Immunology of Transplantation
This lab is focused on five major research areas:
- Graft-versus-host disease (GVHD). GVHD is a multi-organ system disorder in which donor T cells recognize host alloantigens present on antigen-presenting cells and tissues in the context of an inflammatory response. Studies are directed toward identifying and modifying signals that drive or inhibit acute and chronic GVHD generation. These include the analysis of positive costimulatory molecules and negative regulators of the immune response that counterbalance positive costimulation as well as intracellular signaling and metabolic pathways along with pro- and anti-inflammatory cytokines that regulate these responses at the level of the GVHD target organ. These researchers have analyzed the biochemical events associated with tolerance induction and have applied these findings to the development of new approaches to induce tolerance via the use of inhibitors of signal transduction or cell cycle progression. They are also examining cell based therapies such as regulatory T cells (see below) and myeloid-derived suppressor cells. They have also used a newly developed model of chronic GVHD that results from T:B cooperativity, leading to alloantibody and subsequently, collagen deposition, culminating in multi-organ system injury and pulmonary and liver fibrosis.
- Regulatory T cells. The Blazar lab has developed new approaches to propagate and expand CD4+25+ T regulatory cells that can suppress alloresponses and GVHD. They are analyzing the biochemical, molecular, cytokine, and cell surface factors that regulate murine and human CD4+25+ T cell development, expansion, and function in vitro and in vivo. They are also investigating how CD4+25+ T cells affect hematopoiesis and immune function in mice including models of human lymphohematopoiesis. The in vivo biological effects of the immune manipulations are being monitored using whole-body imaging techniques to track donor effector or regulatory T cells using transgenic mice expressing green fluorescent protein and firefly luciferase. Some of these studies have been translated into the clinic.
- Immune post-transplant. Because GVHD and the conditioning regimens used for bone marrow transplantation induce severe thymic injury, this group is also exploring new approaches to protect the thymic epithelial cells (TEC) against injury including the use of cytokines that stimulate TEC proliferation/repair, agents that protect against genotoxic stress, and those that repair stromal cell injury in the thymus and periphery. The mechanism(s) responsible for the protective effects of these biological agents are being explored in wild-type and in transgenic mice with disruptions of various signaling pathways. Within TECs, the researchers are examining the thymocyte signals that regulate TEC function and characterizing the effects of micro-RNA regulation on TEC regeneration and function. In complimentary studies, they are developing strategies to induce pluriopotent progenitor cells to differentiate into TECs, which will be used as a cellular therapy to replace damaged TEC. They are also analyzing the mature T cell response to foreign antigens in transplanted mice to better understand the qualitative defects associated with post-transplant T cell reconstitution and applying those to novel strategies to repair injury stromal cells in peripheral lymphoid organs.
- Graft-versus-leukemia (GVL). Projects are ongoing to identify the host mechanisms responsible for tumor-mediated immune suppression of endogenous T effector cells, focusing on negative regulators of immune response expressed on the cell surface or via intracellular pathways. Adoptive T cell immunotherapy is being tested using new approaches to generate T effector cells that have superior in vivo cytolytic potential and/or result in increased persistence of transferred T cells. T cell immune therapy is used in combination with approaches that dampen the host immune suppressive response , cause homeostatic expansion of T cells via the induction of lymphopenia, target tumor cells or support T cell recruitment and survival within secondary lymphoid organs.
- Gene therapy/repair. As an alternative to transplantation, the group is using molecular strategies to correct congenital disorders. To treat immune deficiency disorders, studies are being performed to achieve homologous recombination or site-directed integration for gene replacement using zinc finger nucleases or TALENS in hematopoietic stem cells. Recipients are analyzed for molecular and phenotypic correction.
Dr. Bruce Blazar