Pretransplantation Blood Transfusion Revisited

Twuyver, E. van; Mooijaart, R. J. D.; Berge, Ineke J. M. ten; Horst, A. R. van der; Wilmink, J. M.; Kast, W. Martin; Melief, C. J. M.; Waal, L. P. de

doi:10.1056/nejm199110243251704

Cited by 208 publications

(54 citation statements)

References 18 publications

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“…However, the use of DSBT clinically has become less popular with the advent of calcineurin inhibitors and because a clear understanding of the mechanisms involved had remained elusive (11)(12). Recently, our group demonstrated in a rodent transplant model (in which DSBT alone induces tolerance) that Tregs operate (15).…”

mentioning

confidence: 99%

Early Presence of Regulatory Cells in Transplanted Rats Rendered Tolerant by Donor-Specific Blood Transfusion

Kitade

Kawai

Rutgeerts

et al. 2005

The Journal of Immunology

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Mechanisms by which donor-specific blood transfusion (DSBT) promotes organ allograft acceptance are unclear. In a rat fully mismatched cardiac allograft model, we found that DSBT alone (without immunotherapy) induces the development of regulatory T cells (DSBT-Tregs) posttransplant, thereby shedding new light in the mechanisms of the transfusion effect. Compartments and timing of expansion, requirements, and phenotype of DSBT-Tregs are unknown. It is generally assumed that some time is necessary before Tregs develop. However, we show—by adoptive transfer from DSBT—tolerant into naive recipients: 1) the presence of DSBT-Tregs at 5 days posttransplant in spleen and lymph nodes; 2) their gradual expansion in these compartments; and 3) their presence in the graft 14 of 30 days posttransplant. DSBT-Tregs are donor specific and do not protect third-party allografts. Splenocytes from DSBT-treated nontransplanted recipients or from transplanted DSBT-untreated (rejecting) recipients do not transfer tolerance, indicating that both DSBT and graft are required for sufficient numbers of DSBT-Tregs to develop. Thymectomy (or splenectomy) before DSBT (not at transplantation) abrogate DSBT-Tregs generation and tolerance, showing that thymus (and spleen) are required for DSBT-Tregs generation (not for expansion/maintenance). In contrast with other Tregs models, DSBT-Tregs activity is not restricted to CD4+CD25+ but to CD4+CD45RC− cells, whereas CD4+CD45RC+ cells act as effector cells and accelerate rejection. In conclusion, DSBT alone induces—rapidly posttransplant—the development of alloantigen-specific Tregs in lymphoid tissues and in the graft. DSBT, graft, thymus, and spleen are required for DSBT-Tregs generation. DSBT-Tregs in this model are CD4+CD45RC− (identical to Tregs protecting from autoimmunity in rats).

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confidence: 99%

Early Presence of Regulatory Cells in Transplanted Rats Rendered Tolerant by Donor-Specific Blood Transfusion

Kitade

Kawai

Rutgeerts

et al. 2005

The Journal of Immunology

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“…The mechanism by which DLI induces operational transplantation tolerance remains elusive. The promotion of chimerism was suggested as a possible mechanism by which DLI or donor-specific transfusion modulates allogeneic immune responses and leading to graft acceptance (18). However, we did not identify donor leukocytes in the secondary lymphoid organs of DLI/anti-CD4-treated mice 30 days after xenotransplantation (Fig.…”

Section: Discussionmentioning

confidence: 77%

Both Infiltrating Regulatory T Cells and Insufficient Antigen Presentation Are Involved in Long-Term Cardiac Xenograft Survival

Chen

Diao

Stepkowski³

et al. 2007

The Journal of Immunology

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We have previously shown that pretransplant donor lymphocyte infusion (DLI) together with transient depletion of CD4+ T cells could induce permanent rat-to-mouse heart graft survival, whereas depleting CD4+ T cells alone failed to do so. In this study, we investigated the mechanism leading to long-term xenograft survival. We found that peripheral CD4+ T cells from DLI/anti-CD4-treated mice could mount rat heart graft rejection after adoptive transfer into B6 CD4−/− mice. Infusing donor-Ag-loaded mature dendritic cells (DCs) could break long-term cardiac xenograft survival in DLI/anti-CD4-treated mice. Interestingly, when the number and phenotype of graft-infiltrating cells were compared between anti-CD4- and DLI/anti-CD4-treated groups, we observed a significant increase in both the number and suppressive activity of αβ-TCR+CD3+CD4−CD8− double negative regulatory T cells and decrease in the numbers of CD4+ and CD8+ T cells in the xenografts of DLI/anti-CD4-treated mice. Moreover, there was a significant reduction in MHC class II-high DCs within the xenografts of DLI/anti-CD4-treated recipients. DCs isolated from the xenografts of anti-CD4- but not DLI/anti-CD4-treated recipients could stimulate CD4+ T cell proliferation. Our data indicate that functional anti-donor T cells are present in the secondary lymphoid organs of the mice that permanently accepted cardiac xenografts. Their failure to reject xenografts is associated with an increase in double negative regulatory T cells as well as a reduction in Ag stimulation by DCs found within grafts. These findings suggest that local regulatory mechanisms need to be taken into account to control anti-xenograft T cell responses.

