Central Role of CD45RA− Foxp3hi Memory Regulatory T Cells in Clinical Kidney Transplantation Tolerance

Braza, Faouzi; Dugast, Emilie; Panov, Ivo; Paul, Chloé; Vogt, Katrin; Pallier, Annaïck; Chesneau, Mélanie; Báron, Daniel; Guérif, Pierrick; Lei, Hong; Laplaud, David‐Axel; Volk, Hans‐Dieter; Degauque, Nicolas; Giral, Magali; Soulillou, Jean‐Paul; Sawitzki, Birgit; Brouard, Sophie

doi:10.1681/asn.2014050480

Cited by 103 publications

(118 citation statements)

References 55 publications

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“…While several groups including our own have demonstrated an association between B cells and renal allograft tolerance, other cell populations have been implicated as well, including myeloid-derived dendritic cells and regulatory T cells (36, 37). Although it is not yet possible to integrate these various findings into a comprehensive model describing the development of tolerance, these data suggest that factors beyond B cells alone are likely to play an important role.…”

Section: Discussionmentioning

confidence: 93%

Longitudinal Studies of a B Cell–Derived Signature of Tolerance in Renal Transplant Recipients

Newell

Asare

Sanz

et al. 2015

American Journal of Transplantation

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Biomarkers of transplant tolerance would enhance the safety and feasibility of clinical tolerance trials and potentially facilitate management of patients receiving immunosuppression. To this end, we examined blood from spontaneously tolerant renal transplant recipients and patients enrolled in two interventional tolerance trials using flow cytometry and gene expression profiling. Using a previously reported tolerant cohort as well as newly identified tolerant patients we confirmed our previous finding that tolerance was associated with increased expression of B cell-associated genes relative to immunosuppressed patients. This was not accounted for merely by an increase in total B cell numbers, but was associated with the increased frequencies of transitional and naïve B cells. Moreover, serial measurements of gene expression demonstrated that this pattern persisted over several years although patients receiving immunosuppression also displayed an increase in the two most dominant tolerance-related B cell genes, IGKV1D-13 and IGLL-1, over time. Importantly, patients rendered tolerant via induction of transient mixed chimerism, and those weaned to minimal immunosuppression, showed similar increases in IGKV1D-13 as did spontaneously tolerant individuals. Collectively, these findings support the notion that alterations in B cells may be a common theme for tolerant kidney transplant recipients, and a useful monitoring tool in prospective trials.

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Section: Discussionmentioning

confidence: 93%

Longitudinal Studies of a B Cell–Derived Signature of Tolerance in Renal Transplant Recipients

Newell

Asare

Sanz

et al. 2015

American Journal of Transplantation

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“…Activated/effector T regulatory cells are depleted during HIV infection [18] and are thought to play an important role in controlling alloreactivity after kidney transplant [19]. In our cohort, the number of CD4 + CD25 high T cells was lowest amongst patients categorized to the upper activation tertile (Table 1); this finding suggests that the frequency of T cells with potential regulatory function do not explain the lower risk of allograft rejection we observed among patients with the highest levels of immune activation.…”

Section: Discussionmentioning

confidence: 99%

Influence of immune activation on the risk of allograft rejection in human immunodeficiency virus-infected kidney transplant recipients

Lorio

Rosa

Suárez

et al. 2016

Transplant Immunology

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Background HIV infection is associated with high rates of acute rejection following kidney transplantation. The underlying mechanisms for such predisposition are incompletely understood. Pathological immune activation is a hallmark of chronic HIV infection that persists despite effective antiretroviral therapy. We hypothesized that the baseline levels of T cell activation in HIV+ candidates would correlate with their risk of acute rejection following kidney transplantation. Methods Single-center retrospective cohort analysis of HIV+ adult kidney transplants performed between October 2006 and September 2013. The frequency of CD3+HLA-DR+ cells measured by flow cytometry served as a surrogate marker of immune activation. Patients were categorized into tertiles of activation, and the rates of biopsy-proven acute rejection were compared across groups. Results (1) Compared to matched HIV− controls, the baseline number of CD3+HLA-DR+ cells was higher in HIV+ kidney transplant candidates. (2) Abnormally high levels of activation did not decrease with transplant-associated immunosuppression. (3) Patients categorized within the lower and middle CD3+HLA-DR+ tertiles had higher probability of rejection during the first 3 years post-transplant compared to those in the higher activation tertile (36.9% vs. 0%; log-rank P= .04). Conclusions Pathological immune activation in HIV+ transplant candidates does not explain their increased susceptibility to allograft rejection. Paradoxically, those with the highest levels of immune activation seem to be less prone to rejection.

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“…The rare kidney transplant recipients who spontaneously develop a state of operational tolerance demonstrate an increased frequency of highly suppressive memory Tregs with a fully demethylated FOXP3 Treg-Demethylated Region (TSDR), a hallmark epigenetic change of stable Tregs [65]. Similarly, marked enrichment of FOXP3-expressing Tregs during the early post-transplant course has been observed following the non-myeloablative anti-CD2 mAb-based CKHCT protocol that leads to transient chimerism [31, 66].…”

Section: Ii) Tolerance Mechanisms Associated With Transient Mixed Chimentioning

confidence: 99%

Mechanisms of Mixed Chimerism-Based Transplant Tolerance

Zuber

Sykes

2017

Trends in Immunology

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Immune responses to allografts represent a major barrier in organ transplantation. Immune tolerance to avoid chronic immunosuppression is a critical goal in the field, recently achieved in the clinic by combining bone marrow transplantation with kidney transplantation following non-myeloablative conditioning. At high levels of chimerism, such protocols can permit central deletional tolerance, yet with a significant risk of graft-versus-host disease (GVHD). In contrast, transient chimerism-based tolerance is devoid of GVHD risk and appears to initially depend on regulatory T cells followed by a gradual, presumably peripheral, clonal deletion of donor-reactive T cells. Here, we review recent mechanistic insights into tolerance and the development of more robust and safer protocols for tolerance induction that will be guided by innovative immune monitoring tools.

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Central Role of CD45RA− Foxp3hi Memory Regulatory T Cells in Clinical Kidney Transplantation Tolerance

Abstract: Tregs with a specific Foxp3 TSDR demethylation pattern, which may contribute to the maintenance of graft tolerance.

Cited by 103 publications

References 55 publications

Longitudinal Studies of a B Cell–Derived Signature of Tolerance in Renal Transplant Recipients

Longitudinal Studies of a B Cell–Derived Signature of Tolerance in Renal Transplant Recipients

Influence of immune activation on the risk of allograft rejection in human immunodeficiency virus-infected kidney transplant recipients

Mechanisms of Mixed Chimerism-Based Transplant Tolerance

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