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* Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02129; and
Department of Surgery, Division of Transplantation, Vienna General Hospital, Medical University of Vienna, Austria
Mixed chimerism and donor-specific tolerance are achieved in mice receiving 3 Gy of total body irradiation and anti-CD154 mAb followed by allogeneic bone marrow (BM) transplantation. In this model, recipient CD4 cells are critically important for CD8 tolerance. To evaluate the role of CD4 cells recognizing donor MHC class II directly, we used class II-deficient donor marrow and were not able to achieve chimerism unless recipient CD8 cells were depleted, indicating that directly alloreactive CD4 cells were necessary for CD8 tolerance. To identify the MHC class II+ donor cells promoting this tolerance, we used donor BM lacking certain cell populations or used positively selected cell populations. Neither donor CD11c+ dendritic cells, B cells, T cells, nor donor-derived IL-10 were critical for chimerism induction. Purified donor B cells induced early chimerism and donor-specific cell-mediated lympholysis tolerance in both strain combinations tested. In contrast, positively selected CD11b+ monocytes/myeloid cells did not induce early chimerism in either strain combination. Donor cell preparations containing B cells were able to induce early deletion of donor-reactive TCR-transgenic 2C CD8 T cells, whereas those devoid of B cells had reduced activity. Thus, induction of stable mixed chimerism depends on the expression of MHC class II on the donor marrow, but no requisite donor cell lineage was identified. Donor BM-derived B cells induced early chimerism, donor-specific cell-mediated lympholysis tolerance, and deletion of donor-reactive CD8 T cells, whereas CD11b+ cells did not. Thus, BM-derived B cells are potent tolerogenic APCs for alloreactive CD8 cells.
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1 This work was supported by National Institutes of Health Grant R01HL49915. T.F. was supported by a research fellowship from the Swiss Foundation for Medical and Biological Grants (with support from Novartis Switzerland) and a research fellowship from the Walter and Gertrud Siegenthaler Foundation (Medical Faculty, University of Zurich, Switzerland). F.H. was supported by a research fellowship from the Fondation pour la Recherche Medicale (France) and a research fellowship from the American Society of Blood and Marrow Transplantation.
2 Current address: Clinic of Nephrology, University Hospital, Raemistrasse 100, CH-8091 Zurich, Switzerland.
3 Current address: Institut Nationale de la Santé et de la Recherche Médicale Unité 643, Nantes, Institut de Transplantation et de la Recherche en Transplantation Univ Nantes, Unité Enseignement et Recherche de Medicine, Nantes, France.
4 Address correspondence and reprint requests to Dr. Megan Sykes, Transplantation Biology Research Center, Massachusetts General Hospital, MGH East Building 149-5102, 13th Street, Boston, MA 02129. E-mail address: megan.sykes{at}tbrc.mgh.harvard.edu
5 Abbreviations used in this paper: BM, bone marrow; BMT, BM transplant; CML, cell-mediated lympholysis; GVHD, graft-versus-host disease; TBI, total body irradiation; DTR tg, diphtheria toxin receptor transgenic; BMC, BM cell; DC, dendritic cell; FC, facilitating cell; WBM, whole bone marrow cell.
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