Abstract
Transfer of recipient regulatory T cells (Tregs) induces mixed chimerism and tolerance in an irradiation-free bone marrow (BM) transplantation (BMT) model involving short-course co-stimulation blockade and mTOR inhibition. Boosting endogenous Tregs pharmacologically in vivo would be an attractive alternative avoiding the current limitations of performing adoptive cell therapy in the routine clinical setting. Interleukin-6 (IL-6) potently inhibits Treg differentiation and its blockade was shown to increase Treg numbers in vivo. Therefore, we investigated whether IL-6 blockade can replace adoptive Treg transfer in irradiation-free allogeneic BMT. Treatment with anti-IL-6 instead of Treg transfer led to multi-lineage chimerism (persisting for ~12 weeks) in recipients of fully mismatched BM and significantly prolonged donor skin (MST 58 days) and heart (MST > 100 days) graft survival. Endogenous Foxp3+ Tregs expanded in anti-IL-6-treated BMT recipients, while dendritic cell (DC) activation and memory CD8+ T cell development were inhibited. Adding anti-IL-17 to anti-IL-6 treatment increased Treg frequencies, but did not further prolong donor skin graft survival significantly. These results demonstrate that IL-6 blockade promotes BM engraftment and donor graft survival in non-irradiated recipients and might provide an alternative to Treg cell therapy in the clinical setting.
Highlights
Long-term allograft survival without the need of permanent immunosuppression remains an important goal in transplantation medicine [1]
CD62Lhigh/CD44low and (E) CD62Llow/CD44high CD3+CD8+ blood T cells was followed over time in bone marrow (BM) recipients treated with anti-IL-6 (n = 10) or without (n = 5). (F) Two-color flow cytometry plots from representative mice are shown at week 3 post-BM transplantation (BMT). (G) Survival of second donor skin grafts transplanted on the opposite flank 21 days after the rejection of a first donor graft is shown
(+CB+Rapa+anti-IL-6) were treated with in vivo antibodies against IL-17A or IL-6 receptor and groups performed within this one experiment were compared to each other. (A) Mean percentage of blood CD3+CD4+Foxp3+ regulatory T cells were compared between indicated groups (n = 6/grp) 21 and 42 days post-BMT. (B) Mean percentage of donor Mac-1 chimerism in the indicated groups was followed over time. (C) Percentage of donor chimerism among indicated leukocyte lineages is shown for individual mice 42 days post-BMT. (D) Survival of donor skin is shown for BM transplantation (BMT) recipients treated with anti-IL-6 alone or in combination with anti-IL17 or anti-IL6R (*p ≤ 0.05)
Summary
Long-term allograft survival without the need of permanent immunosuppression remains an important goal in transplantation medicine [1]. In this context, the co-transplantation of allogeneic bone marrow (BM) for the induction of mixed chimerism (i.e., co-existence of donor and recipient hematopoietic cells) evolved to be an attractive strategy [2]. Our group has recently developed a regimen free of myelosuppression that induces chimerism and long-term tolerance through a combination of donor BM transplantation (BMT) and recipient regulatory T cell (Treg) therapy under short-course CB (anti-CD40L and CTLA4-Ig) and of mTOR inhibition [6,7,8,9]. With regard to non-cytotoxic BMT, our group could recently show that IL-2 complexes cannot replace adoptive Treg therapy [17] and alternative strategies need to be developed for this setting
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