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Blood, 1 June 2004, Vol. 103, No. 11, pp. 4336-4343. Prepublished online as a Blood First Edition Paper on February 12, 2004; DOI 10.1182/blood-2003-08-2642. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-08-2642v1 103/11/4336    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kurtz, J. Articles by Sykes, M. Search for Related Content PubMed PubMed Citation Articles by Kurtz, J. Articles by Sykes, M. Related Collections Immunobiology Transplantation Immunotherapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  TRANSPLANTATION Mechanisms of early peripheral CD4 T-cell tolerance induction by anti-CD154 monoclonal antibody and allogeneic bone marrow transplantation: evidence for anergy and deletion but not regulatory cells Josef Kurtz, Juanita Shaffer, Ariadne Lie, Natalie Anosova, Gilles Benichou, and Megan Sykes From the Bone Marrow Transplantation Section, Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston; Cellular and Molecular Immunology (CMI) Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston. Anti-CD154 (CD40L) monoclonal antibody (mAb) plus bone marrow transplantation (BMT) in mice receiving CD8 cell-depleting mAb leads to long-term mixed hematopoietic chimerism and systemic donor-specific tolerance through peripheral and central deletional mechanisms. However, CD4+ T-cell tolerance is demonstrable in vitro and in vivo rapidly following BMT, before deletion of donor-reactive CD4 cells is complete, suggesting the involvement of other mechanisms. We examined these mechanisms in more detail. Spot enzyme-linked immunosorbent (ELISPOT) analysis revealed specific tolerization (within 4 to 15 days) of both T helper 1 (Th1) and Th2 cytokine responses to the donor, with no evidence for cytokine deviation. Tolerant lymphocytes did not significantly down-regulate rejection by naive donor-reactive T cells in adoptive transfer experiments. No evidence for linked suppression was obtained when skin expressing donor alloantigens in association with third-party alloantigens was grafted. T-cell receptor (TCR) transgenic mixing studies revealed that specific peripheral deletion of alloreactive CD4 T cells occurs over the first 4 weeks following BMT with anti-CD154. In contrast to models involving anti-CD154 without BMT, BMT with anti-CD154 leads to the rapid induction of anergy, followed by deletion of pre-existing donor-reactive peripheral CD4+ T cells; the rapid deletion of these cells obviates the need for a regulatory cell population to suppress CD4 cell-mediated alloreactivity. (Blood. 2004;103:4336-4343) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: F. Haspot, T. Fehr, C. Gibbons, G. Zhao, T. Hogan, T. Honjo, G. J. Freeman, and M. Sykes Peripheral deletional tolerance of alloreactive CD8 but not CD4 T cells is dependent on the PD-1/PD-L1 pathway Blood, September 1, 2008; 112(5): 2149 - 2155. [Abstract] [Full Text] [PDF] T. Fehr, F. Haspot, J. Mollov, M. Chittenden, T. Hogan, and M. Sykes Alloreactive CD8 T Cell Tolerance Requires Recipient B Cells, Dendritic Cells, and MHC Class II J. Immunol., July 1, 2008; 181(1): 165 - 173. [Abstract] [Full Text] [PDF] M. A. Kriegel, S. Adam-Klages, C. Gabler, N. Blank, M. Schiller, C. Scheidig, J. R. Kalden, and H.-M. Lorenz Anti-HLA-DR-triggered monocytes mediate in vitro T cell anergy Int. Immunol., April 1, 2008; 20(4): 601 - 613. [Abstract] [Full Text] [PDF] C. H. Cook, A. A. Bickerstaff, J.-J. Wang, T. Nadasdy, P. Della Pelle, R. B. Colvin, and C. G. Orosz Spontaneous Renal Allograft Acceptance Associated with "Regulatory" Dendritic Cells and IDO J. Immunol., March 1, 2008; 180(5): 3103 - 3112. [Abstract] [Full Text] [PDF] S. I. Alexander, N. Smith, M. Hu, D. Verran, A. Shun, S. Dorney, A. Smith, B. Webster, P. J. Shaw, A. Lammi, et al. Chimerism and Tolerance in a Recipient of a Deceased-Donor Liver Transplant N. Engl. J. Med., January 24, 2008; 358(4): 369 - 374. [Abstract] [Full Text] [PDF] C. Domenig, A. Sanchez-Fueyo, J. Kurtz, S. P. Alexopoulos, C. Mariat, M. Sykes, T. B. Strom, and X. X. Zheng Roles of Deletion and Regulation in Creating Mixed Chimerism and Allograft Tolerance Using a Nonlymphoablative Irradiation-Free Protocol J. Immunol., July 1, 2005; 175(1): 51 - 60. [Abstract] [Full Text] [PDF] L. M. Bagenstose, R. K. Agarwal, P. B. Silver, D. M. Harlan, S. C. Hoffmann, R. L. Kampen, C.-C. Chan, and R. R. Caspi Disruption of CD40/CD40-Ligand Interactions in a Retinal Autoimmunity Model Results in Protection without Tolerance J. Immunol., July 1, 2005; 175(1): 124 - 130. [Abstract] [Full Text] [PDF] R. Flierman, H. J. Witteveen, E. I. H. van der Voort, T. W. J. Huizinga, R. R. P. de Vries, W. E. Fibbe, R. E. M. Toes, and J. M. van Laar Control of systemic B cell-mediated autoimmune disease by nonmyeloablative conditioning and major histocompatibility complex-mismatched allogeneic bone marrow transplantation Blood, April 1, 2005; 105(7): 2991 - 2994. 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