Pretransplant blood transfusion without additional immunotherapy generates CD25+CD4+ regulatory T cells: a potential explanation for the blood-transfusion effect

Bushell, Andrew; Karim, Mahzuz; Kingsley, Cherry I.; Wood, Kathryn J.

doi:10.1097/01.tp.0000083043.84630.99

Cited by 88 publications

(78 citation statements)

References 29 publications

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“…Since TGF-b activation from TGF-b latent complex is known to be tightly regulated and lead to a transient effect restricted to neighbor cells, 38 Treg expansion after massive apoptotic cell death may be responsible for long-term autoimmunity control (either locally or in other sites). Interestingly, induction of Treg cells in the spleen after random blood product transfusion has been reported previously 39 and nonspecific immunomodulatory effects of preoperative blood product transfusion has been proposed to be related to the presence of apoptotic leukocytes present in stored blood products. 16,40,41 The immunomodulatory role of apoptotic leukocytes can be also extended to the prevention of alloimmune responses.…”

Section: Discussionmentioning

confidence: 78%

Intravenous apoptotic spleen cell infusion induces a TGF-β-dependent regulatory T-cell expansion

et al. 2005

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Apoptotic leukocytes are endowed with immunomodulatory properties that can be used to enhance hematopoietic engraftment and prevent graft-versus-host disease (GvHD). This apoptotic cell-induced tolerogenic effect is mediated by host macrophages and not recipient dendritic cells or donor phagocytes present in the bone marrow graft as evidenced by selective cell depletion and trafficking experiments. Furthermore, apoptotic cell infusion is associated with TGF-bdependent donor CD4 þ CD25 þ T-cell expansion. Such cells have a regulatory phenotype (CD62L high and intracellular CTLA-4 þ ), express high levels of forkhead-box transcription factor p3 (Foxp3) mRNA and exert ex vivo suppressive activity through a cell-to-cell contact mechanism. In vivo CD25 depletion after apoptotic cell infusion prevents the apoptotic cell-induced beneficial effects on engraftment and GvHD occurrence. This highlights the role of regulatory T cells in the tolerogenic effect of apoptotic cell infusion. This novel association between apoptosis and regulatory T-cell expansion may also contribute to preventing deleterious autoimmune responses during normal turnover.

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Section: Discussionmentioning

confidence: 78%

Intravenous apoptotic spleen cell infusion induces a TGF-β-dependent regulatory T-cell expansion

et al. 2005

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“…In mice and rats, regulatory CD25 + T cells have been shown to control host anti-graft responses in recipients tolerant to skin allografts following multiple pretransplant donor-specific transfusions [20,27]. CD25 - The acquisition of antigen-specific regulatory functions by CD25 -T cells in tolerant animals could reveal an education [44,45] of conventional alloreactive CD25 -T cells by "natural" regulatory CD25 + T cells [37,38].…”

Section: Discussionmentioning

confidence: 99%

“…In mice and rats, regulatory CD25 + T cells have been shown to control host anti-graft responses in recipients tolerant to skin allografts following multiple pretransplant donor-specific transfusions [20,27]. CD25 - T cells have been also suggested to harbor a regulatory population able to control responses against minor MHC-incompatible antigen ( [33] and [28] for review).…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, the spleen [18], and possibly the graft itself [19], 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). Various types of cells, including CD4 + and CD8 + splenocytes [18,26] harvested from long-term recipients, have been described to transfer tolerance to naive syngeneic hosts when injected at the time of transplantation.…”

Section: Introductionmentioning

confidence: 99%

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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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Transfused Red Blood Cell Characteristics and Kidney Transplant Outcomes Among Patients Receiving Early Posttransplant Transfusion

Gaiffe,

Vernerey,

Bardiaux

et al. 2023

JAMA Netw Open

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ImportanceRed blood cell transfusion (RBCT) is frequently required in the early post–kidney transplant period, but long-term outcomes associated with RBCT is controversial. Therefore, it may be relevant to investigate the association between RBCT characteristics and transplant outcomes.ObjectiveTo study the association between RBC storage duration and transplant outcomes.Design, Setting, and ParticipantsThis was a nationwide retrospective cohort study based on data linking between 2 prospective French nationwide registries. Clinical transplant parameters, outcomes, and RBCT characteristics were extracted from the CRISTAL registry of the Agence de la Biomédecine and the national database of the Etablissement Français du Sang. All 12 559 patients having received a first kidney transplant in France between January 1, 2002, and December 31, 2008, were included. Patients were followed up from transplant to graft loss, death with a functional graft, or data retrieval in June 2016. Data were analyzed from April 2019 to June 2022.ExposuresClinical outcomes of transplant recipients who underwent early RBCT were analyzed considering transfusion characteristics.Main Outcomes and MeasuresCox proportional hazards regression models were fitted to evaluate transplant failure defined as graft loss or death with a functional graft.ResultsAmong 12 559 patients who underwent kidney transplant, 3483 received an RBCT during the first 14 days posttransplant. The median (IQR) age of patients was 53.0 (41.5-61.2) years, and 1929 patients (55.4%) were male. Median (IQR) follow-up was 7.8 (7.6-8.0) years. In multivariable analysis, longer (vs shorter) storage duration of transfused RBC was associated with a decrease in risk of transplant failure (hazard ratio, 0.99; 95% CI, 0.98-1.00 for each additional storage day; P = .06). Patients transfused with at least 1 RBC unit stored for more than 20 days had a 5% absolute decrease in transplant failure at 3 years and 7% at 5 years compared with those who received RBC stored for less than 20 days.Conclusions and RelevanceIn this study, longer RBC storage duration was associated with a decreased risk of transplant failure among patients who received kidney transplants and RBC transfusions. Preferential use of RBC with longer storage duration might improve kidney graft survival following transplant and transfusion.

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Pretransplant blood transfusion without additional immunotherapy generates CD25+CD4+ regulatory T cells: a potential explanation for the blood-transfusion effect

Abstract: These results provide a basis for understanding the blood-transfusion effect in transplantation and, by providing a link between naturally occurring regulatory cells and those induced by alloantigen, may shed new light on the fundamental basis of the effect itself.

Cited by 88 publications

References 29 publications

Intravenous apoptotic spleen cell infusion induces a TGF-β-dependent regulatory T-cell expansion

Intravenous apoptotic spleen cell infusion induces a TGF-β-dependent regulatory T-cell expansion

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

Transfused Red Blood Cell Characteristics and Kidney Transplant Outcomes Among Patients Receiving Early Posttransplant Transfusion

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Pretransplant blood transfusion without additional immunotherapy generates CD25+CD4+ regulatory T cells: a potential explanation for the blood-transfusion effect

Abstract: These results provide a basis for understanding the blood-transfusion effect in transplantation and, by providing a link between naturally occurring regulatory cells and those induced by alloantigen, may shed new light on the fundamental basis of the effect itself.

Cited by 88 publications

References 29 publications

Intravenous apoptotic spleen cell infusion induces a TGF-β-dependent regulatory T-cell expansion

Intravenous apoptotic spleen cell infusion induces a TGF-β-dependent regulatory T-cell expansion

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

Transfused Red Blood Cell Characteristics and Kidney Transplant Outcomes Among Patients Receiving Early Posttransplant Transfusion

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