Long-Term Allograft Tolerance Is Characterized by the Accumulation of B Cells Exhibiting an Inhibited Profile

Texier, Laëtitia Le; Thébault, Paméla; Lavault, Amélie; Usal, Claire; Mérieau, Emmanuel; Quillard, Thibaut; Charreau, Béatrice; Soulillou, Jean Paul; Cuturi, Maria‐Cristina; Brouard, Sophie; Chiffoleau, Elise

doi:10.1111/j.1600-6143.2010.03336.x

Cited by 119 publications

(83 citation statements)

References 49 publications

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“…Whereas these observations support a role for ELFs in chronic terminal rejection,120 two studies suggest that ELFs may actual elicit beneficial outcomes 121, 122. These findings in experimental models of kidney and cardiac allografts emphasize that ELF development promotes the recruitment of T cells and B cells displaying inhibitory or regulatory phenotypes 121, 122. Such activities would be predicted to suppress destructive alloimmune responses and promote graft tolerance.…”

Section: Elfs As Perpetuators Of Inflammation‐driven Pathologymentioning

confidence: 99%

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

2015

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SummaryLymphoid neogenesis is traditionally viewed as a pre‐programmed process that promotes the formation of lymphoid organs during development. Here, the spatial organization of T and B cells in lymph nodes and spleen into discrete structures regulates antigen‐specific responses and adaptive immunity following immune challenge. However, lymphoid neogenesis is also triggered by chronic or persistent inflammation. Here, ectopic (or tertiary) lymphoid organs frequently develop in inflamed tissues as a response to infection, auto‐immunity, transplantation, cancer or environmental irritants. Although these structures affect local immune responses, the contribution of these lymphoid aggregates to the underlining pathology are highly context dependent and can elicit either protective or deleterious outcomes. Here we review the cellular and molecular mechanisms responsible for ectopic lymphoid neogenesis and consider the relevance of these structures in human disease.

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Section: Elfs As Perpetuators Of Inflammation‐driven Pathologymentioning

confidence: 99%

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

2015

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“…7,8,12 The role of B cells has also been reported in experimental rodent models, in which transfer of B cells from tolerant rats prolonged graft survival when administered to untreated recipients. 15 The mechanisms involved in the maintenance of this phenomenon remain elusive, and the identification of related biomarkers remains instrumental to achieving safe drug minimization or complete weaning in clinical practice.…”

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confidence: 99%

Upregulation of miR-142-3p in Peripheral Blood Mononuclear Cells of Operationally Tolerant Patients with a Renal Transplant

Danger

Pallier²,

Giral³

et al. 2012

Journal of the American Society of Nephrology

105

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Achieving drug-free tolerance or successfully using only small doses of immunosuppression is a major goal in organ transplantation. To investigate the potential mechanisms by which some kidney transplant recipients can achieve operational tolerance, we compared the expression profiles of microRNA in peripheral blood mononuclear cells of operationally tolerant patients with those of stable patients treated with conventional immunosuppression. B cells from operationally tolerant patients overexpressed miR-142-3p. The expression of miR-142-3p was stable over time and was not modulated by immunosuppression. In Raji B cells, overexpression of miR-142-3p modulated nearly 1000 genes related to the immune response of B cells, including potential miR-142-3p targets and molecules previously identified in the blood of operationally tolerant patients. Furthermore, our results suggested that a negative feedback loop involving TGF-b signaling and miR-142-3p expression in B cells may contribute to the maintenance of tolerance. In summary, miR-142-3p expression in peripheral blood mononuclear cells correlates with operational tolerance. Whether upregulation of miR-142-3p modulates inflammatory responses to promote tolerance or is a result of this tolerance state requires further study.

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“…Description of a clear phenotype for Bregs and RegMCs in the literature is still very controversial (40)(41)(42)(43), and we and other believe that the situation and model in which those cells were identified are crucial to determine the phenotype (41). In addition, in rat, there is very little description of those cells (3,44). In this study, we did not intend to fully characterize Bregs and RegMCs, but rather understand their signature, their contribution to alloresponses control and possible mechanisms of action.…”

Section: Discussionmentioning

confidence: 99%

“…Despite the fact that we could not specifically deplete CD4 + Tregs in absence of specific tools in rats, we believe that they play an important role in supporting the function of Bregs and RegMCs. Although Bregs and RegMCs have already been described as involved in transplantation tolerance (3,5,11,12,39), their possible synergistic and equal involvement in inhibition of antidonor immune responses had never been described. As for CD8 + CD45RC low Tregs, we believe that Bregs and RegMCs emerge at early time point in presence of Ags (14).…”

Section: Discussionmentioning

confidence: 99%

“…In particular, the regulatory potential of new subsets such as B cells or myeloid cells (MCs) has been unraveled and lots of efforts are being done to identify specific markers and mechanisms, as it has been done for CD4 + regulatory T cells (Tregs), and more recently for CD8 + Tregs (1). We and others have demonstrated the immunoregulatory potential of regulatory B cells (Bregs) in transplantation tolerance in rodents and human (2)(3)(4)(5)(6)(7)(8) and described different subsets of Bregs with distinct mechanisms (9,10). Regulatory MCs (RegMCs) have been less studied, but data are emerging demonstrating their protective potential in rodent models of transplantation, but also more recently in clinical trials (11,12).…”

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confidence: 99%

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Compensatory Regulatory Networks between CD8 T, B, and Myeloid Cells in Organ Transplantation Tolerance

Bézie

Picarda

Ossart

et al. 2015

The Journal of Immunology

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In transplantation tolerance, numerous regulatory populations have the capacity to inhibit allograft rejection; however, their compensatory capacities have never been clearly evidenced. We have previously demonstrated that the tolerogenic effect mediated by CD8+CD45RClow regulatory T cells (Tregs) in a model of organ transplantation with CD40Ig could be abrogated by permanent depletion of CD8+ cells that resulted in allograft rejection in half of the recipients. This result demonstrated that CD8+ Tregs were essential, but also that half of the recipients still survived indefinitely. We also demonstrated that no other regulatory populations, besides CD8+ Tregs, could induce and maintain allograft tolerance in CD40Ig-treated tolerant animals. In the current study, we analyzed the mechanisms that arose following CD8+ Treg depletion and allowed establishment of networks of new regulatory cells to maintain allograft survival. We identified regulatory B cells (Bregs) and regulatory myeloid cells (RegMCs) as being responsible of the maintenance of the long-term allograft survival. We demonstrated that both regulatory cell subsets efficiently inhibited antidonor immune responses in adoptively transferred recipients. Although Bregs were induced, they were not essential for the maintenance of the graft as demonstrated in IgM-deficient recipients. In addition, we showed that RegMCs were the most suppressive and acted alone, whereas Bregs activity was associated with increased suppressive activity of other subsets in adoptively transferred recipients. Altogether, to our knowledge, we demonstrated in this study for the first time the emergence of both Bregs and RegMCs following Tregs depletion and highlighted the importance of regulatory cell networks and their synergistic potential in transplantation.

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Long-Term Allograft Tolerance Is Characterized by the Accumulation of B Cells Exhibiting an Inhibited Profile

Cited by 119 publications

References 49 publications

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

Upregulation of miR-142-3p in Peripheral Blood Mononuclear Cells of Operationally Tolerant Patients with a Renal Transplant

Compensatory Regulatory Networks between CD8 T, B, and Myeloid Cells in Organ Transplantation Tolerance

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