Developing novel strategies to enhance thymic recovery and T-cell reconstitution following bone marrow transplantation.

Abstract

Allogeneic HSCT is a valuable treatment option for many malignant and nonmalignant disorders. A significantly limiting factor for a favorable outcome following HSCT is the prolonged T-cell deficiency following transplant, which is primarily due to thymic injury caused by the intense chemotherapy/radiation-conditioning regimen given prior to transplant. The submitted work details the development of novel approaches to restore thymic function and enhance T-cell reconstitution following bone marrow transplantation (BMT). The preclinical research described in this dissertation investigates the therapeutic potential of combinatorial administration of keratinocyte growth factor, androgen regulators and general radioprotectants in restoring thymic function and T-cell reconstitution following BMT. The data suggest that pre-conditioning treatment of BMT recipients with combinations of these agents lead to rapid and durable restoration of thymic function and accelerated peripheral reconstitution of donor-derived, naïve CD4 and CD8 T-cells. Importantly, enhanced T-cell reconstitution correlates with superior antigen-specific CD4 and CD8 T-cell responses in vivo. This work also describes research aimed at characterizing the kinetics of depletion and recovery of thymic epithelial cells (TEC) following BMT and elucidating the role of thymocyte:TEC crosstalk in promoting TEC regeneration. A more thorough understanding of this process will allow for the identification of more focused targets for therapies aimed at promoting thymic and T-cell reconstitution following BMT. Taken together, this work has generated novel findings that will advance the field of immune reconstitution following bone marrow transplantation.