Blockade of OX40/OX40L pathway combined with ethylene-carbodiimide-fixed donor splenocytes induces donor-specific allograft tolerance in presensitized recipients

Xingqiang Lai, Zhongpeng Yao, Fen Ning, Lei Zhang, Jiali Fang, Guanghui Li, Lu Xu, Yunyi Xiong, Luhao Liu, Rongxin Chen, Junjie Ma, Zheng Chen


Background: Memory T cells (Tms) are the major barrier preventing long-term allograft survival in presensitized transplant recipients. The OX40/OX40L pathway is important in the induction and maintenance of Tms.
Methods: In this study, we added anti-OX40L mAb to ethylene-carbodiimide-fixed donor splenocytes (ECDI-SPs)—a method which is effective in inducing allograft tolerance in non-presensitized mouse heart transplant model. Recipient mice received heart transplantation after 6 weeks of donor skin presensitization and were treated with anti-OX40L mAb, ECDI-SPs or anti-OX40L mAb + ECDI-SPs, respectively.
Results: Our data showed that the combination of ECDI-SPs and anti-OX40L mAb induced donor- specific tolerance in skin-presensitized heart transplant recipients, with the mechanism for this being associated with suppression of Tms and upregulation of CD4+CD25+Foxp3+ T regulatory cells (Tregs). Importantly, CD25+ T-cell depletion in the combined therapy-treated recipients broke the establishment of allograft tolerance, whereas adoptive transfer of presensitization-derived T cells into tolerant recipients suppressed Tregs expansion and abolished established tolerance.
Conclusions: Blockade of OX40/OX40L pathway in combination with ECDI-SPs appears to modulate the Tms/Tregs imbalance so as to create a protective milieu and induce graft tolerance in presensitized recipients.

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