Allogeneic stem cell transplantation (alloSCT) is life-saving therapy for hematologic malignancies and inherited disorders such as sickle cell anemia and thalassemia. T cells in alloSCT grafts play two pivotal roles: 1) they reconstitute T cell immunity in adults who, due to thymic involution, do not develop significant numbers of donor stem cell-derived T cells;and 2) they mediate an antineoplastic effect. Unfortunately, donor T cells also cause Graft-vs.-Host Disease (GVHD), the attack of donor T cells against recipient tissues. Therefore, all patients receive GVHD prophylaxis either via depletion of T cells from the allograft or with agents that impair T cell function. Nevertheless, GVHD and the infectious complications of immunosuppression are the major causes of morbidity in alloSCT. Professional antigen presenting cells (APCs) initiate alloimmune T cell responses by priming rare alloreactive T cells. Several features distinguish antigen presentation in transplantation. First, alloSCT recipients are chimeric for donor and host APCs. Our work to date focused on characterizing the distinct roles for donor and host APCs in GVHD pathogenesis. Second, DCs comprise a diverse set of cells with overlapping but distinct properties and the roles for these DC subsets are not well defined in transplantation models. Third and perhaps most important to the present application, the current paradigm for DCs in adaptive immunity, in which pathogenderived ligands for pattern associated molecular pattern receptors (in particular Toll-like receptors), stimulate immature DCs to mature and migrate to secondary lymph nodes, may not apply in alloSCT where there are no specific infectious pathogens and signals that induce DC maturation are unknown. In this proposal we plan to use a combination of reagents and gene deficient mice to define critical APC subsets in GVHD, their pathways of maturation, and will test the hypothesis that their modulation can alter alloimmunity for a therapeutic gain.
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