibodies, Monoclonal - therapeutic use; Antigens, CD; Antigens, Differentiation - physiology; CD4-Positive T-Lymphocytes - physiology; CD40 Ligand; CTLA-4 Antigen; Female; Graft Survival; Immunoconjugates; Interferon-gamma - physiology; Interleukin-4 - physiology; Male; Membrane Glycoproteins - physiology; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Skin Transplantation - immunology; Spleen - cytology; Thymectomy; Transplantation, Homologous
• ISSN: 0021-9738
• DOI: 10.1172/JCI2703

Treatment of C57BL/6 mice with one transfusion of BALB/c spleen cells and anti-CD154 (anti-CD40-ligand) antibody permits BALB/c islet grafts to survive indefinitely and BALB/c skin grafts to survive for approximately 50 d without further intervention. The protocol induces long-term allograft survival, but the mechanism is unknown. We now report: (a) addition of thymectomy to the protocol permitted skin allografts to survive for > 100 d, suggesting that graft rejection in euthymic mice results from thymic export of alloreactive T cells. (b) Clonal deletion is not the mechanism of underlying long-term graft survival, as recipient thymectomized mice were immunocompetent and harbor alloreactive T cells. (c) Induction of skin allograft acceptance initially depended on the presence of IFN-gamma, CTLA4, and CD4(+) T cells. Addition of anti-CTLA4 or anti-IFN-gamma mAb to the protocol was associated with prompt graft rejection, whereas anti-IL-4 mAb had no effect. The role of IFN-gamma was confirmed using knockout mice. (d) Graft survival was associated with the absence of IFN-gamma in the graft. (e) Long-term graft maintenance required the continued presence of CD4(+) T cells. The results suggest that, with modification, our short-term protocol may yield a procedure for the induction of long-term graft survival without prolonged immunosuppression.