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Jonathan S. Bromberg, MD, PhD

Academic Title:

Professor

Primary Appointment:

Surgery

Secondary Appointment(s):

Microbiology and Immunology

Administrative Title:

Vice Chair For Research

Additional Title:

Professor of Surgery and Microbiology and Immunology

Location:

22 S. Greene Street, S8B06

Phone (Primary):

410-328-0008

Phone (Secondary):

410-328-5408

Fax:

410-328-0401

Education and Training

EDUCATION

 

            1970-1973          Wyoming High School, Wyoming, OH

            1973-1974          Gresham’s School, Holt, Norfolk, England

            1974-1977          Harvard College, Cambridge, MA; A.B. (summa cum laude, phi beta kappa, Biology)

            1978-1983          Harvard Medical School, Boston, MA; M.D.

            1979-1983          Harvard Graduate School of Arts and Sciences, Boston, MA; Ph.D.

                                       (Immunology, Drs. Baruj Benacerraf and Mark Greene)

 

POSTGRADUATE AND POSTDOCTORAL TRAINING

 

            1977-1978          Postgraduate researcher, ICRF Tumor Immunology Unit, University College, London (Drs. N. Avrion Mitchison and P. Lake)

 

            1983-1988          Intern, resident, chief resident, Department of General Surgery,

                                       University of Washington Affiliated Hospitals, Seattle, WA

 

            1986-1988          Coinvestigator, Human Antigen-Specific T Suppressor Cell Genetic

                                       Markers, University of Washington and Virginia Mason Research

                                       Center, Seattle, WA (Dr. Jerry Nepom)

 

            1988-1990          Fellow, Division of Transplantation, Department of Surgery,

                                       Hospital of the University of Pennsylvania, Philadelphia, PA

Biosketch

A. Personal Statement

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.

B.  Positions and Honors

 

Academic Appointments

1988-1990       Clinical Instructor, Hospital of the University of Pennsylvania

1990-1994                   Assistant and Associate (1992) Professor of Surgery and Microbiology and Immunology, MUSC

    1. Associate Professor and Full Professor (1998) of Surgery and Microbiology and Immunology, University of Michigan

      1999-2010       Professor of Surgery and Gene and Cell Medicine, Chief Kidney/Pancreas Transplantation, Transplant Research, Transplantation Institute, Mount Sinai School of Medicine

      2010-present   Professor of Surgery and Microbiology and Immunology, Chief and Director of Research, Division of Transplantation, Director of Strategic Planning for Transplantation Services, University of Maryland School of Medicine

      C. Contributions to Science

      1. Major questions in 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 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.

            a. 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.

            b. 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

            c. 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

            d. 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

      2. The understanding of induction, stimulation, maintenance, and activity of FoxP3+ CD4+ suppressive regulatory T cells (Treg) is critical to manipulating immunity. We were 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. 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.

            a. 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. PMID: 15367216

            b. 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

            c. 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

            d. 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

      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.

            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.

            a. 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

            b. 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

            c. 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

            d.   Brinkman CC, Iwami D, Hritzko MK, Xiong, Y Ahmad, Bromberg JS. Treg engage lymphotoxin beta receptor for afferent lymphatic transendothelial migration. Nature Communications 2106; 7:12021. PMID: 27323847

      4. 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 to investigations of other discrete cells and structures, their regulation, and their roles in immunity and tolerance. During tolerization we showed 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 between the 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.

            a. 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

            b. 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

            c. 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, 99:1119-1125. PMID: 25769074

            d. Tostanoski LH, Chui Y-C, Gammon JM, Simon T, Andorko J, Bromberg JS, Jewell CM. Reprogramming the local lymph node microenvironment during autoimmunity promotes systemic, yet antigen-specific tolerance. Cell Reports 2016, 16:2940–2952. PMID: 27626664

      5. 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.

            a. 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

            b. 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

            c. 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

            d. 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

       

      Link to my full CV:

      http://www.ncbi.nlm.nih.gov/sites/myncbi/jonathan.bromberg.1/bibliography/41147754/public/?sort=date&direction=ascending

       

       

Research/Clinical Keywords

Transplantation, Immunology, Tolerance, Migration, Microbiota

Highlighted Publications

Tostanoski LH, Chui Y-C, Gammon JM, Simon T, Andorko J, Bromberg JS, Jewell CM. Reprogramming the local lymph node microenvironment during autoimmunity promotes systemic, yet antigen-specific tolerance. Cell Reports 2016, 16:2940–2952. PMID: 27626664

Brinkman CC, Iwami D, Hritzko MK, Xiong, Y Ahmad, Bromberg JS. Treg engage lymphotoxin beta receptor for afferent lymphatic transendothelial migration. Nature Communications 2106; 7:12021. PMID: 27323847

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

 

Research Interests

 

  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.

