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 use of conditional and inducible knockout mice, transgenic mice, small molecule and drug inhibitors, and antibody/protein therapy. A major emphasis is being placed on 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-inflammatory cytokines and inflammasome activation responses that regulate these responses at the level of the GVHD target organ. We are also examining cell-based therapies such as regulatory T cells (see below) and myeloid-derived suppressor cells. Additional in vivo mechanistic insights are being gained by 2-photon microscopy imaging of mice with GVHD. We are using a newly developed model of chronic GVHD that results from Tfollicular helper/germinal center B cell cooperativity, leading to alloantibody and subsequently, collagen deposition, culminating in multi-organ system injury and pulmonary and liver fibrosis. These studies include targeted approaches that affect Tfollicular helper or regulatory cells, germinal center B cells, and anti-fibrogenic directed therapies to treat established chronic GVHD.
2. Regulatory T cells. We are analyzing and manipulating intracellular signaling pathways that restrain murine and human Treg function. We have coupled these findings to multi-spectral imaging, 2-photon microscopy, phosphoproteomics, miR-mRNA array and microarray assays and are now using these data bases to interrogate the outcome of Treg potency and survival in vitro and in vivo using gain- and loss- of function strategies. We have developed new approaches to direct Tregs to home to the gut, a primal GVHD target organ, and to sites of inflammation.
3. 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 providing Tprogenitor cells, genetically modified to express signaling molecules that support thymocyte/TEC cross-talk and thymus regeneration. Chemokine directed approaches are being used to recruit Tprogenitors to the thymus and 2-photon microscopy imaging to understand how radiation and chemokines influence recruitment to and migration within the thymus. In a second project we are examining novel approaches to regenerate secondary lymphoid organs by facilitating T- and B-cell recruitment to such organs and by providing signals needed for lymphoid organogenesis. To assess immune responses, viral and bacterial pathogen as well as leukemia immune responses are being assessed.
4. Anti-leukemia immune effector cells. Human T cell subsets have been reprogrammed into iPSCs that are being genetically modified to provide chimeric antigen receptor (CAR) expressing T cells directed against leukemia associated antigens. This technology is being used to identify critical transcription factors that are associated with various T cell differentiation states and to manipulate these transcription factors to optimize the potency and longevity of adoptively transferred T cells. In a parallel effort, novel platforms for CAR expressing T cells are being used to identify approaches that preferentially eliminate leukemia cells, while preserving normal immune function.
Selected Recent Publications:
- Parmar S, Liu X, Najjar A, Shah N, Yang H, Yvon E, Rezvani K, McNiece I, Zweidler-McKay P, Miller L, Wolpe S, Blazar BR, Shpall EJ. Ex vivo fucosylation of third-party human regulatory T cells enhances anti-graft-versus-host disease potency in vivo. Blood. 2015 Feb 26;125(9):1502-6.
- Flynn R, Allen JL, Luznik L, MacDonald KP, Paz K, Alexander KA, Vulic A, Du J, Panoskaltsis-Mortari A, Taylor PA, Poe JC, Serody JS, Murphy WJ, Hill GR, Maillard I, Koreth J, Cutler CS, Soiffer RJ, Antin JH, Ritz J, Chao NJ, Clynes RA, Sarantopoulos S, Blazar BR. Targeting Syk Activated B-cells in murine and human chronic graft-versus-host disease. Blood Apr 7. 2015. [Epub ahead of print].
- McDonald-Hyman C, Turka LA, Blazar BR. Advances and challenges in immunotherapy for solid organ and hematopoietic stem cell transplantation. Sci Transl Med. Mar 25;7(280):280rv2. Review. 2015.
- Hoseini SS, Hapke M, Herbst J, Wedekind D, Baumann R, Heinz N, Schiedlmeier B, Vignali DA, van den Brink MR, Schambach A, Blazar BR, Sauer MG. Inducible T-cell receptor expression in precursor T cells for leukemia control. Leukemia. Feb 5. [Epub ahead of print], 2015.
- Veenstra RG, Flynn R, Kreymborg K, McDonald-Hyman C, Saha A, Taylor PA, Osborn MJ, Panoskaltsis-Mortari A, Schmitt-Graeff A, Lieberknect E, Murphy WJ, Serody JS, Munn DH, Freeman GJ, Allison JP, Mak TW, van den Brink M, Zeiser R, Blazar BR. B7-H3 expression in donor T cells and host cells negatively regulates acute graft-versus-host disease lethality. Blood. Mar 26. [Epub ahead of print] 2015.
- Blazar BR, Flynn R, Lee R, Marcucci G, Caliguiri MA, Heeger PS. Strategies to inhibit alloantibody production in alloprimed murine recipients of hematopoietic stem cell grafts. 2015. Am J Transplant. Apr;15(4):931-41
- Reichenbach DK, Schwarze V, Matta BM, Tkachev V, Lieberknecht E, Liu Q, Koehn BH, Pfeifer D, Taylor PA, Prinz G, Dierbach H, Stickel N, Beck Y, Warncke M, Junt T, Schmitt-Graeff A, Nakae S, Follo M, Wertheimer T, Schwab L, Devlin J, Watkins SC, Duyster J, Ferrara JL, Turnquist HR, Zeiser R, Blazar BR. The IL-22/ST2 axis augments effector T cell responses during acute GVHD. Blood Mar 26, 2015 (Epub ahead of print)
- Hechinger AK, Smith BA, Flynn R, Hanke K, McDonald-Hyman C, Taylor PA, Pfeifer D, Hackanson B, Leonhardt F, Prinz G, Dierbach H, Schmitt-Graeff A, Kovarik J, Blazar BR, Zeiser R. Therapeutic activity of multiple common y-chain cytokine inhibition in acute and chronic GVHD. Blood 125(3):570-80, 2014.
