Jonathan S. Bromberg, MD, PhD

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.

Kidney and pancreas transplantation

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

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.