Alloreactive Regulatory T Cells Allow the Generation of Mixed Chimerism and Transplant Tolerance.

Paulina Ruiz,Yessia Hidalgo,Mario Rosemblatt,Paula Maldonado,Daniela Sauma,Maria Rosa Bono

doi:10.3389/fimmu.2015.00596

Paulina Ruiz, Yessia Hidalgo + Show 4 more

Open Access

https://doi.org/10.3389/fimmu.2015.00596

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Abstract

The induction of donor-specific transplant tolerance is one of the main goals of modern immunology. Establishment of a mixed chimerism state in the transplant recipient has proven to be a suitable strategy for the induction of long-term allograft tolerance; however, current experimental recipient preconditioning protocols have many side effects, and are not feasible for use in future therapies. In order to improve the current mixed chimerism induction protocols, we developed a non-myeloablative bone-marrow transplant (NM-BMT) protocol using retinoic acid (RA)-induced alloantigen-specific Tregs, clinically available immunosuppressive drugs, and lower doses of irradiation. We demonstrate that RA-induced alloantigen-specific Tregs in addition to a NM-BMT protocol generates stable mixed chimerism and induces tolerance to allogeneic secondary skin allografts in mice. Therefore, the establishment of mixed chimerism through the use of donor-specific Tregs rather than non-specific immunosuppression could have a potential use in organ transplantation.

Highlights

Achieving transplant tolerance as a means to improve the outcome of organ transplantation is one of the main challenges of modern immunology
We developed a protocol using retinoic acid (RA)-iTregs to induce mixed chimerism
We combine RA-iTregs with a NM-bone-marrow transplant (BMT) avoiding the need of CD40/CD40L signaling inhibition

Summary

Introduction

Achieving transplant tolerance as a means to improve the outcome of organ transplantation is one of the main challenges of modern immunology. Current immunosuppressive drug regimens succeed in preventing acute organ rejection; they fail to induce long-term operational tolerance and cannot prevent chronic rejection [1,2,3]. The generation of mixed chimerism has become an attractive alternative to achieving the induction of long-term tolerance to allografts [4, 5]. There is robust evidence showing that the induction of mixed chimerism allows the generation of alloantigen-specific tolerance in animal models [7,8,9,10,11] and humans [12,13,14,15]

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