Specialty	Surgery
Subspecialty	Abdominal Organ Transplant
Clinical Interests	Dialysis Access Procedures
	Kidney Transplant
	Pancreas Transplant
	Surgery, General
Gender	Male
E-mail	jon.bromberg@mountsinai.org
Education and Training	MD, Harvard Medical School
	PhD, Harvard Graduate School of Arts and Sciences
	Residency, Surgery, University of Washington Med Ctr.
	Fellowship, Transplantation, Hospital of The University Of Penn.
Awards	2009 Best Doctors New York Magazine
	2002 Andrew Lazarovits Lecture Canadian Society of Transplantation
	2001 Joel J. Roslyn Commemorative Lecture, New Considerations in Tolerization Society of University Surgeons
	2000 Mary Jane Kugel Award Juvenile Diabetes Foundation, International
	1998 ASTS Roche Presidential Travel Award
	1997 Excellence in reviewing Journal of Surgical Research
	1992 - 1994 American Surgical Association Foundation Fellowship Award
	1992 Thomas A. and Shirley W. Roe Foundation Award
	1988 - 1990 Sandoz Award American Society of Transplant Surgeons
	1983 James Tolbert Shipley Prize Harvard Medical School
	1979 - 1983 Medical Scientist Training Program Fellowship Harvard Medical School

Dr. Bromberg earned his M.D. and his Ph.D. from Harvard University. He completed his surgical residency at the University of Washington and his multiorgan transplantation fellowship at the University of Pennsylvania. His most recent appointment was at the University of Michigan, where he was Professor of General Surgery in the Division of Transplantation and Professor of Microbiology and Immunology. Before that, he held appointments at the University of Pennsylvania and the Medical University of South Carolina. In each of these positions, Dr. Bromberg took leadership roles in starting, building, and reorganizing critical components of multiorgan transplant programs. He is widely recognized as an outstanding clinician, highly regarded by his medical and nursing colleagues, his students, and his patients.

In addition to his clinical transplantation practice, Dr. Bromberg is also pursuing highly regarded research on transplant rejection. A gifted, innovative investigator, he has devoted his career to basic and clinical research involving immunology and transplantation. His laboratory at the University of Michigan was one of the first to use gene transfer techniques to show that gene therapy vectors could be used to transfer immunosuppressive cytokine genes to allografts and that expression of these genes within allografts would prolong graft survival. His current projects are focused on the effects of chemokines and cell migration on the immune response. He has received major grant support for these and other investigations from the NIH as well as from biomedical foundations and research corporations.

In the News

Dr. Bromberg discusses organ transplants and immunology research in The Daily News feature "The Daily Check Up." View the PDF.

Education and Training	MD, Harvard Medical School
	PhD, Harvard Graduate School of Arts and Sciences
	Residency, Surgery, University of Washington Med Ctr.
	Fellowship, Transplantation, Hospital of The University Of Penn.
Board Certification	Surgery

Specialty	Surgery
Subspecialty	Abdominal Organ Transplant
Clinical Interests	Dialysis Access Procedures
	Kidney Transplant
	Pancreas Transplant
	Surgery, General
Board Certification	Surgery

Research
Specific Clinical/Research Interest:
Basic: molecular and cellular transplantation immunology. Clinical: pediatric and adult kidney and pancreas transplantation.

Current Students: William Van der Touw

Postdoctoral Fellows: Yu Yang, Ghirdari Lal, Bryna Burrell, Na Yin, Yumi Nakayama, Jiangnan Xu

Research Personnel: Peter Boros, Dan Chen, Yansui Li, Jianhua Liu

Summary of Research Studies:
Peripheral tolerance induction to alloantigen in the mature immune system remains an elusive goal. A number of maneuvers which interfere with signal 1 (antigen receptors), signal 2 (costimulatory receptors), so-called signal 3 (inflammatory cytokines), or antigen processing can result in prolonged or indefinite allograft survival via mechanisms including clonal abortion, deletion, anergy, deviation, and/or agnosia. It is not certain which methods, mechanisms, cells or molecules are most relevant for achieving nontoxic, long-lived, alloantigen specific tolerance, free from chronic immunosuppression and chronic rejection. The general failure to reach these goals suggests that there are additional levels of immune regulation. It is noteworthy that the majority of approaches to tolerance have examined molecular and cellular mechanisms in vitro, or graft survival in vivo, without regard to structural and anatomic compartmentalization that may dictate additional levels of reg! ulation. Therefore, the definition of the anatomic domains where alloantigen is presented to induce tolerance, and where lymphocytes interact with antigen and immunosuppressants to become tolerized (deleted, anergized, deviated, ignorant) are likely to be critical determinants of the tolerization process. Our preliminary data demonstrate that T lymphocytes must utilize L-selectin to remain in the lymph node in order to induce alloantigen specific tolerance in models that perturb signal 1 or signal 2. We hypothesize that lymph node homing and localization are required for peripheral tolerance induction, and that the lymph node domain is uniquely suited to peripheral, alloantigen specific tolerance. Corollaries are that localization of T lymphocytes to other compartments, or lymph node depletion of T lymphocytes, will prevent peripheral tolerance induction. Additional implications are that quantitative distribution, such as the ratio or absolute number of T cells in lymph! nodes versus other compartments (e.g., peripheral blood, spl! een), and temporal distribution during tolerization regimens determine the balance between immunity and tolerance. We are investigating this hypothesis as follows:

