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Jonathan S. Bromberg

Jonathan S. Bromberg M.D., Ph.D.

Academic Title: Professor
Primary Appointment: Surgery
Secondary Appointments: Microbiology and Immunology
Administrative Title: Division Head, Transplant Surgery
Location: 29 S. Greene Street, Suite 200
Phone: (410) 328-5408

Personal History:

Best known for his innovative research involving immunosuppressive therapies, Dr. Bromberg has devoted his career to investigating the role of immunology in tolerance, with a current focus on the effects of chemokines and cell migration on the immune response. A committed clinician with an active practice, he also has been named among New York Magazine’s New York's Best Doctors for five years in a row.

Over the course of 20 years, Dr. Bromberg's work has been continuously supported by the NIH. Since 1999, he has received more than $11 million in federal funding, including $1.4 million in 2008 alone, and more than $1.5 million support in non-federal funding. Significant research accomplishments include:

  • the first to show that anti-CD2 mAbs were immunosuppressive and prolonged graft survival.
  • the first to show that the combination of anti-CD2 plus anti-CD3 mAbs induced alloantigen specific tolerance.
  • the first to show that IL-10 gene transfer could prolong allograft survival.
  • the first to show the structure-function relations of viral and human IL-10 binding to the IL-10 receptor in terms of affinity, avidity, STAT activation, and downstream biological effects.
  • first to show that tolerance is an active immunological process that takes place in the lymph nodes to generate regulatory suppressive Foxp3+ T cells, while immunization takes place in the spleen to generate effector cells that reject the graft.
  • first to show that plasmacytoid dendritic cells take up exogenous antigens and present them for tolerance or immunity.
  • first to show that natural thymus derived regulatory suppressive T cells are activated and function in peripheral tissues, while peripherally induced suppressor cells are activated and function in secondary lymphoid organs. each of these subsets subsequently migrates through lymphatics to secondary locations to continue their suppressive programs and functions.
  • first to show that sphingosine-1 phosphate (S1P) and the S1P receptor 1 regulate T cell migration from tissues into afferent lymphatics and subsequently into draining lymph nodes.
  • the first to show that the immunosuppressant FTY720, an analogue of S1P, acts through activation of the Abc transporter molecules in T cell surface to change the efflux of lipid mediators of cell migration.

After completing both his M.D. and PhD from Harvard, Dr. Bromberg completed a surgical residency at the University of Washington. His training continued with a transplantation fellowship at the University of Pennsylvania. Prior to his arrival at Maryland, he held academic titles at the University of Michigan, where he was Professor of General Surgery in the Division of Transplantation and Professor of Microbiology and Immunology, and at the University of Pennsylvania, the Mount Sinai School of Medicine, and the Medical University of South Carolina.

Dr. Bromberg has authored more than 230 publications, of which includes 193 peer-reviewed publications. Additionally he has been an invited speaker for numerous presentations and has received several national honors, including most recently the Joel J. Roslyn Commemorative Lecture (New Considerations in Tolerization, Society of University Surgeons), the 2002 Andrew Lazarovits Lecture (Canadian Society of Transplantation), and the 2005 Alfred and Florence Gross Professor of Surgery.

Honors and Awards

1975-Edwards-Whitaker Award; 1975,76,77-John Harvard Award; 1976-Phi Beta Kappa; 1977-Detur Book Prize; 1977-Summa Cum Laude, Biology; 1979-83-Medical Scientist Training Program Fellowship; 1983-James Tolbert Shipley Prize; 1988-90-Sandoz Award, American Society of Transplant Surgeons; 1992-94-American Surgical Association Foundation Fellowship Award; 1992-Thomas A. and Shirley W. Roe Foundation Award; 1997-Excellence in reviewing, Journal of Surgical Research; 1998-ASTS Roche Presidential Travel Award; 1992-present: NIAID, NIDCR, SAT, and SBIR study sections; 2001-Roslyn Commemorative Lecture, Society of University Surgeons; 2000-2014-American Journal of Transplantation, Associate Editor, Deputy Editor, Section Editor for Literature Watch; 2000-2005-Journal of Immunology, Section Editor; 2002–Lazarovits Commemorative Lecture, Canadian Society of Transplantation; 2013-AST Basic Science Established Investigator Award; 2014-present-Transplantation, Clinical Sciences Executive Editor; 2014-NKF of Maryland, Kidney Champion Award

