Immune responses are critical in determining the outcome of allogeneic hematopoietic cell transplantation (HCT). Allogeneic immune responses of donor cells against host antigens lead to both graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL). In contrast, deficient reconstitution of immune responsiveness leads to opportunistic infections with a variety of microbial and viral pathogens. Inadequate recognition and destruction of residual tumor cells by a newly engrafted donor immune system also permits recurrence of a patient's underlying malignancy. An accurate understanding of immune reconstitution after allogeneic HSCT is necessary to design and implement strategies to regulate immune responsiveness. Hopefully, by so doing, anti-tumor reactivity can be enhanced while minimizing complications such as GVHD and immune deficiency. This Program Project will build on the central theme of reconstitution and manipulation of immune function post-transplant that we have pursued vigorously during the past funding cycles of the Program. Project 1 will focus on vaccination strategies designed to stimulate anti-leukemic immunity without producing an indiscriminate allogeneic response. Based upon studies performed in the non-transplant setting which have confirmed safety and induction of robust immunologic activity, vaccinations with recipient-derived irradiated autologous tumor cells engineered to secrete GM-CSF will be administered to high risk patients after non-myeloablative allogeneic transplantation. Examination of T and B cell responses to vaccination will hopefully lead to the identification of new genes and antigens which can serve as targets for future vaccination strategies. Determining and establishing the optimal environmental milieu to maximize a specific immune response will be critical to the success of this Project. Regulatory T cells are thought to play an important role in the development and control of allogeneic immune responses (GVH and GVL reactions) post-transplant, and it is likely they will impact on immune responses to other antigens as well. Attempts to generate specific immunity against microbial pathogens or residual tumor cells may be profoundly influenced by the activity of these regulatory cells. Project 2 will focus on the characterization of regulatory T cells and their correlation with GVHD and anti-tumor immune responses in patients undergoing HCT. Project 3 will develop experimental murine models to study the impact of exogenous administration of these regulatory T cells on allogeneic and tumor specific responses. This is highly interactive Program will bring together experimental animal models, patient based clinical trials, and correlative laboratory investigation to better understand the regulation of immune responses so that they may be modulated to improve transplant outcome.
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