Transplantation tolerance of kidney allografts has been achieved in both non-human primates (NHPs) and patients using a non-myeloablative conditioning regimen, costimulation blockade, and infusion of recipients with bone marrow cells from the organ donor. However, until now, this protocol has consistently failed to significantly prolong the survival of lung allografts in NHPs. In this study, we investigated whether co-administration of an anti-IL-6R mAb designed to reduce inflammation and Th17 cell activation, while potentially promoting the activation and expansion of Tregs, could induce tolerance of MHC-mismatched lung transplants in cynomolgus monkeys.

Six NHPs received a lung allograft from a MHC-mismatched donor, using a conventional triple drug immunosuppressive regimen, consisting of tacrolimus, mycophenolate mofetil and prednisone. Recipients were also treated with ATG or ATG + aIL-6R mAb. After four months, the recipients were infused with frozen bone marrow cells (BMT) from their donor and treated with either one of the two following conditioning regimens: Group A (n=3) received low dose TBI, local thymic irradiation, ATG, anti-CD40L mAb and anti-CD8 mAb, and group B (n=3) received the same regimen, but with half the dose of the anti-CD8 mAb and an additional course of anti-IL-6R mAb. The recipients were also treated for 28 days after BMT with cyclosporine, after which all immunosuppression was withdrawn.

The three recipients in group A survived 65 days (median survival time) post-BMT, and two of them developed severe PTLD. In contrast, in group B, the first recipient achieved stable long-term lymphoid chimerism and tolerance for more than 360 days after DBMT (ongoing). This recipient never developed anti-donor antibodies and has developed donor-specific T cell hypo-responsiveness. The two other recipients in group B are currently at d8 and day 71 post-BMT, and display multi-lineage chimerism.

This is, to our knowledge, the first demonstration of stable mixed hematopoietic chimerism in a fully-MHC mismatched donor-recipient combination and of tolerance induction in NHP lung transplantation. Work is in progress to investigate the mechanisms by which tolerance is induced and how the anti-IL-6R mAb contributes to this process.

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