Rapid Deletional Peripheral CD8 T Cell Tolerance Induced by Allogeneic Bone Marrow: Role of Donor Class II MHC and B Cells

Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02129, USA.
The Journal of Immunology (Impact Factor: 4.92). 10/2008; 181(6):4371-80. DOI: 10.4049/jimmunol.181.6.4371
Source: PubMed


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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Available from: Thomas Fehr, Oct 06, 2015
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    • "This loss of tolerance may be avoided by removal of the thymus before depletion of donor cells, highlighting the importance of the intrathymic chimerism in the maintenance of tolerance. In less intensive conditioning mechanisms where costimulatory blockade is used to facilitate mixed chimerism, intrathymic deletion remains an important mechanism contributing to tolerance and there is no evidence of a role for Treg (Wekerle et al., 2000; Fehr et al., 2008). Nevertheless, regimens that produce less complete deletion of pre-existing donor-reactive T cells may be dependent on peripheral tolerance mechanisms. "
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    ABSTRACT: Manipulation of the immune system to prevent the development of a specific immune response is an ideal strategy to improve outcomes after transplantation. A number of experimental techniques exploiting central and peripheral tolerance mechanisms have demonstrated success, leading to the first early phase clinical trials for tolerance induction. The first major strategy centers on the facilitation of donor-cell mixed chimerism in the transplant recipient with the use of bone marrow or hematopoietic stem cell transplantation. The second strategy, utilizing peripheral regulatory mechanisms, focuses on cellular therapy with regulatory T cells. This review examines the key studies and novel research directions in the field of immunological tolerance.
    Frontiers in Immunology 08/2012; 3:254. DOI:10.3389/fimmu.2012.00254
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    • "In organ transplantation , donor B cell tolerogenicity has been suggested by Niimi et al (1998), in a model of allogeneic cardiac grafts with depletion of recipient B cells by anti IgD monoclonal antibody. A recent study tried to identify the donor cells that promoted CD8 tolerance in a murine model of bone marrow allograft (Fehr et al, 2008). Mice were engrafted after treatment with a conditioning regimen that included total body irradiation and anti CD154 monoclonal antibody. "
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    ABSTRACT: The potential role of the infused B cell subset after Hematopoietic Stem Cell Transplantation has not been yet studied. The present study analyzed the impact of B cells on transplant outcome in 254 patients who received a bone marrow graft from a human leucocyte antigen-identical sibling donor. The influence of B lineage-specific hematopoietic progenitor cells (CD34(+) CD19(+)) and B cells (immature and mature B cells, CD34(-) CD19(+)) was also analyzed. All included patients received a myeloablative regimen. The cumulative incidence function of acute graft-versus-host (GvHD) grade II to IV was 48% and was inversely associated with the number of CD34(+) CD19(+). There were no statistically significant associations between B cell subsets and chronic GvHD or survival. The CD34(+) CD19(+) B cell subset remained significantly associated with acute GvHD in multivariate analysis (Relative risk = 0.32, 95% confidence interval: 0.11-0.92, P = 0.035). In conclusion, a higher B lineage-specific hematopoietic progenitor cells (CD34(+) CD19(+)) cell dose is associated with a significant decrease incidence of acute GvHD.
    British Journal of Haematology 02/2009; 145(1):107-14. DOI:10.1111/j.1365-2141.2008.07574.x · 4.71 Impact Factor
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    ABSTRACT: The induction of donor-specific immune tolerance is the "holy grail" of transplantation, as it would avoid the toxicities of chronic immunosuppressive therapies while preventing acute and chronic graft rejection. A large number of approaches to tolerance induction have been described in the experimental literature, but only hematopoietic cell transplantation has shown preliminary success for intentional tolerance induction in pilot clinical trials. This review summarizes the conditions that allow progress to be made in moving strategies for tolerance induction from the bench to the bedside and discuss the mechanisms by which tolerance may be achieved through hematopoietic cell transplantation.
    Transplantation 03/2009; 87(3):309-16. DOI:10.1097/TP.0b013e31819535c2 · 3.83 Impact Factor
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