期刊
JOURNAL OF IMMUNOLOGY
卷 181, 期 6, 页码 4371-4380出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.181.6.4371
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资金
- National Institutes of Health [R01 HL49915]
- Swiss Foundation for Medical and Biological Grants
- Walter and Gertrud Siegenthaler Foundation (Medical Faculty, University of Zurich, Switzerland)
- Fondation pour la Recherche Medicale (France)
- American Society of Blood and Marrow Transplantation
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 chimerisin depends on the expression of MHC class 11 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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