Center for Transplantation Sciences
Molecular Biology Laboratory
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The Molecular Biology Laboratory in the Center for Transplantation Sciences (CTS) at Massachusetts General Hospital provides new insights into the role of major histocompatibility class II molecules (MHCII) in the regulation of immune responses.
Although first described half a century ago, the mechanism by which MHCII molecules regulate the function of T and B lymphocytes remains unclear. Our previous research has established that transfer of donor MHCII genes prior to grafting promoted transplantation tolerance to vascularized transplants. MHCII gene transfer down-regulated both the acute and chronic arms of graft rejection. These results were initially obtained by our laboratory in a preclinical large animal model of renal transplantation (miniature swine) and were confirmed in a murine model of cardiac grafts. Additional experiments demonstrated that the regulatory function of MHCII proteins was initiated by MHCII-derived peptides, but accomplished by a subset of lymphocytes, the regulatory T cells, or Tregs. These results promoted conceptual advances in basic immunology (MHCII genes regulate T cell responses via MHCII peptide synthesis) and fostered the development of translational studies (use of MHCII peptides as therapeutic inducers of immune tolerance).
The new concept stems from our hypothesis that immune regulation by MHCII relies on a twist in antigen presentation, by which MHCII molecules present their own peptides to activate cognate Tregs. Results from current studies performed in murine models support the hypothesis and call for further studies to characterize the nature of MHCII peptides involved in thymic Treg differentiation. Our translational studies include establishing optimal and safe MHCII gene therapy protocols to induce transplantation tolerance to kidney allografts in primates and defining the amino acid sequences of regulatory MHCII peptides.
These projects are carried out in collaboration with several principal investigators from the Mass General Department of Surgery, including Joren C. Madsen, MD, James F. Markmann, MD and Gilles Benichou, PhD. Additionally, we work with Philippe LeBoulch, MD, and the Institute of Emerging Diseases and Innovative Therapy (IMETI) of the CEA in Fontenay-aux-Roses, Paris, France on our primate studies.
Christian LeGuern, PhD
Senior Investigator/Head, Molecular Biology Laboratory, Center for Transplantation Sciences (CTS)
Associate Immunologist, Massachusetts General Hospital
Associate Professor of Surgery & Immunology, Harvard Medical School
Professor, University Paris Sorbonne
Sharon Germana, MS
The following selected publications highlight accomplishments by the Molecular Biology Laboratory:
- The first recombinant retroviral vectors for expression of major histocompatibility class (MHC) genes in various contexts:
- Shafer GE, Emery DW, Gustafsson K, Germana S, Anderson WF, Sachs DH, et al. Expression of a swine class II gene in murine bone marrow hematopoietic cells by retroviral-mediated gene transfer. Proc Natl Acad Sci U S A. 1991;88(21):9760-4.
- MHCII gene vectors show remarkable expression in large animal bone marrow cells:
- Emery DW, Shafer GE, Karson EM, Sachs DH, LeGuern C. Retrovirus-mediated transfer and expression of an allogeneic major histocompatibility complex class II DRB cDNA in swine bone marrow cultures. Blood. 1993;81:2460-5.
- Emery DW, Sachs DH, LeGuern C. Culture and characterization of hematopoietic progenitor cells from miniature swine. ExpHematol. 1996;24(8):927-35.
- Pre-transfer of graft-type MHCII genes in recipient bone marrow cells prevented acute and chronic rejection of allotransplants that were accepted indefinitely. This was studied in a preclinical large animal model and in a murine cardiac transplant model:
- Sonntag KC, Emery DW, Yasumoto A, Haller GW, Germana S, Sablinski T, et al. Tolerance to solid organ transplants through transfer of MHC class II genes. The Journal of clinical investigation. 2001;107:65-71.
- Emery DW, Sablinski T, Shimada H, Germana S, Gianello P, Foley A, et al. Expression of an allogeneic MHC DRB transgene, through retroviral transduction of bone marrow, induces specific reduction of alloreactivity. Transplantation. 1997;64(10):1414-23.
- LeGuern C, Akiyama Y, Tanaka K, Germana S, Iwamoto Y, Fernandez L, et al. Intracellular MHC class II controls regulatory tolerance to allogeneic transplants. J Immunol. 2010;184(5):2394-400.
- Studies showed that contrary to MHCII genes, MHC class I gene therapy did not promote tolerance to allografts, indicating that tolerance induction was unique to MHCII genes. Current studies focus on the impact of MHCII peptide presentation on Treg development and functions:
- LeGuern C. Regulatory T Cells for Tolerance Therapy: Revisiting the Concept. Crit Reviews Immunol. 2011;31(3):189-207.
- LeGuern C. Tolerogenic property of MHC class I and class II molecules: lessons from a gene therapy approach. Frontiers in bioscience. 2007;12(9):3133-9.
Center for Transplantation Sciences
The Center for Transplantation Sciences (CTS) at Massachusetts General Hospital conducts critical research to increase the success rates of transplantation and meet the growing demand for organ and bone marrow transplantation.