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Section: Introductionmentioning

confidence: 99%

“…Donor-specific blood transfusion (DST) is a clinically and experimentally proven method to induce hyporesponsiveness and does not necessarily require additional immunotherapy [2][3][4][5][6]. However, the use of DST clinically has become less popular with the advent of calcineurin inhibitors and because a clear understanding of the mechanisms involved had remained elusive [4,6].In adult rats, long-term survival of MHC-incompatible vascularized allografts (heart or kidney) can be obtained by priming the recipients with donor blood cells [7,8]. We and others have shown that inhibition of early allograft rejection by DST mostly affects helper T cell functions [9][10][11] and requires intact resident dendritic cells at the time of transplantation [12].…”

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Development of CD25^– regulatory T cells following heart transplantation: Evidence for transfer of long‐term survival

et al. 2006

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Donor-specific heart allograft acceptance can be induced in the MHC-mismatched LEW.1 W to LEW.1A rat by donor-specific transfusions. Whereas the induction phase of tolerance has been studied in detail, its maintenance remained poorly understood. Here, we performed a side-by-side comparison of CD25 + and CD25 -splenic T cells of 100-day tolerant rats. Administration of CD25 -T cells from tolerant rats to sublethally irradiated recipients transferred long-term graft survival. These CD25 -T cells displayed a decreased donor-specific response in the mixed lymphocyte reaction and presented suppressive activity. These CD25 -T cells accumulated IFN-c, IL-10 and Foxp3 transcripts. The in vitro suppressive activity of CD25 -T cells required both cell contact and soluble factors (IL-10 and IFN-c). The CD25 + T cells from tolerant rats did not show any modification of their regulatory properties. We show that splenic CD25 -T cells of tolerant rats contribute to the maintenance of tolerance following the transplantation. Our data show that regulatory T cells are not restricted to the CD4 + CD25 + T cell subset and provide new insights on the mechanisms of tolerance to allograft following donor cell priming. IntroductionInduction of specific tolerance for donor antigens (see [1] for review) is one of the most actively explored fields in transplantation immunology. Donor-specific blood transfusion (DST) is a clinically and experimentally proven method to induce hyporesponsiveness and does not necessarily require additional immunotherapy [2][3][4][5][6]. However, the use of DST clinically has become less popular with the advent of calcineurin inhibitors and because a clear understanding of the mechanisms involved had remained elusive [4,6].In adult rats, long-term survival of MHC-incompatible vascularized allografts (heart or kidney) can be obtained by priming the recipients with donor blood cells [7,8]. We and others have shown that inhibition of early allograft rejection by DST mostly affects helper T cell functions [9][10][11] and requires intact resident dendritic cells at the time of transplantation [12]. Early production of and differentiation of CD8 + clonal regulatory cells [14][15][16] are also involved. DST treatment results in a complex state where symptoms of chronic graft rejection coexist [17] with mechanisms controlling the host acute anti-donor immune response. Long-term recipients accept a donor-derived skin graft whereas a third-party graft is rejected [17]. Moreover, the spleen [18], and possibly the graft itself [19], * These authors contributed equally to this paper. ** These authors contributed equally to this paper. harbors donor-specific regulatory T cells able to protect naive recipients from allogeneic heart rejection. Therefore, the immunological status of allograft recipients following DST pre-conditioning provides another example of the differentiation of regulatory cells described in mice [20][21][22][23] or in rats [18,24] following different "tolerance" induction maneuvers (see [25] for review)...

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Pretransplantation Blood Transfusion Revisited

Cited by 208 publications

References 18 publications

Early Presence of Regulatory Cells in Transplanted Rats Rendered Tolerant by Donor-Specific Blood Transfusion

Early Presence of Regulatory Cells in Transplanted Rats Rendered Tolerant by Donor-Specific Blood Transfusion

Both Infiltrating Regulatory T Cells and Insufficient Antigen Presentation Are Involved in Long-Term Cardiac Xenograft Survival

Development of CD25^– regulatory T cells following heart transplantation: Evidence for transfer of long‐term survival

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Pretransplantation Blood Transfusion Revisited

Cited by 208 publications

References 18 publications

Early Presence of Regulatory Cells in Transplanted Rats Rendered Tolerant by Donor-Specific Blood Transfusion

Early Presence of Regulatory Cells in Transplanted Rats Rendered Tolerant by Donor-Specific Blood Transfusion

Both Infiltrating Regulatory T Cells and Insufficient Antigen Presentation Are Involved in Long-Term Cardiac Xenograft Survival

Development of CD25– regulatory T cells following heart transplantation: Evidence for transfer of long‐term survival

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Development of CD25^– regulatory T cells following heart transplantation: Evidence for transfer of long‐term survival