To date, only allogenic bone marrow transplantation (alloBMT) can cure patients (pts) afflicted with congenital diseases of the hematopoietic stem cell. This approach, however, has been severely limited by the availability of suitable histocompatible donors as well as the need to administer toxic, nonspecific chronic immunosuppression in an attempt to control grafts vs. host disease (GVHD). Host alloreactive T cells present in the donor bone marrow (BM) are responsible for the generation of GVHD. Although the incidence and severity of GVHD using presently available approaches to prevent and treat GVHD may be acceptable for matched sibling donors, severe and unacceptable GVHD complicates the clinical course of the majority of haploidentical and unrelated donor alloBMTs. The goal of the present proposal is to reduce or ameliorate the incidence and complications of GVHD by attempting to anergize or clonally delete host alloreactive T cells present in haploidentical donor BM. If successful, haploidentical alloBMT could provide a readily available source of donor BM for most pts with congenital diseases of the hematopoietic stem cell. To become functional, alloreactive T cells must receive two signals. One signal is delivered by alloantigen (alloAg) via the T cell receptor and the other by a member of the B7 family via the T cell CD28 molecule. Blockade of B7 family mediated costimulation is both necessary and sufficient to induce anergy to alloAg. Using this approach, anergy to fully mismatched allogeneic donor T cells can be induced ex vivo. However, since anergy might potentially be reversed in vivo, we also propose to attempt to specifically clonally delete alloreactive T cells in the donor BM. If long-lasting and irreversible unresponsiveness to alloAg can be induced, the associated attendant clinical toxicities of GVHD would be ameliorated while the eligible donor pool would be increased without sacrificing immunity to infectious agents. To achieve these goals, Four Aims are proposed. First, to ex vivo anergize host alloreactive T cells in donor BM for reinfusion into pts undergoing haploidentical BMT for congenital disease of the stem cell. Second, to determine which molecular pathways are critical to the induction and prevention of alloAg specific T cell clonal deletion. Third, to develop and optimize in vitro techniques to clonally delete host alloreactive T cells in the donor hapoidentical BM, Fourth, to ex vivo clonally delete host alloreactive T cells in the donor BM and test this concept in the clinic, first in pts with hematologic malignancies and then in pts with congenital diseases of the hematopoietic stem cell. Project 4 relies upon and is highly interdependent with Project 3 (for stem cells assays), Project 5 (for preclinical animal models), and Project 6 (clinical trials of induction of T cell anergy and/or T cell clonal deletion of alloreactive T cell in the donor BM).
Showing the most recent 10 out of 88 publications
