Transplantation Immune Tolerance
Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy for hematological malignancies and hereditary disorders as well as refractory autoimmune diseases. It also is one of the most reliable approaches for induction of organ transplantation tolerance; however, graft versus host disease (GVHD) remains a major obstacle in classical HCT. Classical HCT requires recipients undergo conditioning with total body irradiation (TBI) or high-dose chemotherapy in order to allow donor stem cell engraftment. Recent studies have shown that tissue damage caused by conditioning TBI or chemotherapy plays a critical role in GVHD induction.
One of the research projects in my lab is to understand the pathogenesis of GVHD. Chronic GVHD is the major cause of morbidity and mortality for long-term survivors who received classical HCT, but there has been no improvement in treating chronic GVHD over the past two decades. This is due to poor understanding of its pathogenesis. We recently have developed a new animal model of DBA/2 donor to BALB/c recipient in which the recipients develop characteristic features of human chronic GVHD such as excessive collagen deposition in tissues, scleroderma and high levels of serum autoantibodies. Donor CD4+ T and B cells in transplants are required for the disease induction, as well. We are currently investigating the role of allo- and auto-reactive CD4+ T (Th1, Th2 and Th17) cells and B cells as well as autoantibodies in the pathogenesis of chronic GVHD. This study will provide new insights into chronic GVHD pathogenesis and may lead to the development of new therapies.
Another project aims to develop a radiation-free GVHD preventive conditioning regimen. We recently have shown that radiation-free, anti-CD3 mAb-based conditioning allows donor CD8+ T cells to facilitate engraftment and mediate graft versus tumor reactions in leukemia recipients. It also can mediate graft versus autoimmunity in recipients with autoimmune diseases (i.e., type-1 diabetes or systemic lupus). We are currently exploring the mechanisms of GVHD prevention in anti-CD3-conditioned recipients, including the role of donor and host regulatory T cells (natural killer T and FoxP3+ T), and regulatory dendritic cells. In addition, we are exploring the mechanism by which allogeneic HCT re-establishes central and peripheral immune tolerance in autoimmune recipients, and we aim to understand how allogeneic HCT augments islet beta cell regeneration in type 1 diabetic recipients.We also are testing whether the pancreas of the chimeric recipient is a better site for islet transplants. These studies will promote the application of HCT in curing a variety of refractory diseases, including type 1 diabetes.