Abstract
BackgroundAnti-CD154 (MR1) monoclonal antibody (mAb) and rapamycin (RAPA) treatment both improve survival of rat-to-mouse islet xenograft. The present study investigated the effect of combined RAPA/MR1 treatment on rat-to-mouse islet xenograft survival and analyzed the role of CD4+CD25+Foxp3+ T regulatory cells (Treg) in the induction and maintenance of the ensuing tolerance.Methodology/Principal FindingsC57BL/6 mice were treated with MR1/RAPA and received additional monoclonal anti-IL2 mAb or anti CD25 mAb either early (0–28 d) or late (100–128 d) post-transplantation. Treg were characterised in the blood, spleen, draining lymph nodes and within the graft of tolerant and rejecting mice by flow cytometry and immunohistochemistry. Fourteen days of RAPA/MR1 combination therapy allowed indefinite islet graft survival in >80% of the mice. Additional administration of anti-IL-2 mAb or depleting anti-CD25 mAb at the time of transplantation resulted in rejection (100% and 89% respectively), whereas administration at 100 days post transplantation lead to lower rejection rates (25% and 40% respectively). Tolerant mice showed an increase of Treg within the graft and in draining lymph nodes early post transplantation, whereas 100 days post transplantation no significant increase of Treg was observed. Rejecting mice showed a transient increase of Treg in the xenograft and secondary lymphoid organs, which disappeared within 7 days after rejection.Conclusions/SignificancesThese results suggest a critical role for Treg in the induction phase of tolerance early after islet xenotransplantation. These encouraging data support the need of developing further Treg therapy for overcoming the species barrier in xenotransplantation.
Highlights
The inhibition of co-stimulation and proliferation of T cell activation by co-stimulatory blockade and rapamycin (RAPA) induces peripheral tolerance to allografts [1,2,3]
In contrast to central tolerance where self-antigen specific T cells are depleted in the thymus, peripheral tolerance is achieved by various mechanisms including: apoptosis of activated T cells, T cell anergy, and active regulation by T regulatory cells (Treg) [4,5]
In our model of islet xenotransplantation the application of RAPA and MR1 for 14 days post Tx allowed long-term survival of concordant islet xenografts over 100 days in the majority of recipients
Summary
The inhibition of co-stimulation (signal 2) and proliferation (signal 3) of T cell activation by co-stimulatory blockade and rapamycin (RAPA) induces peripheral tolerance to allografts [1,2,3]. Induced Treg or ex-vivo generated antigen specific Treg have been shown to protect allografts from immune-mediated damage [7,8,9]. It is still poorly understood where and when tolerization through Treg takes place [10]. Their potential role in xenogeneic models remains to be defined [11]. The present study investigated the effect of combined RAPA/MR1 treatment on rat-to-mouse islet xenograft survival and analyzed the role of CD4+CD25+Foxp3+ T regulatory cells (Treg) in the induction and maintenance of the ensuing tolerance
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