Overview

The laboratory of Richard Pierson, MD, and Agnes Azimzadeh, PhD in the Center for Transplantation Sciences (CTS) at Massachusetts General Hospital explores clinically important questions in transplantation. Working primarily in a cynomolgus monkey heterotopic heart allograft model, we study the pathogenesis of chronic rejection, as well as investigate costimulation and chemokine pathway modulation as approaches to induce operational tolerance. Barriers to successful application of pig-to-human xenotransplantation are studied in lung, liver, heart, kidney and thymosternal composite tissue models, focusing on coagulation pathway regulation, costimulation pathway blockade and cell adhesion mechanisms. Extensive international collaborative interactions support these translational research projects.

During the course of over 30 years working in a variety of allo and xeno models, Dr. Pierson and Dr. Azimzadeh have mentored a wide variety of pre- and postdoctoral trainees. Our research fellows benefit from our diverse array of basic and translational research projects by undertaking individual projects designed around each trainee’s scientific interests to meet their educational and career goals.

Research Projects

The laboratory of Dr. Pierson and Dr. Azimzadeh centers around understanding and preventing the mechanisms of rejected organs, through two main axes of research:

  1. Immunomodulation - Organ transplantation relies on patients taking immunosuppressive drugs to avoid the rejection of the transplanted organ. However, these drugs result in numerous undesirable effects, and they are not effective at preventing late graft loss—a process called chronic rejection. Using various transplant models, the laboratory evaluates novel, selective, immunomodulatory therapies for their ability to modulate innate and adaptive immunity and to induce operational tolerance, while sparing protective immunity. We are particularly interested in the role played by costimulation signals and their effects on the host immune response, including inhibition of memory T cell and humoral responses and stimulation of regulatory T cells development and function. Our studies contributed to a better mechanistic understanding of allograft rejection and promoted CD28 and CD154 blockade as promising immunomodulatory therapies for transplantation. Additional interests include chemokine blockade, transplant-associated autoimmunity and tolerogenic antigen exposure.
  2. Xenotransplantation - Organ transplantation is severely constrained by an inadequate availability of donor organs. If immunologic obstacles can be safely surmounted, animal organs (xenografts) could eliminate the shortage of donor allografts prolong life and improve the quality of life for many patients. The laboratory has documented the dramatic benefit of genetic modifications of the donor pig in models of lung, liver, heart and kidney xenotransplant models. Current studies explore further genetic modifications of the donor organ, in combination with pharmaceutical interventions, focusing on the role of antibody, complement, coagulation dysregulation, inflammation and innate cellular recognition and adhesion mechanisms.

Meet the Team

Principal Investigators

Richard N. Pierson III, MD
Director of the laboratory of Dr. Pierson and Dr. Azimzadeh
CTS Scientific Director

Dr. Pierson holds the W. Gerald and Patricia Austen Chair in cardiac surgery and is the scientific director of the CTS. As such, he is centrally involved in the training, education and mentorship of research fellows and other trainees. Moreover, Dr. Pierson is a professor of surgery at Harvard Medical School and visiting surgeon at Mass General, where he participates clinically in thoracic transplantation, mechanical circulatory support and cardiac surgical intensive care. He is an established National Institutes of Health (NIH)-funded investigator in the areas of translational cardiac allograft tolerance induction and the immunobiology of lung, heart, kidney and liver xenotransplantation. He has authored over 175 peer-reviewed original scientific papers, review articles and book chapters.

Dr. Pierson received his medical degree from the Columbia University of Physicians and Surgeons. His postgraduate clinical training included general surgery at the University of Michigan, cardiothoracic surgery at Mass General and a clinical and research fellowship in cardiothoracic transplantation at Papworth Hospital, in affiliation with Cambridge University. After serving on the faculty at Vanderbilt University from 1994-2002 and University of Maryland from 2002-2018, he was recruited in 2017 to his current position. He is a past president (2007-2009) and current ethics committee chair for the International Xenotransplantation Association.