1) Determine why inhibition of CD62L dependent T cell LN homing prevent s tolerance;
2) Determine what other receptors and ligands are important for T cell homing and tolerance induction;
3) Determine the role of specific anatomic sites during tolerance induction.

Despite marked improvements in understanding the immune system, tolerance is still not reliably achieved. Recent studies have shown that intercellular regulation is required to modulate immune responses and induce or maintain tolerance. In particular, regulatory T cells (Treg) have emerged as major elements of the apparatus that controls immunity and tolerance. Among the regulatory T cells that have been described are anergic CD4+CD25+ Treg. These cells express the Foxp3 transcription factor, which is to date the most specific marker for cells that possess the Treg suppressive function. Foxp3 may be a  master switch  for the transcriptional program for Treg function. Despite progress in the field, many issues and characteristics remain incompletely defined or unexplored. For e xample, how are Foxp3 and the Treg program induced and maintained? What is the function of Foxp3 and the gene set induced down stream? What is the function of Treg that express all or part of th! e Foxp3 program? How do Treg modify innate and adaptive immunity? Our preliminary results show that TGFbeta enhances survival of Treg which are already committed to express the Foxp3 program. Importantly, TGFbeta induces de novo Foxp3 expression and Treg function in uncommitted na ve cells, and Foxp3 induction is blocked by CD28 co-stimulation in an IL-4 dependent fashion. Committed or induced Treg inhibit innate immune responses by pancreatic islets, thereby enhancing islet engraftment and cure of diabetes. Based on these findings, we hypothesize that TGFbeta is a key regulator of the signaling pathways that initiate and maintain Foxp3 expression and function of Treg. We are investigating this hypothesis as follows:

1.) Determine how TGFbeta generates Treg. We will investigate the signals important for induction and inhibition of Foxp3 expression. We will investigate the cellular functions of TGFbeta driven Treg that express Foxp3. We will determine the plasticity of the Foxp3/Treg program in individual T cells.
2.) Deter! mine how Foxp3 generates Treg. We will investigate the function of cells in which Foxp3 expression is driven by retroviral gene transfer. We will determine the effects of forced Foxp3 expression on T cell function and the plasticity of that function. We will investigate the signals and molecules that permit or inhibit Foxp3 function. 3.) Determine how Treg function. TGFbeta or Foxp3 driven Treg will be evaluated for their ability to migrate, undergo homeostatic proliferation, and transition to a memory phenotype.

In the autoimmune model of colitis, the ability of these cells to regulate the homeostatic proliferation and autoimmune function of effector T cells will be determined, with attention  and costimulatory,to specific effector molecules, including IL-10 and TGFbeta molecules. The mechanism of Treg suppression of the innate immune response of pancreatic islets will be determined in vitro and in vivo, analyzing effector molecules in Treg-islet interactions. A significant problem in islet transplantation is that it is rarely possible to obtain enough islets from a single donor to fully replete the islet cell mass of a recipient. Furthermore, immediately after transplantation a variety of factors significantly reduce the already putatively marginal islet cell mass. Investigations have shown that trophic factors, ischemia-reperfusion, vascularization, cytokines, innate immune responses, and inflammation all contribute to the success or failure of immediate engraftm d survival of the islets. Other studies demonstrate that islets constitutively produce chemokines, and chemokine production is stimulated by physical manipulation, ischemia-reperfusion, cytokines, and gene transfer vectors. Islet stimulation impairs survival of allogeneic and even syngeneic grafts, and decreased survival is associated with increased inflammation at the graft site, contributed to in large part by chemokines produced by the islets. Our prelimina! ry data now show that CD4+CD25+ regulatory T cells (Treg) directly interact with islets, inhibiting chemokine production and restoring graft survival. We hypothesize that Treg directly regulate islet innate immune responses and this regulation can be harnessed to suppress inflammation and improve islet graft survival. We are investigating this hypothesis with the following specific aims:

1) Determine how Treg regulate islet chemokine  driven de novo Treg will bebresponses. Both naturally occurring Treg and TGF evaluated for their direct interaction with islets and isolated islet cells, and for soluble and cell bound mediators that regulate chemokine responses.

