DESCRIPTION (provided by applicant): Allogeneic stem cell transplantation (allo-HSCT) is an effective therapy for hematological malignancies. But the limiting factor is Graft-versus-disease (GVHD), a result of alloimmune responses elicited by donor T lymphocytes to major and minor antigens (mHA). The disease is characterized primarily by targeted epithelial cell injury in skin, intestine and liver. Although donor T lymphocytes and recipient antigen presenting cells (APCs) are the primarily mediators of GVHD, the molecular and cellular basis are not well understood. Our goal is to elucidate the regulatory mechanisms of alloimmune responses and develop novel therapies for tolerance induction and GVHD prevention. During the last decade innate immunity has been shown to modulate adaptive immunity through the interaction between the complement system and lymphocytes. Complement proteins are involved in different stages of the interaction between dendritic cells (DCs) and lymphocytes: (1) C3 production by DCs is essential for their maturation, differentiation and effective antigen presentation to T cells; (2) Complement proteins also have an autocrine effect on APCs and T cells; (3) T cells also secrete complement proteins and C3-deficient T cells undergo more apoptosis than wild-type T cells. Lack of complement proteins or complement receptors impairs the cognate interaction between APCs and T cells, and thus prevents alloimmune response and rejection of transplanted organs. Although the role of complement proteins in the cognate interaction between alloreactive T cells and APCs has been studied in the setting of allograft rejection, it is unknown whether complement system regulates alloimmune responses in GVHD. In our preliminary studies, we found significantly reduced GVHD mortality and morbidity in C3-deficient recipients in a murine model of bone marrow transplantation (BMT). We put forward the hypothesis that complement activation plays an important role in the pathogenesis of GVHD. We will investigate the role of C3 in donor T cell and recipient DCs responses that have been implicated in mediating GVHD, and explore the possibility of targeting the complement system as potential novel therapeutic interventions in mouse model. PUBLIC HEALTH RELEVANCE: Complement system play an important role in the regulation of T cell and dendrtic cell function. In our preliminary studies, we found significantly reduced GVHD mortality and morbidity in complement C3-deficient recipients in a murine model of bone marrow transplantation. The proposed research is to investigate the molecular mechanisms of complement system in alloimmune responses in GVHD.

Complement system play an important role in the regulation of T cell and dendrtic cell function. In our preliminary studies, we found significantly reduced GVHD mortality and morbidity in complement C3-deficient recipients in a murine model of bone marrow transplantation. The proposed research is to investigate the molecular mechanisms of complement system in alloimmune responses in GVHD.