Bookmark and Share

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
jbromberg@smail.umaryland.edu
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 transplantation, 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.

Research Interests:

CD4+CD25+Foxp3+ regulatory T cells (Treg) are important regulators for virtually all immune responses, and are key elements for establishing and maintaining antigen specific tolerance. While Treg and Foxp3 expression have been the focus of much research, basic aspects of Treg physiology and function remain incompletely understood. In particular, it is not known where and when Treg or their precursors precisely interact with antigen, become activated, and deploy their suppressive regulatory mechanisms. The cellular and molecular mechanisms important for each of these steps are poorly delineated, and the migration and trafficking mechanisms essential for priming at one site and effector function in another site remain largely unknown. In the previous funding period, we published a number of important studies revealing that during tolerization, naïve T cells migrate to lymph nodes (LN), where they are stimulated in the cortical area by specific alloantigen presenting plasmacytoid dendritic cells (pDC), next to the abluminal surface of the high endothelial venules (HEV), to generate adaptive or induced Treg (aTreg). We elucidated several important molecular mechanisms in these interactions including roles for IL-2, TGF-beta, T cell receptor (TCR), chemokines (CCL17, CCL19, CCL21), chemokine receptors (CCR4, CCR7), sphingosine-1-phosphate (S1P), and S1P receptor-1 (S1P1).

In ongoing studies, we have made several additional key observations. First, investigation of molecular factors that control Foxp3 expression revealed an upstream CpG island enhancer that is epigenetically regulated by DNA methylation, and that is completely methylated in aTreg versus being unmethylated in thymus derived natural Treg (nTreg). Manipulation of this enhancer by using DNA methyltransferase (DNMT) inhibitors drives Foxp3 expression, allowing us to generate Treg subsets that resemble either aTreg or nTreg. Second, we demonstrated that nTreg migrate sequentially from the blood through microvascular endothelium into the site of tissue inflammation, and then subsequently from tissue into afferent lymphatics and then the draining LN (dLN), in order to become activated and display suppressor functions for islet allograft survival. Sequential tissue and dLN migration are key components of nTreg function, and migration is coupled to Treg developmental and differentiative steps. In contrast, aTreg precursors migrate first to the LN, and then to sites of inflammation. Third, Treg specifically express increased levels of lymphotoxin-alpha (LT-alpha) and LT-beta. In contrast, endothelial cells, including lymphatic endothelial cells, express LT-beta receptor (LT-beta-R). Inhibition of the LTalpha-beta-LT-beta-R receptor-ligand interaction prevents Treg translymphatic endothelial migration (nTreg more so than aTreg), and inhibits tolerance to islet and cardiac allografts. Together these novel observations demonstrate important differences in the physiology and function of aTreg versus nTreg. We hypothesize that aTreg and nTreg have distinct requirements for induction, migration, trafficking and suppressive function, and that these distinctions are critically important for their separate roles in immune suppression and regulation. To investigate this hypothesis, we propose the following three specific aims:

Aim 1. Elucidate mechanisms of Treg migration from blood to tissues to dLN, and how sequential migration regulates Treg differentiation and suppressive function. Using adoptive transfer and islet transplant models, we will investigate the separate steps of migration of aTreg and nTreg from blood into tissues and then tissues into dLN. The experiments will determine the molecular and cellular mechanisms that regulate Treg migration at each step, determine how these steps regulate Treg activation, and determine how these Treg responses then regulate immunity. aTreg will be compared to nTreg, as the Preliminary data demonstrate that distinct mechanisms of action and molecular signatures distinguish between these Treg subsets.

Aim 2. Define mechanisms of LT-alpha-beta
-LT-beta-R regulation of Treg migration and suppressor function. Using adoptive transfer, islet transplant and inflammatory models, and a novel in vitro model of afferent lymphatic migration, we will investigate the functional interaction of LT-alpha-beta on Treg with LT-beta-R on lymphatic vascular endothelial cells and antigen presenting cells, and how this interaction regulates Treg induction, proliferation, suppressor function, and migration.

Aim 3.
Determine how Treg regulate lymphatic migration. Using in vitro models and adoptive transfer with islet transplant and inflammatory models, we will investigate the interaction of Treg with afferent lymphatics and how this interaction alters lymphatic function and the migration of other leukocyte subsets, including B cells, CD4+ and CD8+ T cells, macrophages, and dendritic cells (DC). Molecular mechanisms involving chemokines, integrins, S1PRs, and LT-beta-R on these other leukocyte subsets will be investigated.