2) Determine the chemokine-driven migratory interactions among Treg, effector T cells (Te), and islets. Migration studies will probe the cellular and molecular interactions that regulate Treg and Te migration to islets, and how Treg directly and indirectly alter the migration of Te to islets, benefiting isl! et survival.
3) Determine how Treg facilitate islet engraftment and survival.

In vivo studies will determine how natural and TGFbeta driven de novo Treg alter chemokine responses, inflammatory responses, Treg and Te migration to grafts, and graft survival. Overall, these studies will provide important information for how to improve islet survival and engraftment, preserve islet cell mass, and harness Treg biology for improved graft survival. Trafficking of lymphocytes through lymphatics is important in the generation of an immune response. Na ve T cells from the thymus are released into the blood and migrate to secondary lymphoid tissues, entering lymph nodes (LN) from the blood through high endothelial venules (HEV). This process is well-defined, following a sequence of events that includes rolling, integrin activation through chemokine signaling, firm adhesion, and diapedesis. Unlike na ve T cells, memory and effector T cells efficiently enter non-lymphoid tissues, as well as sites of active inflammation or infection, from the blood through post-capillary venules, and subsequently traffic to local LN via afferent lymphatic vessels. Although there is a preference for memory and effector versus na ve T cells to migrate through non-lymphoid tissues, na ve cells are also found within peripheral tissues.

In contrast to the wealth of knowledge that has accumulated regarding the regulation of HEV transendothelial migration, the mechanisms that govern migration out of peripheral tissues and into afferent lymph are less well understood. Classically, it has been postulated that exit from peripheral tissues is random and passive, since the cellular composition of afferent lymph mirrors that of the peripheral tissues. It was not until recently that this idea has been questioned and explored in greater detail, and a role identified for the chemokine receptor CCR7 in regulating the exit of na ve cells from peripheral tissues. It has also recently been demonstrated that a significant number of na ve T cells perpetually migrate through non-lymphoid tissues under steady-state conditions, suggesting that this represents a previously unrecognized physiologic pathway for na ve T cell trafficking. Besides regulation by CCR7 signali systems are currently known to be involved in lymphocyte trafficking from tissues to afferent lymphatics. The bioactive phospholipid sphingosine 1-phosphate (S1P) is a regulator of the immune system. S1P is found in high concentrations in the blood and efferent lymph. FTY720 is a microbial derived, immunosuppressive that is phosphorylated in vivo to become an analog of S1P. FTY720 binds and is an agonist to four of the five known S1P receptors. FTY720 prolongs graft survival in animals and humans, and its major action relates to sequestration of T cells within peripheral LN. Mechanistic studies of FTY720 show that it causes enhanced migration of T cells into LN, upregulation of junctional complexes on lymphatic sinus endothelial cells within LN, and T cell migration arrest. Given these results, we hypothesized that S1PR may be instrumental in regulating lymphatic migration. Indeed, our preliminary data now demonstrate that agonism of the S1PR, S1P1, prevents T cell migration across lymphatic endothelium and into afferent lymphatics. To further investigate this hypothesis we propose the following Specific Aims:
1.) Investigate the migration and interaction of T cells with lymphatic endothelium in vivo;
2.) Investigate the migration and interaction of T cells with lymphatic endothelium in vitro.

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.

Ledgerwood LG, Lal G, Zhang N, Garin A, Esses SJ, Ginhoux F, Peche H, Lira SA, Ding Y, Yang Y, He X, Schuchman EH. Sphingosine 1-phosphate receptor S1P1 causes tissue retention by inhibiting peripheral tissue T lymphocyte entry into afferent lymphatics. Nature Immunol 2008; 9: 42-53.

Akalin E, Dinavahi R, Dikman S, de Boccardo G, Friedlander R, Schroppel B, Sehgal V, Bromberg JS, Heeger P, Murphy B. Transplant glomerulopathy may occur in the absence of donor-specific antibody and C4d staining. J. Am. Soc. Nephrol 2007; 2: 1261-1267.

Merad M, Collin M, Bromberg J. Dendritic cell homeostasis and trafficking in transplantation. Trends in Immunology 2007; 28: 353-359.

Chin EH, Hazzan D, Edye M, Herron DM, Gaetano JN, Ames SA, Bromberg JS. Laparoscopic donor nephrectomy. Surg. Endoscopy 2007; 21(4): 521-526.

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.

Chen D, Bromberg JS. T regulatory cells and migration. Am. J. Transplantation 2006; 6: 1.

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, Bromberg JS. Alloantigen-presenting plasmacytoid dendritic cells mediate tolerance to vascularized grafts. Nature Immunology; 7: 652-662.

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, 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.