Nowhere are the promises and problems of T cell based therapy, clearer than following bone marrow transplantation (BMT). While on the one hand T cells can induce potentially lethal graft vs. host disease (GVHD), they also are capable of 1) mediating graft vs. tumor (GVT) effects, 2) facilitating hematopoietic stem cell (HSC) engraftment and 3) providing defense against pathogenic organisms commonly encountered in the post-BMT period. Thus, an idealized population of T cells would be one possessing these positive attributes and lacking the negative. vs T cells are a rarely occurring population of T cells whose function is largely unknown. Few studies have evaluated the role of vs T cells in BMT and existing studies present conflicting results. While some have found that vs T cells do not cause GVHD, others implicate vs T in pathogenesis of GHVD. Moreover, studies suggest that vs T cells may mediate GVT, facilitate HSC engraftment and provide defense against a variety of pathogens. Thus, vs T cells potentially are an attractive candidate population for adoptive immunotherapy. Given the paucity of vs T cells in the peripheral blood, immunotheraptic approaches are impractical without methods for the expansion of such a rare population. We recently have discovered that under in vitro activation conditions, the outgrowth of vs T cells is inhibited by alpha/betaTCR+CD8+ T cells. With this information, we have developed methodology for the ex vivo expansion of large numbers of vs T cells. The long-range goal of this project is to determine whether ex vivo expanded T cell populations add benefit to bone marrow transplantation. The objective of this proposal is to evaluate the role of ex vivo expanded vs T cells in animal models of BMT. The central hypothesis to this work is that vs T cells can be ex vivo expanded and that such populations provide important benefits in the post-BMT period. This hypothesis will be tested by pursuing three specific aims: 1) to evaluate the effect of CD8+ T cells on the ex vivo expansion of vs T cells; 2) to determine the in vitro biological characteristics of expanded vs T cells; and 3) to evaluate the in vivo biological activity of expanded vs T cells with respect to GVHD, GVT and facilitation of HSC engraftment. The proposed work is innovative because we will be studying and transferring an otherwise rare population of cells in sensitive animal models of GVHD, GVT and facilitation of engraftment. It is expected that these studies will provide preclinical information regarding the use of expanded vs T cells in the post-BMT setting. This work is significant in that it will examine the interactions between CD8+T cells and vs T cells. Further, we will evaluate how vs T cells function and traffic in the post-BMT setting. The proposed training program is in a dynamic research setting with extensive intellectual and technical support. Thus, the candidate will acquire the skills to secure a faculty position as a pediatric bone marrow transplantation clinical-scientist.

K08HL004505

2001-04-06

2006-03-31