Research Program: Transplant Biology and Therapy
Regents Professor, Department of Pediatrics, Hematology-Oncology
Section Chief, Pediatric Blood and Marrow Transplantation
Director, Center for Translational Medicine

blaza001@umn.edu
612-626-1926 — office
Preferred method of contact: Phone

Dr. Blazar's clinical profile
(University of Minnesota Physicians Web site)

Dr. Blazar's laboratory Web site

Dr. Blazar is a professor of pediatrics in the Division of Hematology-Oncology and Blood and Marrow Transplantation and attends on the Pediatric Blood and Marrow Transplantation (BMT) service. He is the director of the Center for Translational Medicine, created to bring innovative, early phase therapies into the clinic. He also is principal investigator for the Clinical and Translational Sciences Institute that is being established and designed to transform health through clinical translational science, and community and university partnerships by streamlining and facilitating community-relevant research while collaborating across disciplines, organizations, and communities.

Dr. Blazar has served as a past chair of the National Institutes of Health Cancer Immunopathology and Immunotherapy Study Section, Food and Drug Administration Biological Response Modifiers Advisory Committee, and the Leukemia and Lymphoma Translational Research Award Committee. He is a current member of the American Society of Gene Therapy Immunology Committee, Immune Tolerance Network Executive Committee, and the National Cancer Institute Board of Scientific Counselors for Clinical Sciences and Epidemiology, Center for Cancer Research. Dr. Blazar is the recipient of an NIH MERIT Award and is the principal investigator of several other NIH-funded studies focusing on BMT and cancer immunobiology in preclinical model systems and in the clinic. He is the recipient of the Andersen Chair in Transplantation Immunology and a member of the Academic Health Center's Academy of Excellence in Health Research which recognize his pioneering work in the development of novel immune-based therapies. He is the author of more than 400 manuscripts, which have appeared in premier peer-reviewed publications.

Research Interests

1. Prevention of graft-versus-host disease (GVHD). We developed new approaches to propagate and expand CD4+25+ T regulatory cells that can suppress alloresponses after in vivo adoptive transfer and have isolated novel populations that have more potent regulatory/suppressor cell activity. In other studies, we have uncovered the effects of novel pathways that regulate T cell responses in lymphoid organs and in the periphery and developed an ex vivo induction of tolerance as a means of preventing GVHD. 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. Such methodologies are being applied to the analysis of CD4+25+ T regulatory cells. Ongoing studies are testing regulatory T cells in patients undergoing hematopoietic cell transplantation.
2. Development of new strategies to enhance immune recovery after transplantation. Because GVHD and the conditioning regimens used for bone marrow transplantation induce severe thymic injury, we also are exploring novel approaches to protect the thymic epithelial cells (TEC) against injury including the use of cytokines that stimulate TEC proliferation/repair (keratinocyte growth factor), agents that protect against genotoxic stress, and those that prevent endogenous hormone induced suppression of thymopoiesis (sex steroid hormone blockade) along with cellular replacement approaches.
3. Prevention of tumor/leukemia relapse. Projects are ongoing to utilize dendritic cell hybrid fusion vaccines as a means of inducing anti-leukemia immune responses in vivo. Adoptive T cell immunotherapy is being utilized alone, in conjunction with dendritic cell fusion vaccines. For adoptive immunotherapy, we have developed new approaches to simultaneously track green fluorescent cytotoxic lymphocytes that are generated in vitro against leukemia cells and tumor cells and are focused upon the cell intrinsic and extrinsic properties that limit adoptive T cell efficacy.
4. Gene therapy and tissue repair. As an alternative to allotransplantation, we will use molecular strategies to correct immune and enzymatic disoders. Transposans and zinc finger nucleases that are being tested to provide more site directed gene correction. Both reporter gene constructs and disease correction constructs are being tested in murine models and in murine models in which human cord blood cells are given. In addition, we are infusing non-hematopoietic stem cells as a means of repairing tissue injuries or providing a source of gene corrected cells for inherited disorders.

For a more information, please visit the Blazar Laboratory Web site.

Selected Publications

(2007-present)

Taylor PA, Ehrhardt MJ, Lees CJ, Tolar J, Weigel BJ, Panoskaltsis-Mortari A, Serody JS, Brinkmann V, Blazar BR. Insights into the mechanism of FTY720 and compatibility with regulatory T cells for the inhibition of graft-versus-host disease (GVHD). Blood. 110:3480-8, 2007.

Burchill MA, Yang J, Vogtenhuber C, Blazar BR, Farrar MA. IL-2 receptor beta-dependent STAT5 activation is required for the development of Foxp3. regulatory T cells. J Immunol. 178:280-90, 2007.

Serafini M, Dylla SJ, Oki M, Heremans Y, Tolar J, Jiang Y, Buckley SM, Pelacho B, Burns TC, Frommer S, Rossi DJ, Bryder D, Panoskaltsis-Mortari A, O'Shaughnessy MJ, Nelson-Holte M, Fine GC, Weissman IL, Blazar BR, Verfaillie CM. Hematopoietic reconstitution by multipotent adult progenitor cells: precursors to long-term hematopoietic stem cells. J Exp Med. 204:129-39, 2007

Tolar J, Wang X, Braunlin E, McElmurry RT, Nakamura Y, Bell S, Xia L, Zhang J, Hu Q, Panoskaltsis-Mortari A, Zhang J, Blazar BR, he host immune response is essential for the beneficial effect of adult stem cells after myocardial ischemia. Exp Hematol. 35:682-90, 2007.

