Gilles Benichou, PhD, DSc

Benichou Laboratory

The Benichou Laboratory in the Center for Transplantation Sciences (CTS) at Massachusetts General Hospital studies the immune mechanisms underlying the allorecognition and alloresponse by T and B cells in transplant rejection and tolerance.

Overview

The Benichou Laboratory in the Center for Transplantation Sciences (CTS) at Massachusetts General Hospital is dedicated to:

  • Elucidating the mechanisms underlying the recognition of donor antigens by recipient lymphocytes after transplantation of allogeneic (from the same species) organs and tissues
  • Characterizing the nature of the cells and their mechanisms of action involved in the rejection or tolerance of allogeneic transplants

Allorecognition is the ability of an organism to distinguish its own tissues from that of another. Our laboratory has developed a series of mouse models to study the different pathways of allorecognition (direct, indirect and semi-direct) by different T cell subsets (TH1, TH2, memory T cells and regulatory T cells), and the role of major histocompatability complex (MHC) cross-dressing and exosomes in the initiation and regulation of the immune responses leading to rejection or tolerance of allogeneic transplants.

In addition, we are investigating donor cell trafficking after transplantation and the roles of new blood and lymphatic vessels (neovascularization and lymphangiogenesis) in the immune response leading to allograft rejection. Based upon this knowledge, we are attempting to design novel strategies to achieve tolerance of allografts (same-species transplants) in mice using skin, heart and pancreatic mouse transplant models.

Additionally, we are currently evaluating the nature and mechanisms of action to different subsets of memory T cells in rejection and tolerance of allografts in transgenic and wild type mice.

Our laboratory is studying the immune mechanisms underlying tolerance of organ transplants in non-human primates. We have recently demonstrated that pre-existing alloreactive memory T cells (donor-reactive memory T cells present in the host prior to transplantation) prevent tolerance of allografts in primates via costimulation blockade (blocking the signal for T-cell activation) and hematopoietic chimerism. We are currently characterizing the precise nature of these memory T cells and investigating the mechanisms by which they impair tolerance. Based on this knowledge, we are currently designing clinically applicable strategies intended to suppress selectively these memory T cells and restore tolerance of kidney, heart and lung allografts in monkeys and patients.

Group Members

Principal Investigator

Gilles Benichou, PhD, DSc

Senior Investigator/Head, Benichou Laboratory, Center for Transplantation Sciences (CTS)
Immunologist, Massachusetts General Hospital
Associate Scientist, Department of Medicine, Boston Children’s Hospital
Associate Professor of Surgery and Immunology, Harvard Medical School

Gilles Benichou, PhD, DSc, is an associate professor of surgery and immunology at Harvard Medical School, senior immunologist at Mass General and head of the Benichou Laboratory in the Center for Transplantation Sciences (CTS) at Mass General. Dr. Benichou is a basic scientist who received his doctorate in Immunology in 1987 at the Pasteur Institute and the University of Science in Paris, France, for his studies of cell surface signaling by anti-major histocompatability complex (MHC) antibodies. He also received his Doctor of Science from the University of Science in Paris in 1997. Since 1987, his research has been focused on the mechanisms underlying the recognition of self versus non-self antigens by the immune system in cancer and transplantation.

Specifically, Dr. Benichou’s laboratory has shown the contribution of cryptic self-peptides to the induction of autoimmunity. Dominant and cryptic p53 peptides, which induce CD4+ T cell immune responses to tumors in mice and melanoma patients, have been identified and are currently being tested as cancer vaccines. In 1991, Dr. Benichou published the first article demonstrating the role of MHC-derived peptides in indirect alloreactivity during the course of allotransplant rejection.

Since then, Dr. Benichou’s laboratory has been studying the cellular and molecular mechanisms underlying direct and indirect types of allorecognition, including post-transplant autoimmunity in mouse models. In 2001, Dr. Benichou was recruited to the Department of Surgery at Mass General to develop clinical protocols for tolerance induction to allotransplants in primates. His most recent research at Mass General has led to the demonstration that the donor-specific memory T cells that present in primates pre-transplantation represent a formidable barrier to transplant tolerance induction.

Recently, Dr. Benichou’s studies revealed that primates displaying low frequencies of memory T cells against their donors could be successfully rendered tolerant of kidney allografts via the mixed chimerism protocol established at Mass General.

Instructor

Georges Tocco, PhD

Postdoctoral Research Fellows

Mohamed Babiker, MD
Jose Marino, MD
Felipe Naranjo, MD

Students

William Orent
Alex Hoslet

Technicians

Joshua Paster

Research Projects

The Benichou Laboratory in the Center for Transplantation Sciences is leading the following research projects:

Studies using mouse models:

  • Pathways of allorecognition by T cells: We are studying the contribution of direct, indirect and semi-direct allorecognition by T cells to the alloresponses involved in rejection and tolerance of allogeneic transplants.

