INVESTIGATING THE ROLE OF CYTOKINES AND REGULATORY T CELLS IN A NOVEL TREATMENT FOR GRAFT-VERSUS-HOST DISEASE USING EXOSOMES FROM ACTIVATED MESENCHYMAL STROMAL CELLS

Abstract

The development of graft-vs-host disease (GVHD) is a significant complication in the treatment of leukemia, wherein the graft of transplanted hematopoietic tissues from a donor (allo-HCT) attacks the recipient cells of the patient. The primary challenge in developing a treatment for GVHD is to establish a treatment that prevents GVHD while maintaining graft-vs-leukemia (GVL) activity. Previously, our lab has identified a T regulatory cell (Treg) population that is correlated with the prevention of GVHD. We have also developed a novel treatment involving exosomes collected from mesenchymal stromal cells stimulated with the lipid A analog CRX-527 to form immunosuppressive CRX-exosomes (CRX-exos) that limit GVHD without inhibiting GVL activity in an animal model. Here, I hypothesized that CRX-exos stimulate the expression of cytokine IL-6, which then induces Treg activation required for the prevention of xeno-GVHD. I tested this hypothesis by quantifying Tregs and their cytokine expression followed by blocking IL-6 receptors in both an in-vitro and in-vivo model. I found that blocking IL-6 receptors did not significantly reduce Tregs in both models, suggesting that IL-6 is not the main molecular mechanism by which CRX-exos induce Treg activation. Interestingly, blocking IL-6 receptors did increase CD4/CD8 double positive T cells (DPTs) and appeared to confer some protection from GVHD in the xenogeneic transplant model.