Despite the detailed understanding of signals 1, 2, and 3 and the critical function of T cells and dendritic cells (DC), clinical transplantation tolerance is almost never achieved. In transplantation, models of immune function, and interventions designed to promote immune regulation, have been based on simplified receptor-ligand and cell-cell interaction models. There has been a lack of studies that place immunological recognition within anatomic contexts and evaluate the critical role of anatomic microdomains in the regulation of the immune response. Our preliminary data now demonstrate that during tolerization there is alloantigen specific clustering of T cells and plasmacytoid DC (pDC) in the T cell areas of the lymph node (LN) near the abluminal surface of the high endothelial venules (HEV). Within these clusters T cells undergo either priming or development into de novo CD4+CD25+ regulatory T cells (Treg). Importantly, B cells presenting specific alloantigen are present in these cell clusters and contribute to Treg development.

We hypothesize these multicellular clustered interactions in the LN are key to the induction and maintenance of tolerance. Specifically, we hypothesize that the precise interaction of T-APC (pDC, B cells) determines the outcome of T cell migration, positioning, proliferation, and maturation, and ultimately whether rejection or tolerance are induced. This hypothesis integrates many of the known receptor-ligand and cell-cell interactions, and places these interactions in the context of secondary lymphoid organ structure. To investigate the role of these cellular and structural elements in LN clustered interactions, we propose the following specific aims:

Aim 1. What are the T-APC-LN interactions that are important for tolerance? Using a transplant model that allows the tracking of alloantigen specific T cells, specific alloantigen presenting APC, and the positioning of the cells with respect to HEV, we will characterize specific receptor-ligand interactions between T-HEV and pDC-HEV that regulate tolerance, and define the interactions between T-pDC and other DC that determine the generation of Treg and inhibition of effector T cells within the LN.

Aim 2. How is the priming of effector T cells altered in the LN during tolerance? This aim will study the specific interaction between effector T cells and Treg in the LN clusters during tolerization. We will determine how Treg-T effector interactions regulate effector T cell migration, proliferation, and differentiation. We will characterize specific receptor-ligand interactions between Treg and T effector cells that determine whether T cell priming and rejection versus suppression and tolerance predominate in the immune response.

Aim 3. Determine the role of B cells in tolerance in the LN We will investigate the roles of B cells in the LN during the T-APC clustered interaction that results in tolerization. Analyses will focus on B cell APC function, chemokine production, and immunoglobulin production.

Our currently funded investigations are focused on the fate and differentiation of Treg, on T cell migration and trafficking in tolerance, and on the role of T-pDC interactions that regulate both Treg and T cell trafficking. While T cell responses have a central role in transplantation tolerance, our new preliminary data suggest novel and important roles in the LN for B cells, stromal cells, stromal fibers, and other LN elements in the clustered interaction that leads to tolerization. To investigate the role of these novel cellular and structural elements in LN clustered interactions, we propose the following specific aims:

Aim 1. Determine the roles of B cells in LN structure and tolerance Using a transplant model that allows the specific tracking of antigen specific T cells and specific alloantigen presenting antigen presenting cells (APC), we will investigate the roles of B cells in the LN during the T-APC clustered interaction that results in tolerization. Analyses will focus on B cell APC function, chemokine production, and immunoglobulin production.

Aim 2. Determine the LN stromal structures and cells essential for tolerance We will investigate the role of stromal cells and stromal cell derived elements in the LN in the T-APC clustered interaction during tolerization.

Aim 3. Determine the role of invariant innate cellular immune responses in tolerance We will determine how NK1.1+ cells, that respond to innate and invariant signals, affect the T-APC clustered interaction, LN structure, and tolerization.

We hypothesize these multicellular clustered interactions in the LN are key to the induction and maintenance of tolerance to islet allografts. Specifically, we hypothesize that the precise interaction of T-pDC determines the outcome of T cell migration, positioning, proliferation, and maturation, and ultimately whether rejection or tolerance are induced. This novel hypothesis integrates many of the known receptor-ligand and cell-cell interactions, and places these interactions in the context of secondary lymphoid organ structure and function. To investigate the role of these cellular and structural interactions in LN clustered interactions, we propose the following specific aims:

Aim 1. Determine the T-DC-LN interactions that are required for tolerance Using a transplant model that allows the tracking of alloantigen specific T cells, specific alloantigen presenting antigen presenting cells (APC), and the positioning of the cells with respect to HEV, we will characterize specific receptor-ligand interactions between T-HEV and pDC-HEV that regulate tolerance, and define the interactions between T-pDC and other DC that determine the generation of Treg and inhibition of effector T cells within the LN.

Aim 2. Determine the LN stromal structures and cells essential for tolerance We will investigate the role of stromal cells and stromal cell derived elements in the LN in the T-DC clustered interaction during tolerization.


Clinical Speciality:

Kidney and pancreas transplantation

Presentations:

Anatomy of Tolerance: Lymph Node Migration and Induction of Treg, Transplant Grand Rounds, University of Wisconsin, Madison, WI, September 18, 2012.

