Using Regulatory T Cells to Establish the Specific Tolerance toward Composite Tissue Allotransplants

Using regulatory T cells to establish the specific tolerance toward composite tissue allotransplants Composite tissue allotransplantation (CTA), referring to the transplantation of an allograft composed of a variety of heterogeneous antigenic tissues. It holds great clinical potential since it can be applied to treat defects that can not be mended using autologous tissues. However, the immunological barrier between donor and recipient leads to rejection and is difficult to overcome. Although immunosuppresants such as cyclosporine A has been widely used to treat rejection clinically, various potentially serious side effects do not justify their use for non-life-saving CTAs. We therefore focus on investigating methods that will induce and maintain tolerance to the CTA and ultimately reduce reliance on long term immunosuppression. Regulatory T cells (Treg) are a specific subset of T cells that possess a suppressive role in the immune system. Increase in the number of Tregs has been to shown to associate with inducing tolerance in organ transplantation systems. In this proposal, we will try to induce allo-specific tolerance by raising the number of Tregs in the recipients that have gone through CTA. Two specific aims are proposed: 1. To acquire large amount of Treg cells and to develop a protocol for establishing donor-specific tolerance in CTA with Tregs Tregs from rat splenocytes will be isolated and expanded in vitro using modified protocols originally set up for mice or human cells. These Tregs will be infused into recipient rats combining with lymphodepletion reagents along with immunosuppreants. Their effects on inducing tolerance after CTA will be evaluated. 2. To develop a protocol with reagents that expand Tregs in vivo for establishing donor-specific tolerance in CTA The critical Treg marker Foxp3 is a transcription factor, whose activities are found to be regulated by various molecular modifications. Recent studies have shown that reagents that alter Foxp3 modification also regulate the numbers of Tregs. Therefore we will test these reagents on CTA system to evaluate their effects on inducing tolerance. After finishing these aims, we expect to be able to acquire Tregs in large amount in vitro for infusion and expand their population in vivo. With increase in Treg number and thus the ratio of Treg to T effector cells in the recipients, achieving tolerance to the allotransplant is anticipated. In the long term, we hope the knowledge gained from this research would be applicable for establishing donor-specific tolerance in clinical CTA cases.

Project ID:PC9909-0116
External Project ID:NSC99-2314-B182-016-MY2