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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: 410-328-0008
Cell: 917-968-4428
Lab: 410-706-8070

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.
  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.
  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.
  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.
  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.
  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.

Research Interests:

I have been involved continuously in basic cellular and molecular transplant immunology for over 25 years and have been continuously funded for the entire time. My basic research has always focused on T cell immunobiology, and for more than 15 years has also focused on issues of migration, trafficking, secondary lymphoid organ structure and function, and lymphatic structure and function, and how these processes and structures influence T cell immunity and T cell tolerance in models of cardiac transplantation and pancreatic islet transplantation. I have also maintained an active clinical practice in solid organ transplantation and am thus constantly exposed to the problems of patients and their immune systems, including cellular and humoral rejection, opportunistic infections, chronic viral disease, autoimmune organ failure, and immunosuppression medication side effects. My basic research and clinical interests are especially well suited to complement and inform each other, and to keep each aspect of my professional life current and relevant.

Lab Techniques and Equipment:

  • Murine models of islet and cardiac transplantation.
  • Migration and trafficking of T cells and dendriticcells.

Clinical Specialty:

Transplant Surgery, Kidney and Pancreas Transplantation

Grants and Contracts:

PI: Bromberg; NIH 1R01AI114496-01; 5/1/15-4/30/20; Lymph Node Structure and Function in Tolerance: Role of Laminins.

The major goals of this project are:  1.) Determine the role of CR laminins in transplant tolerance; Determine how laminins regulate HEV and CR entry of T cells and their conversion to iTreg in tolerance; and 3.) Determine how laminins regulate the migration and fate of a later cohort of naive T cells that newly enter the HEV and CR tolerant environment.

Co-PI and mentor for C. Colin Brinkman; Living Legacy Foundation Transplantation Grant, 7/1/14-6/30/16, The role of lymphotoxin in Treg migration and suppressor function.

The major goals of this project are: 1.) If Treg migrate from blood to tissues, but cannot migrate out of tissues, does this change suppression of nonTreg in the tissues?; 2.) What is the fate of non-migrated Treg and are they suppressive?; and 3.) If Treg cannot migrate out of tissues, does this change suppression of nonTreg cells in the dLN?

Co-PI with Emmanuel Mongodin, Living Legacy Foundation Transplantation Grant, 7/1/14-6/30/16, Microbiota Structure and Transplant Outcomes: Preclinical Studies.

The major goals of this project are: 1.) Determine the effects of different microbiota on allograft survival and alloimmunity; 2.) Determine how the microbiota population structure evolves during allograft survival and rejection; and 3.) Determine how transplantation, immunosuppression and antibiotics alter microbiota structure

PI: Jewell. University of Maryland Innovation Initiative; 4/6/15-1/6/16; Exploiting intra-lymph node controlled release to combat autoimmunity without broad immunosuppression.

The major goals of this project are: 1.) Test if depots promote TREGS and prevent or reverse progressive autoimmune disease (EAE); 2.) Determine the roles that signal ratio, location, and delivery kinetics play in TREG induction; 3.) Define the impact of depots on local lymph node structure and function; and 4.) Test if depots can prevent or reverse relapsing-remitting autoimmune disease (RR-EAE).

PI: Jewell. National Multiple Sclerosis Society; 10/1/15-9/30/18; Harnessing intra-lymph node controlled release to promote myelin-specific tolerance.

The major goals of this project are: 1.) Test if depots promote TREGS and stop or reverse progressive autoimmune disease (EAE); 2.) Decipher the local and systemic changes in myelin response that lead to tolerance; and 3.) Test if depots can stop or reverse relapsing-remitting autoimmune disease (RR-EAE).

PI: Bromberg; NIH 1RO1AI062765; 8/1/15-1/31/20; Induction and Migration of Regulatory T Cells: Role of Lymphotoxin.

The major goals of this project are: 1.) Determine if LT regulation of Treg afferent lymphatic migration is required for suppression of Tconv in tissues and dLN; and 2.) Determine how Treg LTï ¡ï ¢ - LEC LTï ¢R interactions regulate migration.


See Dr. Bromberg's publications at the NCBI website.

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.

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. PMID: 15905542

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. PMID: 16633346

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. PMID: 22176785

Fu S, Yopp AC, Mao M, Chen D, Zhang H, Chen D, Bromberg JS. TGF-ï ¢ induces Foxp3+ T regulatory cells from CD4+CD25- precursors. Am.J.Transplant., 2004, 4:1614-1627. PMID: 15367216

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. PMID: 19109157

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. PMID: 20551515

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. PMID: 21593401

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. PMID: 19303390

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. PMID: 21219575

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. PMID: 18037890

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. PMID: 22132197 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. PMID: 24691446

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. PMID: 22594431

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. PMID: 25769074

Nakayama Y, Brinkmann, CC, Bromberg JS. Murine fibroblastic reticular cells from lymph node interact with CD4+ T cells through CD40-CD40L. Transplantation, 2015, in press. PMID: 25856408

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. PMID: 11823485

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. PMID: 12618517

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. PMID: 16116177

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. PMID: 18037890