(taken from the application) Controlling allo- and auto-immune responses to islet allografts are essential for islet transplantation to be a successful treatment (defined as long-term insulin independence) for type 1 diabetes. Current immunosuppressive agents used to control rejection of islet allografts have dangerous side effects, may not be effective in preventing recurrence of disease, and may impede islet graft function. The objective of this proposal is to determine the effects of blocking the co-stimulatory molecule, CD40 ligand (using a novel antibody from Biogen, Inc., anti-rat CD40L), expressed on activated T cells, on the inductio and maintenance of donor-specific tolerance to islet allografts and the recurrence of autoimmune diabetes (induced) in the Diabetes Resistant Biobreeding/Worcester (DR-BB) rat. Advances in understanding co-stimulatory pathways essential for initiation and amplification of T cell-dependent immune responses have led to the development of monoclonal antibodies targeted to cel surface molecules that mediate those pathways. The monoclonal antibody, anti-CD40L (gp39), is of interest because it has shown to be effective in controlling auto-immune disease as well as well as rejection of allografts in mice and non-human primates without toxic side effects. Specifically this project will define the conditions (dosage and timing) in which anti-rat CD40L is most effective in protecting islet allografts from rejection and recurrence of disease in chemically induced diabetic DR-BB rats and auto-immune diabetic (induced by depletion of RT6.1+T cells) DR-BB rats. I addition, the effects of co-administration of donor antigen with anti-rat CD40 will be examined on the development and maintenance of tolerance. The association of tolerance with stable microchimerism (persistence of donor cell in the host's lymphoid organs) will be determined by PCR. Antidonor reactivity of tolerant rats will also be tested in vitro, using a mixed leukocyte reactio assay. The results of this research will aid in the design of new immuno-modulatory therapies for islet transplantation (1) that have few unwanted side effects, (2) that are easy to administer, (3) that do not interfere with islet engraftment and function, and (4) that modulate auto-immunity as well as the allo-immune response from the host.
| Kover, K L; Geng, Z; Hess, D M et al. (2000) Anti-CD154 (CD40L) prevents recurrence of diabetes in islet isografts in the DR-BB rat. Diabetes 49:1666-70 |
