Blazar Laboratory
The main research interest in the Blazar laboratory is in immunobiology and transplantation.
There are five basic project areas we are currently investigating:
Graft-Versus-Host Disease Projects
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 GVHD generation. These include the analysis of costimulatory molecules and negative regulators of the immune response, metabolic stress responses, and local gut environmental factors that regulate GVHD. We are 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.
Regulatory T Cells (TREGS) Projects
We have developed new approaches to propagate and expand CD4+25+ Tregs that can suppress alloresponses and GVHD. We are analyzing and manipulating the biochemical, molecular, cytokine and cell surface factors that regulate murine and human thymic-derived and peripheral inducible Treg development, expansion and function in vitro and in vivo. The in vivo biological effects of our immune manipulations are being monitored using in vivo 2-photon, bioluminescent and fluorescent stereomicroscopic imaging. Some of these studies have been translated into the clinic.
Immune Recovery and Regeneration Post-Transplant Projects
Because GVHD and bone marrow transplantation conditioning regimens cause severe thymic and lymph node injury. We are exploring new approaches to protect the thymic epithelial cells (TEC) against injury and repair or replace stromal cells in the thymus and lymph nodes. The mechanism(s) responsible for the protective effects of biological agents and cell therapies are being explored in wild-type and in transgenic mice. We are examining the signals that regulate TEC and lymph node stroma regeneration and function. We are developing new strategies to use embryonic and induced pluriopotent progenitor cells to differentiate into TECs, which will be used as a cellular therapy to replace damaged epithelial and stromal cells. Within the context of bone marrow transplantation, we are analyzing the mature T cell response to viral, bacterial and tumor antigens to better understand the qualitative defects associated with post-transplant immune deficiency.
Graft Versus Leukemia (GVL) Projects
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. 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 are being explored.
Genetic Manipulations and Reprogramming of Immature and Mature Cells Project
We are using gene transfer approaches to introduce transcription factors and cytokine genes into thymic progenitor cells to stimulate thymic epithelial cell signaling, reprogram mature T cells and regulatory T cells into pluripotent stem cells, understand and manipulate mature regulatory T cells, and to examine transcription factors and epigenetic modification process involved in definitive vs non-definitive hematopoiesis.
This research is funded from a combination of government grants, private foundations, and donations.
Agencies that have supported our research:
- National Institutes of Health / National Cancer Institute
- National Institutes of Health / National Institute of Aging
- National Institutes of Health/National Institute of Allergy and Infectious Diseases
- National Institutes of Health/National Heart, Lung and Blood Institute
- Department of Defense
- Children's Cancer Research Fund
- Leukemia and Lymphoma Society
- Minnesota Medical Foundation
- Fanconi Anemia Research Fund, Inc.
- Progeria Research Foundation
- American Heart Association
- DebRA International
The laboratory is actively involved in education, participating in undergraduate, graduate, and postdoctoral training programs.
Below are the current protocols in use in the Blazar Lab.
Dr. Jakub Tolar
Dr. Tolar’s research interests include:
- Integrating clinical observation, molecular biology, immunology, and laboratory research in studying and treating children with lethal diseases—epidermolysis bullosa, bone marrow failure, peroxisomal and lysosomal inborn errors of metabolism, cancer and other devastating disorders.
- Developing cellular therapies (including mesenchymal stromal cells and cellular reprogramming).
- Improving the safety of existing therapies (hematopoietic cell transplantation and its conditioning regimens).
- Investigating mechanisms by which stem cell transplantation is effective in repair of damaged tissues (e.g., heart, skin and brain).
Clinically, Dr. Tolar is currently working on protocols using hematopoietic stem cell transplant as a treatment for epidermolysis bullosa, dyskeratosis congenita, severe aplastic anemia, Fanconi anemia, mucopolysaccharidosis type I – Hurler syndrome, and adrenoleukodystrophy.
Dr. Keli Hippen
Dr. Hippen's research is focused on inhibiting Graft Versus Host Disease (GVHD), which is a frequent and severe complicating factor in bone marrow transplants. GVHD is a T cell mediated disease that arises in autoimmune fashion due to graft-derived immune cells recognizing recipient cells as non-self. Activation of autorective T cells (and those that induce GVHD) is normally prevented by a subset of T cells termed regulatory T cells (Treg). Transplant of donor Treg has been shown to ameliorate disease in mouse models of both GVHD and autoimmunity. Dr. Hippen's specific interest is defining the mechanisms that control human regulatory T cell proliferation and function with the goal of generating large numbers of very active cells that can be co-transferred at the time of bone marrow transplantation and reduce or completely abolish GVHD. These studies have led to 'first-in-man' studies using ex vivo expanded Treg that demonstrated these cells are safe, and can ameliorate GVHD in humans. Dr. Hippen's current projects include: defining Treg signaling pathways that enhance expansion and/or suppressive function and inducing suppressive function using in human T cells (not Treg) via TGFß, nutrient stress, or co-ligation of inhibitory molecules.
Dr. Heather Stefanski
Dr. Stefanski's research is focused on expediting immune reconstitution after transplant. T lymphocytes are critical for effective responses to viruses and fungal infections; after undergoing bone marrow transplantation there are essentially no functional T cells until up to a year after transplant. In her laboratory, she is currently working on T cell reconstitution in order to decrease morbidity and mortality.
Dr. Mark Osborn
Dr. Osborn's research focuses on the following 3 areas:
- Gene Therapy: Non-viral gene transfer for the treatment of inborn errors of metabolism.
- Genome Editing: Correction of disease specific mutations in a precise manner using homologous recombination.
- Cellular Therapy: Ex vivo correction of murine and human adult stem cells.
Principal Investigator
Bruce Blazar, MD, is a Professor of Pediatrics in the Division Pediatric Blood and Marrow Transplantation & Cellular Therapy and attends on the Pediatric Blood and Marrow Transplantation (BMT) service.
He is the recipient of the Andersen Chair in Transplantation Immunology to recognize his pioneering work in the development of novel immune-based therapies.
Select Honors
- Member, Institute of Medicine
- Ernest Beutler Prize and Lectureship, American Society of Hematology
Contact
blaza001@umn.edu
612-626-2734