Anti-CD45RB/Anti-TIM-1-Induced Tolerance Requires Regulatory B Cells

Lee, Kang Mi; Kim, James I.; Stott, Ryan; Soohoo, Julie; O’Connor, Matthew; Yeh, Heidi; Zhao, Gaoping; Eliades, Philip; Fox, Courtney; Cheng, Niancai; Deng, Shaoping; Markmann, James F.

doi:10.1111/j.1600-6143.2012.04055.x

Cited by 92 publications

(103 citation statements)

References 32 publications

(33 reference statements)

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“…Moreover, similar to regulatory T cells, regulatory B cell subsets have the potential to induce tolerance (1). In transplantation models in mice, regulatory B cells generated following treatment with anti-TIM-1 Ab are able to transfer MHC-mismatched islet allograft tolerance by promoting via TGF-b FOXP3 + CD4 + CD25 + regulatory T cells (2)(3)(4). Consistent with a regulatory function for B cells in human transplantation, a clinical trial has shown an increased risk for acute cellular rejection following depletion of B cells prior to transplantation, which could be due to a loss of regulatory B cells (5).…”

mentioning

confidence: 99%

Regulatory B Cells with a Partial Defect in CD40 Signaling and Overexpressing Granzyme B Transfer Allograft Tolerance in Rodents

Durand

Huchet

Mérieau

et al. 2015

The Journal of Immunology

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Emerging knowledge regarding B cells in organ transplantation has demonstrated that these cells can no longer be taken as mere generators of deleterious Abs but can also act as beneficial players. We previously demonstrated in a rat model of cardiac allograft tolerance induced by short-term immunosuppression an accumulation in the blood of B cells overexpressing inhibitory molecules, a phenotype also observed in the blood of patients that spontaneously develop graft tolerance. In this study, we demonstrated the presence in the spleen of regulatory B cells enriched in the CD24intCD38+CD27+IgD−IgM+/low subpopulation, which are able to transfer donor-specific tolerance via IL-10 and TGF-β1–dependent mechanisms and to suppress in vitro TNF-α secretion. Following anti-CD40 stimulation, IgD−IgM+/low B cells were blocked in their plasma cell differentiation pathway, maintained high expression of the inhibitory molecules CD23 and Bank1, and upregulated Granzyme B and Irf4, two molecules described as highly expressed by regulatory B cells. Interestingly, these B cells recognized specifically a dominant donor Ag, suggesting restricted specificity that could lead to a particular B cell response. Regulatory B cells were not required for induction of tolerance and appeared following Foxp3+CD4+CD25+ regulatory T cells, suggesting cooperation with regulatory T cells for their expansion. Nevertheless, following transfer to new recipients, these B cells migrated to the allograft, kept their regulatory profile, and promoted local accumulation of Foxp3+CD4+CD25+ regulatory T cells. Mechanisms of regulatory B cells and their cell therapy potential are important to decipher in experimental models to pave the way for future developments in the clinic.

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confidence: 99%

Regulatory B Cells with a Partial Defect in CD40 Signaling and Overexpressing Granzyme B Transfer Allograft Tolerance in Rodents

Durand

Huchet

Mérieau

et al. 2015

The Journal of Immunology

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“…First, TIM-1 ligation alone, or in combination with anti-CD45RB, increases both the frequency and number of TIM-1+ and IL-10+ B cells and prolongs allograft survival (17, 38). While tolerance induced by anti-TIM-1 is Treg-dependent (38, 39), the expression of TIM-1 on Tregs is minimal (17). In contrast, the induction of tolerance, Tregs, and anti-inflammatory Th skewing by anti-TIM-1 are all dependent on B cells (17, 38).…”

Section: Tim-1 An Inclusive Marker For Bregs Involved In Induction Anmentioning

confidence: 99%

Role of B cells in tolerance induction

Kim

Rothstein

Markmann

2015

Current Opinion in Organ Transplantation

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Purpose B cells are known to play a central role in humoral immunity and to boost cellular immunity, however, in a variety of experimental models, B cell subsets ameliorate inflammation and autoimmune disease, indicating that they can also play a regulatory role. Here we highlight the advances in regulatory B cell (Breg) biology of the past year with an emphasis on findings pertinent to transplantation. Several recent observations highlight the relevance to clinical transplantation. Data from at least three independent groups demonstrated that spontaneously tolerant renal transplant recipients exhibit a peripheral blood B cell signature although the significance of these data remains unclear. Moreover, new data suggest that regulatory B cells may serve as a biomarker for long-term allograft outcomes. Finally, recent evidence suggesting that plasma cells may be an essential component of Bregs raises new concerns about targeting antibody producing cells. Recent findings We describe new information on Breg mechanisms of action to suppress the alloresponse, signals to expand Bregs in vitro, and more functional evidence of Breg involvement in operationally tolerant kidney patients and in maintaining stable allograft function. Summary While lymphocyte depletion remains central to tolerance induction therapy, the sparing or expansion of regulatory B cells may be an additional strategy to preempt graft rejection.

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“…However, Breg activity was found to be either distinct from, or independent of, Tregs in collagen-induced arthritis and EAE models [81,102]. In allograft models, it is uncertain whether the reported requirement for Tregs in the presence of Bregs is due to independent or interdependent effects [103].…”

Section: The Role Of Tim-1 and Bregs In Allograft Modelsmentioning

confidence: 99%

Non-Antibody Mediated Roles of B Cells in Allograft Survival

Chalasani

Rothstein

2014

Curr Transpl Rep

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Antibody production is unquestionably a key effector function of B cells that remains a formidable barrier against long-term graft survival. However, emerging evidence indicates that B cells play a key role in shaping the effector responses by mechanisms that extend beyond their function as antibody producing cells. B cell depletion in transplant recipients has resulted in paradoxical outcomes of increased graft rejection versus improved graft function, implying that B cells function as both enhancers and regulators of the alloimmune response. Based on findings from animal and human studies, we address mechanisms by which B cells modulate the immune response and highlight their role in promoting allograft rejection or tolerance.

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Anti-CD45RB/Anti-TIM-1-Induced Tolerance Requires Regulatory B Cells

Cited by 92 publications

References 32 publications

Regulatory B Cells with a Partial Defect in CD40 Signaling and Overexpressing Granzyme B Transfer Allograft Tolerance in Rodents

Regulatory B Cells with a Partial Defect in CD40 Signaling and Overexpressing Granzyme B Transfer Allograft Tolerance in Rodents

Role of B cells in tolerance induction

Non-Antibody Mediated Roles of B Cells in Allograft Survival

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