Agnes Azimzadeh, PhD
Co-director of the Pierson/Azimzadeh Laboratory
Associate Immunologist, Mass General

Dr. Azimzadeh is an associate immunologist in the CTS at Mass General and member of faculty at Harvard Medical School. Dr. Azimzadeh is a basic scientist who received her doctorate in molecular and cellular biology and immunology in 1992 at the University Louis Pasteur in Strasbourg, France, for her studies of the affinity of monoclonal anti-viral antibodies. She also received her habilitation in transplant immunology from the University Louis Pasteur in Strasbourg in 1997, a degree attributed for excellence in scientific contributions and mentoring, which qualifies researchers for mentoring graduate students. Since 1992, Dr. Azimzadeh’s main research interests have been centered on understanding and preventing the mechanisms of rejection of allo and xenografts, with an emphasis on using novel immunomodulatory agents to modulate innate and adaptive immune responses, so as to promote transplant tolerance.

In allotransplantation, Dr. Azimzadeh has evaluated several novel selective immunomodulatory therapies to modulate alloimmunity and to promote immune tolerance. She is particularly interested by the role played by costimulation signals in immune responses, including memory T cell and humoral responses and development and function of regulatory T cells. She initiated the lab’s focus on selective CD28 blockade—the first to show the beneficial effect of CD28 blockade using monovalent antagonists to immunomodulate allografts in both mice and primates. Additional studies focus on tolerogenic antigen exposure, CD40/CD154 and ICOS/B7h pathway blockade, targeting B cells, and transplant-associated autoimmunity to vimentin after cardiac transplantation. She has contributed to improved mechanistic understanding of allograft rejection, and translational development of CD28 and CD154 blockade as promising immunomodulatory therapies for clinical transplantation.

Dr. Azimzadeh entered the field of xenotransplantation in 1992 under the mentorship of Philippe Wolf, evaluating the effectiveness of organ perfusion to adsorb xenoreactive antibodies, and characterizing the specificity of those antibodies and their effect on complement and coagulation activation. In collaboration with Ignacio Anegon and Jean-Paul Soulillou, working in a rat-to-primate model, she showed that expression of a human complement regulatory protein in a transgenic animal protects organs from hyperacute rejection, work later continued in various pig-to-human models. She was among the first to show that coagulation cascade dysregulation is a major barrier to xenotransplantation.  In collaboration with Jean-Pierre Cazenave at the Hemostasis INSERM Institute in Strasbourg, she evaluated kidneys from pigs lacking von Willebrand factor, and pioneered the use of mechanistic coagulation assays in a pig-to-baboon xenotransplant model, assays that are still used as fundamental readouts in xenogeneic models. Innate immunity and coagulation dysregulation remain foci of her ongoing collaboration with Dr. Pierson, with numerous publications demonstrating important roles for platelets, NK cells and other pathways in lung injury. From 2011 through 2018, funding from the National Institutes of Health Program of Excellence in Glycosciences allowed her to uncover a role for cellular sialyation state and galectins in regulating the adhesion of human neutrophils to porcine endothelial cells. This work paves the way for ongoing mechanistic studies about the role of glycobiology in lung and other xenograft injury, as well as in other facets of transplant biology.

Dr. Azimzadeh has a strong commitment to scientific education, having mentored a wide variety of pre and postdoctoral trainees. She has been involved in direct teaching since 1983, including lectures on xenotransplantation and experimental immunology to MD/PhD students, as well as lectures on the biological features of antibodies, antibody-based assays, cell-cycle analysis techniques, basic immunology for medical students and immunologic costimulation to graduate students. She has served on many local and national committees, she serves on the editorial board of Xenotransplantation, the official journal of IXA, and is the current president of the International Xenotransplantation Association Council (2019-21), having served on the council since 2011 in various capacities.

