Graft-vs-host disease (GVHD) is a potentially lethal complication of allogenic bone marrow transplantation (BMT). A reliable strategy to successfully treat GVHD once initiated has not yet been developed. The applicant has shown that F(ab')2 fragments of CD3 epsilon specific MoAb administered to mice after allogeneic BMT reverses the clinical effects of GVHD and leads to tolerance induction. In leukemia-bearing hosts, however, excessive or ill-timed administration of anti-CD3 F(ab')2 leads to leukemia relapse. The primary goal of this research is to identify mechanisms responsible for the successful treatment of GVHD with anti-CD3 F(ab')2 MoAb in vivo. Extensive preliminary data implicated cytokines in the pathology and regulation of GVHD. The two-part hypothesis to be tested states that (i) depletion of T-cells through activation-induced cell death (AICD or apoptosis) by anti-CD3 (Fab')2 MoAb is an essential prerequisite for treatment of established GVHD and (ii) anti CD3 F(ab')2 activates NK-1.1+ T-cells to secrete cytokines which lead to tolerance induction. Murine models have been developed to test this hypothesis.
Four specific aims are proposed: (a) To assess the importance of AICD in the successful treatment of established GVHD with anti-CD3 F(ab')2 MoAb in vivo and correlate T-cell death with activation state of the T-cells in vitro and in vivo; (b) To determine whether NK-1.1+ T-cells or CD3+ double-negative T-cells contribute to suppression of GVHD after signaling through CD3 epsilon using phenotypic and functional assays in vitro; (c) To ascertain whether IL-4 or other cytokines are essential to the mechanism involved in therapy of GVHD with anti-CD3 F(ab')2 using homozygous deletion mutant mice (""""""""knockout mice""""""""); and (d) To examine immunological factors that contribute to post-BMT leukemia relapse after treatment with anti CD3 F(ab')2 MoAb and the ability of donor leukocyte infusions to prevent relapse. A unique aspect of the proposed studies is the parallel evaluation of the effects of MoAb therapy in vivo on graft-vs-leukemia (GVL) reactivity using acute T-cell lymphoblastic leukemia in AKR mice as a model. Mechanistic insights gained from the studies, together with the biological principles identified, will facilitate the translational application of MoAb to clinical BMT.
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