- Dubovsky JA, Flynn R, Du J, Harrington BK, Zhong Y, Kaffenberger B, Yang C, Towns WH, Lehman A, Johnson AJ, Muthusamy N, Devine SM, Jaglowski S, Serody JS, Murphy WJ, Munn DH, Luznik L, Hill GR, Wong HK, MacDonald KK, Maillard I, Koreth J, Elias L, Cutler C, Soiffer RJ, Antin JH, Ritz J, Panoskaltsis-Mortari A, Byrd JC, Blazar BR. Ibrutinib treatment ameliorates murine chronic graft-versus-host disease. 2014. J Clin Invest. Nov;124(11):4867-76.
- Alexander KA, Flynn R, Lineburg KE, Kuns RD, Teal BE, Olver SD, Lor M, Raffelt NC, Koyama M, Leveque L, Le Texier L, Melino M, Markey KA, Varelias A, Engwerda C, Serody JS, Janela B, Ginhoux F, Clouston AD, Blazar BR, Hill GR, MacDonald KP. CSF-1-dependant donor-derived macrophages mediate chronic graft-versus-host disease. J Clin Invest. 2014 Oct;124(10):4266-80.
- Zhang SL, Wang X, Manna S, Zlotoff DA, Bryson JL, Blazar BR, Bhandoola A. Chemokine treatment rescues profound T-lineage progenitor homing defect after bone marrow transplant conditioning in mice. Blood 124(2):296-304, 2014.
- MacDonald KP, Le Texier L, Zhang P, Morris H, Kuns RD, Lineburg KE, Leveque L, Don AL, Markey KA, Vuckovic S, Bagger FO, Boyle GM, Blazar BR, Hill GR. Modification of T cell responses by stem cell mobilization requires direct signaling of the T cell by G-CSF and IL-10. J Immunol 192(7):3180-9, 2014
- Flynn R, Du J, Veenstra RG, Reichenbach DK, Panoskaltsis-Mortari A, Taylor PA, Freeman GJ, Serody JS, Murphy WJ, Munn DH, Sarantopoulos S, Luznik L, Maillard I, Koreth J, Cutler C, Soiffer RJ, Antin JH, Ritz J, Dubovsky JA, Byrd JC, MacDonald KP, Hill GR, Blazar BR. Increased T follicular helper cells and germinal center B cells are required for cGVHD and bronchiolitis obliterans. Blood. 2014 Jun 19;123(25):3988-98.
- Lin KL, Fulton LM, Berginski M, West ML, Taylor NA, Moran TP, Coghill JM, Blazar BR, Bear JE, Serody JS. Intravital imaging of donor allogeneic effector and regulatory T cells with host dendritic cells during GVHD. Blood 123(10):1604-14, 2014.
- Saha A, Aoyama K, Taylor PA, Koehn BH, Veenstra RG, Panoskaltsis-Mortari A, Munn DH, Murphy WJ, Azuma M, Yagita H, Fife BT, Sayegh MH, Najafian N, Socié G, Ahmed R, Freeman GJ, Sharpe AH, Blazar BR. Host programmed death ligand 1 is dominant over programmed death ligand 2 expression in regulating graft-verus-host disease lethality. Blood 122(17):3062-73. 2013.
- Coghill JM, Fowler KA, West ML, Fulton LM, van Deventer H, McKinnon KP, Vincent BG, Lin K, Panoskaltsis-Mortari A, Cook DN, Blazar BR, Serody JS. CC Chemokine receptor 8 protentiates donor Treg survival and is critical for the prevention of murine graft-versus-host disease. Blood 122(5):825-36, 2013
- Aoyama K, Saha A, Tolar J, Riddle MJ, Veenstra RG, Taylor PA, Blomhoff R, Panoskaltsis-Mortari A, Klebanoff CA, Socié G, Munn DH, Murphy WJ, Serody JS, Fulton LM, Teshima T, Chandraranta RA, Dmitrovsky E, Buo Y, Noelle RJ, Blazar BR. Inhibiting retinoic acid signaling ameliorates graft-versus-host disease by modifyint T-cell differentiation and intestinal migration. Blood 122(12):2125-34 2012
- Zuklys S, Mayer CE, Zhanbekova S, Stefanski HE, Nusspaumer G, Gill J, Barthlott T, Chappaz S, Nitta T, Dooley J, Nogales-Cadenas R, Takahama Y, Finke D, Liston A, Blazar BR, Pascual-Montano A, Holländer GA. MicroRNAs control the maintenance of thymic epithelia and their competence for T lineage Commitment and thymocyte selection. J Immunol. 189(8):3894-904, 2012.
- Veenstra RG, Taylor PA, Zhou Q, Panoskaltsis-Mortari A, Hirashima M, Flynn R, Liu D, Anderson AC, Strom TB, Kuchroo VK, Blazar BR. Contrasting acute graft-versus-host disease effects of Tim-3/galectin-9 pathway blockade dependent upon the presence of donor regulatory T cells. Blood. 2012 Jul 19;120(3):682-90.
- 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. Donor B-cell alloantibody deposition and germinal center formation are required for the development of murine chronic GVHD and bronchiolitis obliterans. Blood. 2012. Feb 9;119(6):1570-80.