View Select Publications
  1. French BM, Sendil S, Sepuru KM, Ranek J, Burdorf L, Harris D, Redding E, Cheng X, Laird CT, Zhao Y, Cerel B, Rajarathnam K, Pierson RN 3rd, Azimzadeh AM. Interleukin-8 mediates neutrophil-endothelial interactions in pig-to-human xenogeneic models. Xenotransplantation. 2018 Mar;25(2):e12385. PMID: 29427404.
  2. OʼNeill NA, Zhang T, Braileanu G, Sun W, Cheng X, Hershfeld A, Laird CT, Kronfli A, Hock LA, Dahi S, Kubicki N, Sievert E, Hassanein W, Cimeno A, Pierson RN 3rd, Azimzadeh AM. Comparative Evaluation of αCD40 (2C10R4) and αCD154 (5C8H1 and IDEC-131) in a Nonhuman Primate Cardiac Allotransplant Model. Transplantation. 2017 Sep;101(9):2038-2047. PMID: 28557955.
  3. Burdorf L, Riner A, Rybak E, Salles II, De Meyer SF, Shah A, Quinn KJ, Harris D, Dandro A, Karavi K, Zhang T, Parsell D, Ali F, Schwartz E, Kang E, Cheng X, Sievert E, Zhao Y, Braileanu G, Phelps CJ, Ayares DL, Deckmyn H, Pierson RN 3rd, Azimzadeh AM. Platelet sequestration and activation during GalTKO.hCD46 pig lung perfusion by human blood is primarily mediated by GPIb, GPIIb/IIIa, and von Willebrand Factor. Xenotransplantation. 2016 May;23(3):222-236. PMID: 27188532.
  4. Harris DG, Benipal PK, Cheng X, Burdorf L, Azimzadeh AM, Pierson RN 3rd. Four-dimensional characterization of thrombosis in a live-cell, shear-flow assay: development and application to xenotransplantation. PLoS One. 2015 Apr 1;10(4):e0123015. PMID: 25830912.
  5. Kelishadi SS, Azimzadeh AM, Zhang T, Stoddard T, Welty E, Avon C, Higuchi M, Laaris A, Cheng XF, McMahon C, Pierson RN 3rd. Preemptive CD20+ B cell depletion attenuates cardiac allograft vasculopathy in cyclosporine-treated monkeys. J Clin Invest. 2010 Apr;120(4):1275-84. PMID: 20335656.
  6. Poirier N, Azimzadeh AM, Zhang T, Dilek N, Mary C, Nguyen B, Tillou X, Wu G, Reneaudin K, Hervouet J, Martinet B, Coulon F, Allain-Launay E, Karam G, Soulillou JP, Pierson RN 3rd, Blancho G, Vanhove B. Inducing CTLA-4-dependent immune regulation by selective CD28 blockade promotes regulatory T cells in organ transplantation. Science Translational Medicine 2010 Feb 3;2(17):17ra10. PMID: 20371478.
  7. Azimzadeh AM, Pfeiffer S, Wu GS, Schröder C, Zhou H, Zorn GL 3rd, Kehry M, Miller GG, Rose ML, Pierson RN 3rd. Humoral immunity to vimentin is associated with cardiac allograft injury in nonhuman primates. Am J Transplant. 2005 Oct;5(10):2349-59. PMID: 16162182.
  8. Crowe JE Jr, Sannella EC, Pfeiffer S, Zorn GL, Azimzadeh A, Newman R, Miller GG, Pierson RN. CD154 regulates primate humoral immunity to influenza. Am J Transplant. 2003 Jun;3(6):680-8. PMID: 12780559.

View all of Dr. Azimzadeh's publications

Faculty

Lars Burdorf, MD
Assistant Investigator of Surgery, Massachusetts General Hospital
Assistant Professor of Surgery, Harvard Medical School

Postdoctoral Research Fellows

  • Zahra Alikhassy Habibabady, MD
  • Maggie O’Connolly, MD
  • Shuhei Miura, MD

Lab Manager

  • Shannon Pratts

Research Staff

  • Madelyn Ma, BS
  • Kaitlyn Petitpas, BS
  • Anthony Calhoun, MS
  • Veronica Ritchie, ALAT