Recent Grant Review Committees and Boards

2010 Two year site review for REMEDI, National University Galway Ireland, Science Foundation Ireland
2010-14 National Institute of Dental and Craniofacial Research, NIH, Board of Scientific Counselors
2010 Israel Science Foundation, ad hoc reviewer
2010 Medical Research Council (England), ad hoc reviewer
2011 TTT NIH Study Section special review panel ZRG IMM-C 02
2011 Swiss National Science Foundation, ad hoc reviewer
2012 Armed Forces Institute of Regenerative Medicine
2013 Clinical and Rehabilitative Medicine Research Program (CRMRP), U.S. Army, Restorative Transplantation Research Cooperative Agreement (RTRCA)
2013 British Heart Foundation, ad hoc reviewer
2013 Leukemia and Lymphoma Research, ad hoc reviewer
2014 State of Pennsylvania, review of PPGs in Diabetes
2014 NIAID Special Emphasis Panel 2015/01 ZAI1 QV-I (J3) 1

Contributions to Science

1. Major questions in the field of organ transplant are where does tolerance take place and what processes determine the choice between tolerance and immunity. Using a variety of pharmacologic and genetic approaches in both cardiac and islet transplant models, my lab demonstrated that normal lymph node functions and structures are required for tolerance induction and maintenance. We demonstrated the requirement for CD4+ T cell migration from blood into lymph nodes, regulated by a variety of selectins, integrins, and chemokines, that determine T cell anergy, apoptosis, and regulatory T cell induction and suppression. In addition, plasmacytoid dendritic cells (pDC) are also required to migrate into lymph nodes and present alloantigen to T cells. These studies provided novel evidence for active roles of the lymph node in determining the fate of T cells and the immune response.

  1. Bai, Y, Liu, J, Wang, Y, Honig, S, Qin, L, Boros, P, Bromberg, JS. L-selectin dependent lymphoid occupancy is required to induce alloantigen specific tolerance. J. Immunol., 2002, 168:1579-1589.
  2. Ochando, JC, Yopp, AC, Yang, Y, Li, Y, Boros P, Llodra, J, Ding, Y, Krieger, N, Bromberg, JS. Lymph node occupancy is required for the peripheral development of alloantigen-specific Foxp3+ regulatory T cells. J. Immunol., 2005, 174:6993-7005.
  3. Ochando JC, Homma C, Yang Y, Hidalgo A, Garin A, Tacke F, Angeli V, Li Y, Boros P, Ding Y, Jessberger R, Lira SA, Randolph GJ, and Bromberg JS,  Alloantigen-presenting plasmacytoid dendritic cells mediate tolerance to vascularized grafts. Nature Immunol., 2006, 7:652-662.
  4. Burrell, BE, Bromberg, JS. Fates of CD4+ T cells in a tolerant environment depend on timing and place of antigen exposure.  Am. J. Transplant., 2012, 12:576-589.

2. There has been a great deal of interest in understanding the induction, stimulation, maintenance, and activity of FoxP3+ CD4+ suppressive regulatory T cells (Treg). My laboratory was one of the first to demonstrate that TGFb is required for Treg induction, and that inflammatory stimuli and cytokines can inhibit Foxp3 induction or stability. Epigenetic regulation of the Foxp3 gene is critical for Treg activity, and Foxp3 gene expression and structure can be manipulated with T cell receptor and costimulatory signals, cytokine and TLR signals, and methyltransferase inhibitors. These results were extended to the generation of human Tregs in vitro for therapeutic use in vivo. We also demonstrated critical roles for IL10, TGFb, and the induction of myeloid derived suppressor cells in the mechanisms of Treg suppression and tolerance. These studies defined important pharmacologic modulators of Treg that can be translated into clinically relevant approaches for therapy.