    Recently, we showed the presence of recipient antigen presenting cells displaying donor major histocompatability complex (MHC) molecules after transplantation and are currently investigating the contribution of this phenomenon in the initiation and perpetuation of alloimmunity and rejection after skin and organ transplantation.

    In addition, we are investigating the trafficking of recipient and donor leukocyte subpopulations and their subcellular vesicles via blood and lymphatic vessels after transplantation using flow imaging and multiphoton intra-vital microscopy
  • Sensitization and tolerance to alloantigens mediated via materno-fetal relationships: Maternal blood cells regularly travel to the fetus and newborn during pregnancy and breast-feeding, respectively. Actually, this includes maternal hematopietic stem cells which give rise to maternal blood cells (which are present during the entire life of the offspring). Therefore, we carry both our immune system and that of our mothers. We are studying the mechanisms by which maternal hematopoietic chimerism influences autoimmune (autoimmune diseases) and alloimmune (transplant rejection) responses in the adult offspring
  • Contribution of “natural” and acquired memory T cells to rejection and tolerance resistance in transplantation: We have recently identified two distinct subtypes of memory T cells (cells induced after vaccination) called “natural” and “induced” TMEM. We are currently studying their functional properties and their contribution to transplant rejection and tolerance resistance using different mouse models. In addition, we are investigating the role of pro-inflammatory (Be) and regulatory (Bregs) B cells as antigen-presenting cells in the generation and reactivation of memory T cells

Studies using nonhuman primate models:

  • Mechanisms underlying T and B cell responses to allogeneic transplants: In collaboration with James Allan, MD, Benedict Cosimi, MD, Tatsuo Kawai, MD, PhD, Joren Madsen, MD, DPhil, and James Markmann, MD, PhD, we study the immune mechanisms underlying the rejection or tolerance of kidney, heart, lung and pancreatic islet allografts in non-human primates
  • Role of memory T and B cells to tolerance resistance in non-human primates: We have recently shown that the presence of memory T cells represents a major barrier tolerance to allogeneic transplants in non-human primates. We are currently studying the mechanisms by which memory T cells prevent tolerance to heart, lung, kidney and pancreatic islet allografts in cynomolgus monkeys. In addition, we are attempting to design novel strategies to prevent or suppress selectively the activation of donor-specific memory T cells after transplantation and/or tolerance induction in primates

Publications

Selected Publications

  • Benichou G, Takizawa PA, Olson CA, McMillan M and Sercarz EE. 1992. Donor major histocompatibility complex (MHC) peptides are presented by recipient MHC molecules during graft rejection. The Journal of Experimental Medicine 175:305-308.
  • Fedoseyeva EV, Tam RC, Orr PL, Garovoy MR and Benichou G. 1995. Presentation of a self-peptide for in vivo tolerance induction of CD4+ T cells is governed by a processing factor that maps to the class II region of the major histocompatibility complex locus. The Journal of Experimental Medicine 182:1481-1491.
  • Benichou, G, Valujskikh A, and Heeger PS. 1999. Contributions of direct and indirect T cell alloreactivity during allograft rejection in mice. J Immunol 162:352-358.
  • Fedoseyeva, EV, Boisgerault F, Anosova NG, Wollish WS, Arlotta P, Jensen PE, Ono SJ and Benichou G. 2000. CD4+ T cell responses to self- and mutated p53 determinants during tumorigenesis in mice. J Immunol 164:5641-5651.
  • Akiyama Y, Caucheteux SM, Vernochet C, Iwamoto Y, Tanaka K, Kanellopoulos-Langevin C and Benichou G. 2011. Transplantation tolerance to a single noninherited MHC class I maternal alloantigen studied in a TCR-transgenic mouse model. J Immunol 186:1442-1449.
  • Nadazdin O, Boskovic S, Wee SL, Sogawa H, Koyama I, Colvin RB, Smith RN, Tocco G, O'Connor DH, Karl JA, Madsen JC, Sachs DH, Kawai T, Cosimi AB and Benichou G. 2011b. Contributions of direct and indirect alloresponses to chronic rejection of kidney allografts in nonhuman primates. J Immunol 187:4589-4597.
  • Nadazdin O, Boskovic S, Murakami T, Tocco G, Smith RN, Colvin RB, Sachs DH, Allan J, Madsen JC, Kawai T, Cosimi AB, and Benichou G. 2011. Host alloreactive memory T cells influence tolerance to kidney allografts in nonhuman primates. Science Translational Medicine 3:86-92.
  • Kant CD, Akiyama Y, Tanaka K, Shea S, Connolly SE, Germana S, Winn HJ, LeGuern C, Tocco G and Benichou G. 2013. Primary vascularization of allografts governs their immunogenicity and susceptibility to tolerogenesis. J Immunol 191:1948-1956.

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