Concomitant loss of regulatory T and B cells is a distinguishing immune feature of antibody-mediated rejection in kidney transplantation

Louis, Kévin; Fadakar, Paul; Macedo, Camila; Yamada, Masaki; Lucas, Matheus Galante Tiopisto Mendonça; Gu, Xinyan; Zeevi, Adriana; Randhawa, Parmjeet; Lefaucheur, Carmen; Metes, Diana

doi:10.1016/j.kint.2021.12.027

Cited by 13 publications

(18 citation statements)

References 49 publications

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“…It is known that IL-10 produced by TrBs promotes differentiation of CD4 1 T cells toward a Treg phenotype, 38,39 and only recently Louis et al found a concomitant sharp decrease in Treg and TrB numbers in DSA-positive patients who later developed antibodymediated rejection, as compared with those who did not, again highlighting the possible importance of both regulatory (T and B) cell populations in maintaining stable graft function. 40 This study has several limitations. We show the 3-year follow-up of ten patients from a 30-day, single-arm, phase 1 clinical trial, in which only four patients received the highest MIC number 7 days before surgery, which was found most effective.…”

Section: Discussionmentioning

confidence: 92%

Induction of Long-Lasting Regulatory B Lymphocytes by Modified Immune Cells in Kidney Transplant Recipients

Morath

Schaier

Ibrahim

et al. 2022

JASN

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Background We recently demonstrated that donor-derived modified immune cells (MICs)—PBMCs that acquire immunosuppressive properties after a brief treatment— induced specific immunosuppression against the allogeneic donor when administered prior to kidney transplantation. We found an up to 68-fold increase in CD19+CD24hiCD38hi transitional B lymphocytes compared with transplanted controls. Methods Ten patients from a phase I clinical trial who had received MIC infusions before kidney transplantation were followed to posttransplant day 1080. Results Patients treated with MICs had a favorable clinical course, showing no donor-specific HLA antibodies or acute rejections. The four patients who had received the highest dose of MICs 7 days before surgery and were on reduced immunosuppressive therapy showed an absence of in vitro lymphocyte reactivity against stimulatory donor blood cells, whereas reactivity against third-party cells was preserved. In these patients, numbers of transitional B lymphocytes were 75-fold and 7-fold higher than in 12 long-term survivors on minimal immunosuppression and four operationally tolerant patients, respectively (P<0.001 for both). In addition, we found significantly higher numbers of other regulatory B lymphocyte subsets, and a gene expression signature suggestive of operational tolerance in three of four patients. In MIC-treated patients, in vitro lymphocyte reactivity against donor blood cells was restored after B lymphocyte depletion, suggesting a direct pathophysiological role of regulatory B lymphocytes in donor-specific unresponsiveness. Conclusions These results indicate that donor-specific immunosuppression after MIC infusion is long-lasting and associated with a striking increase in regulatory B lymphocytes. Donor-derived MICs appear to be an immunoregulatory cell population which, when administered to recipients prior to transplantation, may exert a beneficial effect on kidney transplants.

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Section: Discussionmentioning

confidence: 92%

Induction of Long-Lasting Regulatory B Lymphocytes by Modified Immune Cells in Kidney Transplant Recipients

Morath

Schaier

Ibrahim

et al. 2022

JASN

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“…We next investigated the relationship between peripheral blood CD4+CD25hiCD127lo Tregs and graft rejections. We and others previously reported that compared to patients with stable renal function, patients with acute rejection ( 44 ), chronic rejection ( 45 , 46 ) or ABMR ( 40 ) had lower frequency and/or number of circulating Tregs. However, as aforementioned, those studies were based on small numbers of patients and univariate analyses.…”

Section: Discussionmentioning

confidence: 95%

“…In kidney transplant patients, the most studied B cell subset with regulatory properties is CD4hiCD38hi transitional B cells. Several studies reported that patients with kidney graft rejections, especially ABMR, have a reduction in circulating transitional B cells compared to those with stable graft function (35)(36)(37)(38)(39)(40). In this study, we performed univariate analyses of B cell phenotyping data from more than 300 patients and did not find any significant association between kidney graft rejections and the relative frequency of Breg subsets, including transitional, CD25+, CD9+, Granzyme B+ B cells, and plasmablasts.…”

Section: Discussionmentioning

confidence: 99%

Kidney allograft rejection is associated with an imbalance of B cells, regulatory T cells and differentiated CD28-CD8+ T cells: analysis of a cohort of 1095 graft biopsies

Degauque

Lorent

et al. 2023

Front. Immunol.