  1. Fu S, Yopp AC, Mao M, Chen D, Zhang H, Chen D, Bromberg JS.  TGF-b induces Foxp3+ T regulatory cells from CD4+CD25- precursors. Am.J.Transplant., 2004, 4:1614-1627.
  2. Lal G, Zhang N, van der Touw W, Ding Y, Ju W, Bottinger E, Reid SP, Levy DE, Bromberg JS.  Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. J. Immunol., 2009, 182:259-273.
  3. Rodriguez Garcia M, Ledgerwood L, Yang Y, Xu J, Lal G, Burrell B, Ma G, Grisotto M, Hashimoto D, Li Y, Boros P, van Rooijen N, Matesanz R, Tacke R, Ginhoux F, Ding Y, Chen S-H, Randolph G, Merad M, Bromberg JS, Ochando J.  Monocytic suppressive cells mediate transplantation tolerance in mice.  J. Clin. Invest., 2010, 120:2486-2496.
  4. Hippen, KL, Merkel, SC, Schirm, DK, Sieben, CM, Sumstad, D, Kadidlo, DM, McKenna, DH, Bromberg, JS, Levine, BL, Riley, JL, June, CH, Miller, JS, Wagner, JE, Blazar, BR.  Massive ex vivo expansion of human natural regulatory T cells (Tregs) with minimal loss of in vivo functional activity. Sci. Transl. Med., 2011, 3:83ra41.

3. A major issue concerning Treg suppressive and tolerogenic competence is to discover how to deliver these cells to the right place at the right time. My lab was the first to demonstrate that Treg not only must be induced in lymph nodes, but also must migration from tissues through afferent lymphatics into lymph nodes in order to fully suppress inflammation and immunity and prolong islet allograft survival. Lymphatic migration is regulated by a number of integrins, selectins, chemokines, and sphingosine 1-phospate receptors (S1PR) on the T cell. Treg interact with endothelial cells, parenchymal cells, and antigen presenting cells during their migration, effecting distinct suppressive activities required for graft survival and required for the induction and maintenance of Treg activation and suppressive function. These studies defined novel aspects of Treg function that point toward therapeutically important implications for manipulating immunity and suppression.

  1. Chen D, Zhang N, Fu S, Schroppel B, Guo Q, Xu J, Garin A, Lira SA, Bromberg JS.  CD4+CD25+ T Regulatory cells inhibit the islet innate immune response and promote islet engraftment. Diabetes, 2006, 55:1011-1021.
  2. Zhang N, Schroppel B, Lal G, Jakubzick C, Mao X, Chen D, Jessberger R, Ochando JC, Bromberg JS.  Regulatory T cells sequentially migrate from the site of tissue inflammation to the draining LN to suppress allograft rejection. Immunity, 2009, 30:458-469.
  3. Lal, G, Yin, N, Xu, J, Lin, M, Schroppel, B, Ding, Y, Marie, I, Levy, DE, Bromberg, JS. Distinct inflammatory signals have physiologically divergent effects on epigenetic regulation of Foxp3 expression and Treg function. Am. J. Transplant., 2011, 11:203-214.

4. The structure and function of lymphatic vessels are poorly understood, in large part due to the difficulty of isolating these cells for in vitro work and manipulating and imaging these structures in vivo. Our studies on Treg migration led to more general studies of lymphatic function. We defined a stable lymphatic endothelial cell (LEC) line that recapitulates LEC function in vitro, allowing ablumenal-to-lumenal migration to a chemokine gradient, but not the reverse migration. In contrast, blood endothelial cells permit migration in both directions.  A sphingosine 1-phosphate (S1P) gradient promotes transendothelial migration across LEC, while a high concentration of S1P, such as occurs in acute inflammation, inhibits afferent lymphatic migration, retaining immune cells in tissues. Lymphangiogenesis not only occurs in the presence of inflammation, but also promotes inflammation and can be targeted to prevent allograft rejection. These studies defined new tools for lymphatic research and defined potential novel therapeutic approaches to modulating inflammation.

  1. Ledgerwood, LG, Lal, G, Zhang, N, Garin, A, Esses, SJ, Ginhoux, F, Peche, H, Lira, SA, Ding, Y, Yang, Y, He, X, Schuchman, EH, Allende, ML, Ochando, JC, Bromberg, JS. Sphingosine 1-phosphate receptor S1P1 causes tissue retention by inhibiting peripheral tissue T lymphocyte entry into afferent lymphatics.  Nature Immunol., 2008, 9:42-53.
  2. Yin, N, Zhang, N, Xu, J, Shi, Q, Ding, Y, Bromberg, JS. Targeting          lymphangiogenesis after islet transplantation prolongs islet allograft survival.      Transplantation, 2011, 92:25-30.
  3. Yin, N, Zhang, N, Lal, G, Xu, J, Yan, M, Ding, Y, Bromberg, JS. Lymphangiogenesis is required for pancreatic islet inflammation and diabetes. PLoS ONE, 2011, 6 (11):e28023.
  4. Iwami D, Brinkman CC, Bromberg JS. VEGF-C/VEGFR-3 Signaling regulates chemokine gradients and lymphocyte migration from tissues to lymphatics. Transplantation, 2015, in press.

