Allogeneic hematopoietic cell transplantation (HCT) is an established therapy for a broad range of hematologic malignancies and other disorders. A major limitation of allogeneic HCT Is graft vs host disease (GVHD) caused by alloimmune lymphocytes of the donor recognizing host antigens. GVHD can be characterized as a robust, dysregulated immune response resulting in tissue destruction and ultimately mortality in the most severe forms. Prior work in our laboratory has utilized a novel bioluminescent imaging (BLl) approach to understand the early events in GVHD pathophysiology whereby donor derived T cells migrate to secondary nodal sites and actively proliferate. In these tissues conventional CD4+ and CD8+ T (Tcon) cells up-regulate homing receptors that allow entry into GVHD target organs such as the skin, gastrointestinal tract, liver and immune tissues such as lymph nodes and the thymus. Controlling this robust Immunological reaction is difficult both in murine models and in patients. Recently we have discovered that immune regulatory T cells are capable of controlling GVHD pathophysiology without interfering with graft vs tumor (GVT) reactions and resulting in more effective immune reconstitution due to preservation of immune tissues required for effective immune reconstitution. We have studied both CD4+CD25+FoxP3+ regulatory T cells (Treg) and alpha/betaTCR+CD4+NK1.1+ natural killer T (NK-T) cells. Using BLl and other techniques we have observed that Treg control GVHD by inhibiting Tcon proliferation whereas NK-T cells function through an alternative mechanism. In this Project we will utilize novel animal models and TCR sequencing technologies to explore the biological basis of T cell activation in GVHD and GVT in Specific Aim #1.
In Specific Aim #2 we will compare the impact of Treg and NK-T cells on Tcon proliferation, phenotype and function.
Specific Aim #3 will translate these findings in a clinical trial of allogeneic HCT in patients with high risk malignancies who will receive a CD34+ cell selected graft followed by Treg and Tcon infusion in an effort to reduce GVHD while maintaining GVT and improving immune reconstitution.
This project addresses the biological basis of GVHD induction by alloreactive T cells and the impact of regulatory T cell populations known to control this clinically relevant immune reaction. We hope to gain important biological insights into immune reactions including GVHD and GVT, as well as the function of regulatory T cell populations. Further, we will translate these findings to the clinic to improve upon allogeneic HCT by reducing GVHD risk, maintaining GVT and resulting in more effective immune reconstitution.
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