Donor T cells play a pivotal role in facilitating alloengraftment but also initiate graft versus host disease (GVHD) which is the major complication of allogeneic bone marrow transplantation (BMT). Current paradigms regarding the pathophysiology of GVHD and mechanisms of alloengraftment have been largely predicated on the biology of T cells that express the ab T-cell receptor. In contrast, the role of gd T cells that comprise a minor, yet distinguishable T cell subset, has not been as critically examined. In studies during the last grant period, we have shown that gd T cells are able to facilitate alloengraftment without causing GVHD under conditions where marrow grafts are otherwise rejected. Furthermore, gd T cells can downregulate GVH reactivity induced by non-tolerant ab T cells and accelerate the emergence of bone marrow-derived ab T cells that are tolerant of the recipient. These studies indicate that gd T cells may have a unique role in a allogeneic BMT.
The aim of the current proposal is to build on these observations by further delineating the role of gd T cells in allogeneic marrow transplantation. The goal of this project is to identify mechanisms by which gd T cells promote allogeneic engraftment and to determine whether gd T cells are able to enhance host immunity post transplantation. Our hypothesis is that gd T cells will facilitate allogeneic marrow engraftment through mechanisms that are distinct from those employed by ab T cells. Moreover, we hypothesize that gd T cells will be able to enhance host immunity posttransplant either directly or indirectly by augmenting the immune competency of ab T cells.
The specific aims of this proposal are: 1) To determine how gd T cells facilitate allogeneic marrow engraftment, 2) To identify the subpopulations of gd T cells responsible for facilitating alloengraftment, and 3) To determine whether gd T cells enhance host immunity post transplantation. The overall goal of these studies is that further delineation of the role of gd T cells in allogeneic BMT will establish a pre-clinical foundation for the subsequent clinical application of this approach in order to reduce GVHD without compromising engraftment or immune reconstitution.
| Vodanovic-Jankovic, Sanja; Drobyski, William R (2006) Gammadelta T cells do not require fully functional cytotoxic pathways or the ability to recognize recipient alloantigens to prevent graft rejection. Biol Blood Marrow Transplant 12:1125-34 |