Clinical Specialty Details

Kidney and pancreas transplantation

Awards and Affiliations

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

2015    CMI-B Special Emphasis Panel ZRG1-IMM-C 02 M

2015    2015/10 AICS, Atherosclerosis and Inflammation of the Cardiovascular System Study Section

Grants and Contracts

Research Support

COMPLETED

     PI: Bromberg; NIH RO1 AI41428; 06/15/08 – 05/31/13; Migration and Trafficking in Tolerance.  The major goals of this project are: 1.) What are the T-APC-LN interaction that are important for tolerance; 2.) How is priming of effector T cells altered in the LN during tolerance; and 3.) What are the roles of B cells in the LN in tolerance?

     PI: Bromberg;        American Society of Transplant Surgeons; 07/01/11 – 06/30/13; Changes in the human microbiota induced by post-transplant medication.  The major goals of this project are to: 1.) Enroll kidney transplant patients to collect oral swabs, stool, urine, and blood sample types once before and once after transplantation; 2) Compare changes in the taxonomic composition of the microbial communities before and after transplantation; and 3) Determine the small metabolite composition in urine samples before and after the transplantation.

     PI: Bromberg; NIH R56 AI72039; 08/01/12 – 07/31/13; Lymphoid Structure in Tolerance: Role of Stromal Cells. The major goals of this project are to: 1.) Demonstrate that FRC regulate tolerance; 2.) Demonstrate that FRC regulate T cell function; and 3.) Demonstrate that FRC regulate DC function. 

     PI: Bromberg; NIH RO1 AI062765; 05/01/10-04/30/15; Induction and migration of regulatory T cells.  The major goals of this project are to determine: 1.) Mechanisms of Treg migration from blood to tissues to dLN, and how sequential migration regulates Treg differentiation and suppressive function; 2.) Mechanisms of LTαβ-LTβR regulation of Treg migration and suppressor function; and 3.) Determine how Treg regulate lymphatic migration.

     PI: Bromberg; NIH R56 AI41428; 04/15/14 – 03/31/15; Migration and Trafficking in Tolerance.  The major goals of this project are: 1.) Define the role of cortical ridge stromal structures for transplant tolerance; 2.)  Define the molecular regulation of the pathway for HEV and cortical ridge entry of T cells and conversion to iTreg during tolerance; and 3.) In the tolerant recipient, define how iTreg and pDC regulate the entry and fate of new T cells entering the LN via the HEV.

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).

 

ACTIVE

     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 and Wenji Piao; 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.  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 LTab - LEC LTbR interactions regulate migration.

     PI: Jewell. VA Maryland Health Care System; 12/1/16-11/30/20; Tunable Assembly of Regulatory Immune Signals to Promote Myelin-specific Tolerance. The major goals of this project are: 1.) Characterize iPEM material properties and screen in primary mouse cells and MS patient samples; 2.) Assess potency in progressive autoimmune disease (EAE) and test if tolerance is myelin-specific; 3.) Elucidate the structural and functional changes in LNs, spleen, and the CNS that lead to tolerance; and 4.) Test if tolerance is generalizable to other self-antigens using relapsing-remitting model (RR-EAE).

     PI: Jewell. JDRF; 9/1/16-8/30/18; Engineering local lymph node function to promote systemic, antigen-specific tolerance in T1D. The major goals of this project are: 1.) Design and screen depots loaded with Rapa and T1D antigens in dendritic cell (DC) and transgenic T cell culture; 2.) Test depot efficacy in T1D mouse models during early or late stage treatment and determine the specificity of tolerance; and 3.) Elucidate the structural and functional changes in LNs, spleen, and pancreatic islets that lead to tolerance.

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