MICaB Graduate Program
Main navigation |
Bruce Blazar, M.D.
Immunobiology of transplantation
My laboratory is focused upon the immunobiology of transplantation. There are four basic project areas:
1. 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. We 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. We are also examining cell based therapies such as regulatory T cells (see below) and myeloid-derived suppressor cells. We 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.
2. Regulatory T cells. We have developed new approaches to propagate and expand CD4+25+ T regulatory cells that can suppress alloresponses and GVHD . We 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. We 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 our 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.
2. Immune post-transplant. Because GVHD and the conditioning regimens used for bone marrow transplantation induce severe thymic injury, we also are 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, we 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, we are developing strategies to induce pluriopotent progenitor cells to differentiate into TECs, which will be used as a cellular therapy to replace damaged TEC. We also are 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.
3. 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.
4. Gene therapy/repair. As an alternative to transplantation, we are 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.
Selected Recent Publications:
- Hippen KL, Bucher C, Schirm DK, Bearl AM, Brender T, Mink KA, Waggie KS, Peffault de Latour R, Janin A, Curtsinger JM, Dillon SR, Miller JS, Socie G, Blazar BR. 2012. Blocking IL-21 signaling ameliorates xenogeneic GVHD induced by human lymphocytes. Blood. 119(2):619-28.
- Srinivasan M, Flynn R, Price A, Ranger A, Browning JL, Taylor PA, Ritz J, Antin JH, Murphy WJ, Luznik L, Shlomchik MJ, Panoskaltsis-Mortari A*, Blazar BR* (co-last authors). 2012. Donor B-cell alloantibody deposition and germinal center formation are required for the development of murine chronic GVHD and bronchiolitis obliterans. Blood 119(6):1570-80.
- Hippen KL, Merkel SC, Schirm DK, Sieben CM, Sumstad D, Kadidlo DM, McKenna DH, Bromberg JS, Levine BL, Riley JL, June CH, Scheinberg P, Douek DC, Miller JS, Wagner JE, Blazar BR. 2011. Massive ex vivo expansion of human natural regulatory T cells (Tregs) with minimal loss of in vivo functional activity. Science Translational Medicine 3: 83ra41.
- Zanin-Zhorov A, Dustin ML, Blazar BR. 2011. PKC theta and the immunological synapse: mechanisms and implications. Trends in Immunol. 32:358-63.
- Hippen KL, Merkel SM, Schirm DK, Nelson C, Riley JL, June CH, Miller JS, Wagner JE, Blazar BR. 2011. Generation and large-scale expansion of human inducible regulatory T cells (iTregs) that suppress graft-versus-host disease (GVHD). Amer. J. Transplantation 11:1148-57.
- Zhou Q, Munger ME, Veenestra RG, Weigel BJ, Hirashima M, Munn DH, Murphy WJ, Azuma M, Anderson AC, Kuchroo VK, Blazar BR. 2011. Co-expression of T-Cell Immunoglobulin and Mucin 3 Protein (Tim-3) and Program Death-1 (PD-1) Identifies an Exhaustion Phenotype of T cells in Mice with Dissemminated Acute Myelogenous Leukemia (AML). Blood 117:4501-10.
- Vogtenhuber C, Bucher C, Highfill S, Jasperson LK, Goren E, Panoskaltsis-Mortari A, Taylor PA, Farrar MA, Blazar BR. 2010. Constitutively active Stat5 in CD4+ T cells inhibits graft-versus-host disease lethality associated with increased regulatory T-cell potency and decreased T effector cell responses. Blood 116:466-74.
- Zanin-Zhorov A, Ding Y, Kumari S, Attur M, Hippen KL, Brown M, Blazar BR, Abramson SB, Lafaillie JJ, Dustin ML. 2010. Protein kinase C-theta mediates negative feedback on regulatory T cell function. Science 328:372-6.
- Holländer GA, Krenger W, Blazar BR. Emerging strategies to boost thymic function. Curr Opin Pharmacol. 443-53, 2010.
- Highfill SL, Rodriguez PC, Zhou Q, Goetz CA, Koehn BH, Veenstra R, Taylor PA, Panoskaltsis-Mortari A, Serody JS, Munn DH, Tolar J, Ochoa AC, Blazar BR. 2010. Bone marrow myeloid-derived suppressor cells (MDSC) inhibit graft-versus-host (GVHD) disease via an arginase-1 dependent mechanism that is upregulated by IL-13.
- Zhou Q, Munger ME, Highfill SL, Tolar J, Weigel BJ, Riddle M, Sharpe AH, Vallera DA, Azuma M, Levine BL, June CH, Murphy WJ, Munn DH, Blazar BR. 2010. Program death-1 (PD-1) signaling and regulatory T cells (Tregs) collaborate to resist the function of adoptively transferred cytotoxic T lymphocytes (CTLs) in advanced acute myeloid leukemia. Blood. 116(14):2484-93.
- Vogtenhuber C, Bucher C, Highfill S, Jasperson LK, Goren E, Panoskaltsis-Mortari A, Taylor PA, Farrar MA, Blazar BR. 2010. Constitutively active Stat5 in CD4+ T cells inhibits graft-versus-host disease (GVHD) lethality associated with increased regulatory T-cell (Treg) potency and decreased effector T cell (Teff) responses. Blood 116(3):466-74.
- Kelly RM, Goren EM, Taylor PA, Mueller SN, Stefanski HE, Osborn MJ, Scott HS, Gudkov AV, Hollander GA, Blazar BR. 2010. Short-term inhibition of p53 combined with keratinocyte growth factor improves thymic epithelial cell recovery and enhances T-cell reconstitution after murine bone marrow transplantation. Blood 115:1088-97.
- Bucher C, Koch L, Vogtenhuber C, Goren E, Munger M, Panoskaltsis-Mortari A, Sivakumar P, Blazar BR. 2009. IL-21 blockcade reduces graft-versus-host disease mortality by supporting inducible T regulatory cell generation. Blood 114L5375-84.
- Jasperson LK, Bucher C, Panoskaltsis-Mortari A, Mellor AL, Munn DH, Blazar BR.2009. Inducing the tryptophan catabolic pathway, indoleamine 2,3-dioxygenase (IDO), for suppression of graft-versus-host disease (GVHD) lethality. Blood 114:5062-70.
- Zhou Q, Bucher C, Munger ME, Highfill SL, Vallera DA, Weigel BJ, Blazar BR. 2009. Combined IL2 diptheria toxin and cytotoxic T lymphocyte infusion for treating advanced acute myeloid leukemia. Blood 114:3793-802.
- Highfill SL, Kelly RM, O’Shaughnessy MJ, Zhou Q, Xia L, Panoskaltsis-Mortari A, Taylor PA, Tolar J, Blazar BR .2009. Multipotent Adult Progenitor Cells (MAPC) can suppress graft-versus-host disease via prostaglandin E-2 synthesis and only if localized to sites of allopriming. Blood.114:693-701.
- Riley JL, June CH, Blazar BR. 2009. Human T regulatory cells as therapeutic agents: take a billion or so and call me in the morning. Immunity. [review] 30:656-65.