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IntroductionThe human immune system contains cells with either effector/memory or regulatory functions. Besides the well-established CD4+CD25hiCD127lo regulatory T cells (Tregs), we and others have shown that B cells can also have regulatory functions since their frequency and number are increased in kidney graft tolerance and B cell depletion as induction therapy may lead to acute rejection. On the other hand, we have shown that CD28-CD8+ T cells represent a subpopulation with potent effector/memory functions. In the current study, we tested the hypothesis that kidney allograft rejection may be linked to an imbalance of effector/memory and regulatory immune cells.MethodsBased on a large cohort of more than 1000 kidney graft biopsies with concomitant peripheral blood lymphocyte phenotyping, we investigated the association between kidney graft rejection and the percentage and absolute number of circulating B cells, Tregs, as well as the ratio of B cells to CD28-CD8+ T cells and the ratio of CD28-CD8+ T cells to Tregs. Kidney graft biopsies were interpreted according to the Banff classification and divided into 5 biopsies groups: 1) normal/subnormal, 2) interstitial fibrosis and tubular atrophy grade 2/3 (IFTA), 3) antibody-mediated rejection (ABMR), 4) T cell mediated-rejection (TCMR), and 5) borderline rejection. We compared group 1 with the other groups as well as with a combined group 3, 4, and 5 (rejection of all types) using multivariable linear mixed models.Results and discussionWe found that compared to normal/subnormal biopsies, rejection of all types was marginally associated with a decrease in the percentage of circulating B cells (p=0.06) and significantly associated with an increase in the ratio of CD28-CD8+ T cells to Tregs (p=0.01). Moreover, ABMR, TCMR (p=0.007), and rejection of all types (p=0.0003) were significantly associated with a decrease in the ratio of B cells to CD28-CD8+ T cells compared to normal/subnormal biopsies. Taken together, our results show that kidney allograft rejection is associated with an imbalance between immune cells with effector/memory functions and those with regulatory properties.

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“…Similarly, Louis et al. observed a loss of regulatory T and B cells in kidney transplant recipient serum in the setting of ABMR ( 100 ). Similar to Treg cells, transitional B cells (Trb) play a role in immune suppression, as the authors found that Trb suppressed Tfh activation, Tfh- to B-cell activation, and antibody generation in vivo .…”

Section: Allogenic B-cell Response and Transplant Rejectionmentioning

confidence: 94%

B-cell response in solid organ transplantation

Gaber

Chen

2022

Front. Immunol.

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The transcriptional regulation of B-cell response to antigen stimulation is complex and involves an intricate network of dynamic signals from cytokines and transcription factors propagated from T-cell interaction. Long-term alloimmunity, in the setting of organ transplantation, is dependent on this B-cell response, which does not appear to be halted by current immunosuppressive regimens which are targeted at T cells. There is emerging evidence that shows that B cells have a diverse response to solid organ transplantation that extends beyond plasma cell antibody production. In this review, we discuss the mechanistic pathways of B-cell activation and differentiation as they relate to the transcriptional regulation of germinal center B cells, plasma cells, and memory B cells in the setting of solid organ transplantation.

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Concomitant loss of regulatory T and B cells is a distinguishing immune feature of antibody-mediated rejection in kidney transplantation

Cited by 13 publications

References 49 publications

Induction of Long-Lasting Regulatory B Lymphocytes by Modified Immune Cells in Kidney Transplant Recipients

Induction of Long-Lasting Regulatory B Lymphocytes by Modified Immune Cells in Kidney Transplant Recipients

Kidney allograft rejection is associated with an imbalance of B cells, regulatory T cells and differentiated CD28-CD8+ T cells: analysis of a cohort of 1095 graft biopsies

B-cell response in solid organ transplantation

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