Faculty Research 1990 - 1999

Title

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.

Document Type

Article

Publication Date

1998

Keywords

Animal, Antibodies-Monoclonal, Antigens-Differentiation, CD4-Positive-T-Lymphocytes, Female, Graft-Survival, Interferon-Type-II, Interleukin-4, Membrane-Glycoproteins, Mice Mice-Inbred-BALB-C, Mice-Inbred-C3H, Mice-Inbred-C57BL, Skin-Transplantation, Spleen, Thymectomy, Transplantation-Homologous

JAX Source

J Clin Invest 1998 Jun 1;101(11):2446-55

Grant

DK25306/DK/NIDDK, DK41235/DK/NIDDK, DK36024/DK/NIDDK

Abstract

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.