Rossi SW, Jeker LT, Ueno T, Kuse S, Keller MP, Zuklys S, Gudkov AV, Takahama Y, Krenger W, Blazar BR, Holländer GA. Keratinocyte growth factor (KGF) enhances postnatal T-cell development via enhancements in proliferation and function of thymic epithelial cells. Blood. 109:3803-11, 2007.

O'Shaughnessy MJ, Chen Z-M, Gramaglia I, Taylor PA, Panoskaltsis-Mortari A, Vogtenhuber C, Palmer E, Grader-Beck T, Boussiotis VA, Blazar BR. Elevation of intracellular cyclic AMP in alloreactive CD4+ T cells induces alloantigen-specific tolerance that can prevent GVHD lethality in vivo. Biol Blood Marrow Transplant. 13:530-42, 2007.

Zayed H, Xia L, Yerich A, Yant SR, Kay MA, Puttaraju M, McGarrity GJ, Wiest DL, McIvor RS, Tolar J, Blazar BR. Correction of DNA protein kinase deficiency by spliceosome-mediated RN. trans-splicing an. Sleeping Beaut. transposon delivery. Mol Ther. 15:1273-9, 2007.

Sharma MD, Baban B, Chandler P, Hou D-Y, Singh N, Yagita H, Azuma M, Blazar BR. Mellor AL, Munn DH. Plasmacytoi. dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tres via indoleamine 2,3-dioxygenase. Clin Invest. 117:2570-82, 2007.

Panoskaltsis-Mortari A, Tram KV, Price AP, Wendt CH, Blazar BR. A new murine model for bronchiolitis obliterans post-bon. marrow transplant. Am J Respir Crit Care Med. 176:713-23, 2007.

Miller JS, Weisdorf DJ, Burns LJ, Slungaar. A, Wagner JE, Verneris MR, Cooley S, Wangen R, Fautsch SK, Nicklow R, DeFor T, Blazar BR. Lymphodepletion followed by donor lymphocyte infusion (DLI) causes significantly more acute graft-versus-host disease than DLI alone. Blood. 110:2761-3. 2007.

Guimond M, Leonard WJ, Spolski R, Rossi SW, Veenstra RG, Hollander GA, Mackall CL. Blaza. BR. Thymic stromal lymphopoietin is not necessary or sufficient to mediate the thymopoietic effects of keratinocyte growth factor. Blood. 111:969-70, 2008.

Jasperson LK, Bucher C, Panoskaltsis-Mortari A, Taylor PA, Mellor AL, Munn DH. Blazar BR. Indoleamine 2,3-dioxygenase is a critical regulator of acute graft-versus-host disease lethality. Blood. 111:3257-65, 200.

Kelly RM, Highfill SL, Panoskaltsis-Mortari A, Taylor PA, Boyd RL, Hollander GA, Blazar BR. Keratinocyte growth factor and androgen blockade work in concert to protect against conditioning regimen-induced thymic epithelial damage and enhance T-cell reconstitution following murine bone marrow transplantation. Blood. 111:5734-44, 2008.

Panoskaltsis-Mortari A, Taylor PA, Riddle MJ, Shlomchik MA, Blazar BR. In situ identification of allospecific B cells using pentamers. Blood. 111:3904-5. 2008.

Osborn MJ, McElmurry RT, Peacock B, Tolar J, Blazar BR. Targeting of the CNS in MPS-IH using a nonviral transferrin-α-L-iduronidase) fusion gene product. Mol Ther. Advance online publication 3 June 2008.

Ghosh A, Wolenski M, Klein C, Welte K. Blazar BR, Sauer MG. Cytotoxic T cells reactive to an immunodominant leukemia-associated antigen can be specifically primed and expanded by combining a specific priming step with nonspecific large-scale expansion. J Immunother. 31(2):121-31, 2008.

Golovina TN, Mikheeva T, Suhoski MM, Aqui N, Tai V, Shan X, Liu R, Carroll RG. Blazar BR, June CH, Riley JL. CD28 costimulation is essential for T regulatory expansion and function. J.Immunol. 181:2855-68, 2008

Hippen K, Harker-Murray P, Porter SB, Merkel SC, Londer A, Taylor DK, Bina M, Panoskaltsis-Mortari A, Rubinstein P, Van Rooijen N, Golovina TN, Suhoski MM, Miller JS, Wagner JE, Jun. H, Riley J, Blazar BR. Umbilical cord blood regulatory T cell (Treg) expansion and functional effects of tumor necrosis factor receptor (TNFR) family members OX40 and 4-1BB expressed on artificial antigen-presenting cells (aAPCs). Blood. [epub July 21], 2008.

Taylor PA, Ehrhardt MJ, Lees CJ. Panoskaltsis-Mortari A, Krieg AM, Sharpe AH, Murphy WJ, Serody JS, Hemmi H, Akira S, Levy RB, Blazar BR. TLR agonists regulate alloresponses and uncover a critical role for donor APCs in allogeneic bone marrow rejection. Blood. [epub 9 July] 2008.