Dendritic Cell Subsets and Paths of Maturation in GVHD

Yale University, New Haven CT

Investigators

Linked publications & trials

Abstract

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