Anti-CD45RB monoclonal antibody(University of Groningen/University of Western Ontario/Amgen)

The role of B cells in renal ischemia-reperfusion injury (IRI) remains controversial, and the role of the recently discovered B cell subset, regulatory B cells, in renal IRI has not yet been studied. The authors demonstrated in mouse models that regulatory B cells attenuated renal IRI. They also found that treatment with anti-CD45RB with or without anti–Tim-1, which induces regulatory B cells and suppresses T cells, attenuated acute renal injury when given before IRI and facilitated renal recovery when given after IRI. The main mechanism underlying the anti-CD45RB–mediated reno-protective effects was induction of IL-10+ regulatory B cells. These findings provide insight into the role of regulatory B cells in renal IRI and suggest that anti-CD45RB may be a potential therapeutic strategy in renal IRI.

Regulatory B cells are a newly discovered B cell subset that suppresses immune responses. Recent studies found that both anti-CD45RB and anti–Tim-1 treatments regulate immune responses by inducing regulatory B cells; however, the role of these cells in renal ischemia-reperfusion injury (IRI) is unknown.

Using mouse models, including T cell–deficient (RAG1 knockout and TCRα knockout) mice and B cell–deficient (μMT) mice, we investigated the effects of regulatory B cells and anti-CD45RB on IRI and the mechanisms underlying these effects.

Adoptive transfer of regulatory B cells before or after IRI attenuated renal IRI. Anti-CD45RB treatment with or without anti–Tim-1 before IRI increased renal infiltration of CD19+Tim-1+ regulatory B and regulatory T cells. Anti-CD45RB decreased serum creatinine levels, pathologic injury score, tubular apoptosis, and proinflammatory cytokines levels, whereas IL-10 levels increased. Following IRI, anti-CD45RB with or without anti–Tim-1 also induced regulatory B cells, improving renal function and tubular regeneration. In RAG1 knockout mice with B cell transfer, TCRα knockout mice, and wild-type mice with T cell depletion, anti-CD45RB increased regulatory B cells and attenuated IRI. However, anti-CD45RB did not attenuate IRI in RAG1 knockout mice with T cell transfer or μMT mice and induced only mild improvement in wild-type mice with B cell depletion. Furthermore, B cell–deficient mice receiving B cells from IL-10 knockout mice (but not from wild-type mice) did not show renal protection against IRI when treated with anti-CD45RB.

Anti-CD45RB treatment attenuated acute renal injury and facilitated renal recovery after IRI through induction of IL-10+ regulatory B cells, pointing to anti-CD45RB as a potential therapeutic strategy in renal IRI.

This article describes the majority of transplant tolerance studies-as well as in the general study of peripheral tolerance-arguably tend to focus on CD4+ CD25+ Foxp3+ regulatory T cells (Tregs) as the hallmark mediators of immune regulation.In this article the authors use a pancreatic islet allograft model in which tolerance is induced with a combinational therapeutic regimen consisting of anti-CD45RB monoclonal antibodies plus adjunct rapamycin and IL-10 administration.Graft-destructive T cells persist in functionally tolerant animals since late splenectomy unveils their activity, a result consistent with other studies showing that tolerance can sometimes be broken even during the later maintenance phase were showed.A significant proof of principle that a division of labor can occur in which differing regulatory T cell phenotypes cooperate in an orchestrated process resulting in the initiation and maintenance of induced allograft tolerance were provided.