 

Anatomy of Immunity (or Why Surgeons are so Important for Research), Surgery Grand Rounds, University of Wisconsin, Madison, WI, September 19, 2012.


Grant Award and Service:

Lymphoid Structure in Tolerance, NIH R56 AI072039, 08/01/12-07/31/13, $250,000. (PI)

Service

Grant review for the Armed Forces Institute of Regenerative Medicine, September 2012


Publications:

Burrell, BE and Bromberg, JS. Fates of CD4+ T Cells in a Tolerant Environment Depend on Timing and Place of Antigen Exposure. American Journal of Transplantation. 2012 Mar;12(3):576-589.

Commentary on above article: Burlingham, WJ. Timing Is Everything in Tolerance. American Journal of Transplantation. 2012;12(3):517-518


Selected Publications

Yin, N, Xu, J, Ginhoux, F, Randolph, GJ, Merad, M, Ding, Y, Bromberg, JS.  Functional Specialization of Islet Dendritic Cell Subsets. J. Immunol. 2012, 188: 4921–4930.
 
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.
 
Van der Touw, W, Burrell, B, Lal, G, Bromberg, JS. NK cells are required for co-stimulatory blockade induced tolerance to vascularized allografts. Transplant. 2012, 94:575-584.
 
Ford M, Bromberg JS.  Literature Watch: Memory T Cells: New Insights Into the Molecular Basis of Sensitivity and Heterogeneity.  Am J Transplant, 2012, 12: 1361.
 
Maltzmann JS, Bromberg JS. Literature Watch: Leukocyte: Tempus Fugit Vel Carpe Diem.  Am J Transplant, 2012, 12:1665.
 
Alegre M-L, Bromberg JS. Literature Watch: Commensal Microbiota Determine Intestinal iTreg.  Am J Transplant, 2012, 12:1967.
 
Li XC, Bromberg JS. Literature Watch: Mast Cells: Infl ammatory, Immunoregulatory or Something In Between?  Am J Transplant, 2012, 12:2265.
 
Bromberg, J.S. Book review: Innate Alloimmunity Part 2: Innate Immunity and Allograft Rejection.  Am. J. Transplant. (2012) 12:1950

Ding, Y, Qin, L, Kotenko, SV, Pestka, S, Bromberg, JS. A single amino acid determines the immunostimulatory activity of IL-10. J. Exp. Med., 2000; 191:213-224.

Qin L, Ding Y, Tahara H, Bromberg JS. Viral IL-10 induced immunosuppression requires TH2 cytokines and impairs APC function within the allograft. J. Immunol., 2001, 166:2385-2393.

Ding Y, Qin L, Tarcsafalvi A, Kotenko S, Pestka S, Bromberg, JS. Differential IL-10R1 expression plays a critical role in IL-10 mediated immunoregulation, J.Immunol., 2001, 167:6884-6892.

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.

Ding Y, Chen, D, Tarcsafalvi, A, Su R, Qin L, Bromberg JS. Suppressor of cytokine signaling 1 inhibits IL-10 mediated immune responses. J. Immunol., 2003, 170:1383-1391.

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.

Yopp AC, Fu S, Honig SM, Randolph GJ, Bromberg JS. FTY720 enhanced T cell homing is dependent on CCR2, CCR5, CCR7, and CXCR4: evidence for distinct chemokine compartments. J. Immunol., 2004, 173:855-865.

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

Qu C, Edwards EW, Tacke F, Angeli V, Llodra J, Sanchez-Schmitz G, Garin A, Haque NS, Peters W, van Rooijen N, Sanchez-Torres C, Bromberg J, Charo IF, Jung S, Lira SA, Randolph GJ. Analysis of chemokine pathways that affect migration of monocyte-derived dendritic cells to lymph nodes: identification of a novel function for CCR8. J.Exp.Med., 2004, 200:1231-1241.

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.

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.

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.

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.

Ochando JC, Krieger NR, Bromberg JS. Direct versus indirect allorecognition: visualization of dendritic cell distribution and interactions during rejection and tolerization. Am. J. Transplantation, 2006, 6:2488-2496.

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.

Yang, Y, Niu, Y, Bromberg, JS, Ding, Y. T-bet and Eomes play critical roles in directing T cell differentiation to Th1 versus Th17. J. Immunol., 2008; 181:8700-8710.

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.

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.

Buonamici, S, Trimarchi, T, Ruocco, MG, Reavie, L, Cathelin, S, Klinakis, A, Mar, BG, Lukyanov, Y, Tseng, J-C, Sen, F, Gehrie, E, Li, M, Newcomb, E, Zavadil, J, Meruelo, D, Efstratiadis, A, Lipp, M, Ibrahim, S, Zagzag, D, Bromberg, JS, Dustin, ML, Aifantis, I. CCR7 signaling as an essential regulator of CNS infiltration in T cell leukemia. Nature, 2009; 459:1000-1004.