5. The recognition that lymph nodes are required for tolerance and that there are distinct domains within the lymph node committed to different aspects of immunity, led my lab to investigate other discrete cells and structures, their regulation, and their roles in immunity and tolerance. During tolerization we noted that alloantigen specific Treg and pDC presenting specific alloantigen were concentration around the cortical ridge, an area that encompasses the high endothelial venules and is a site for trafficking into the lymph node and between cortex and medulla. During tolerance there is increased laminin a4 and decreased laminin a5 in the cortical ridge, while during immunity the ratios are reversed. There is a role for fibroblastic reticular cells in regulating lymph node structure and cytokines, antigen presentation, and tolerance. Other stromal fibers, such as ERTR-7, also dictate CD4+ T cell, Treg, and pDC movements and the choice between tolerance and immunity.  These studies defined novel roles for stromal fibers, stromal cells, and the cortical ridge in tolerance.

  1. Warren, KJ, Iwami, D, Harris, DG, Bromberg, JS, Burrell, BE. Vascular basement membrane proteins laminin alpha 4 and laminin alpha 5 differentially influence CD4+ T cell lymph node trafficking and allograft fate. J. Clin. Invest., 2014, 124:2204-2218.
  2. Nakayama, Y, Bromberg, JS. Murine lymphotoxin-beta receptor signaling regulates stromal cell chemokine expression and neutrophil trafficking required for tolerance. Am. J. Transplant., 2012, 12: 2322–2334.
  3. Burrell BE, Warren KJ, Nakayama Y, Iwami, D, Brinkman, CC, Bromberg JS. The lymph node stromal fiber (ER-TR7) functions to modulate CD4+ T cell lymph node trafficking and transplant tolerance. Transplantation, 2015, in press.
  4. Nakayama Y, Brinkmann, CC, Bromberg JS. Fibroblastic reticular cells in lymph node regulate immune responses through CD40-CD40L interactions. Transplantation, 2015, in press.

6. The discovery of the role of S1PR in leukocyte-transendothelial migration has recently opened up new areas of investigation to uncover the role of S1P and S1PR in diverse aspects of immunity and inflammation. We assessed the role of the major T cell S1PR1 receptor in migration, immunity, and tolerance. We uncovered novel activities for the S1PR agonist/antagonist FTY20 in modulating lymph node versus splenic migration, and immunity versus tolerance. My lab discovered that S1PR signaling involves a complex cascade, engaging multidrug transporters and cysteinyl leukotriene synthesis and transport to fully effect changes in lymphocyte migration. S1P acts as both a chemotactic cytokine and as an inhibitor of migration, depending on concentration and gradients. Targeting S1PR promotes graft survival and tolerance. These studies defined novel aspects of S1P and S1PR metabolism and function and shed new light on how activators and inhibitors may have highly complex effects in vivo.

  1. Bai, Y, Liu, J, Wang, Y, Honig, S, Qin, L, Boros, P, Bromberg, JS. L-selectin dependent lymphoid occupancy is required to induce alloantigen specific tolerance. J. Immunol., 2002, 168:1579-1589.
  2. Honig SM, Fu S, Mao X, Yopp A, Gunn MD, Randolph GJ, Bromberg JS.  FTY720 stimulates multidrug transporter and cysteinyl leukotriene dependent T cell chemotaxis to lymph nodes. J. Clin. Invest., 2003, 11:627-637.
  3. Yopp AC, Ochando JC, Mao M, Ledgerwood L, Ding Y, Bromberg JS. Sphingosine 1-phosphate receptors regulate chemokine driven transendothelial migration of lymph node but not splenic T cells. J. Immunol., 2005, 175:2913-2924.
  4. Ledgerwood, LG, Lal, G, Zhang, N, Garin, A, Esses, SJ, Ginhoux, F, Peche, H, Lira, SA, Ding, Y, Yang, Y, He, X, Schuchman, EH, Allende, ML, Ochando, JC, Bromberg, JS. Sphingosine 1-phosphate receptor S1P1 causes tissue retention by inhibiting peripheral tissue T lymphocyte entry into afferent lymphatics.  Nature Immunol., 2008, 9:42-53.

Clinical Specialty:

Kidney and pancreas transplantation.