Abstract
The induction of donor-specific transplant tolerance has always been a central problem for small bowel transplantation (SBT), which is thought to be the best therapy for end-stage bowel failure. With the development of new tolerance-inducing strategies, mixed chimerism induced by co-stimulation blockade has become most potent for tolerance of allografts, such as skin, kidney, and heart. However, a lack of clinically available co-stimulation blockers has hindered efficient application in humans. Furthermore, unlike those for other types of solid organ transplantation, strategies to induce robust mixed chimerism for intestinal allografts have not been fully developed. To improve current mixed chimerism induction protocols for future clinical application, we developed a new protocol using donor-specific regulatory T (Treg) cells from mice with heart allograft tolerance, immunosuppressive drugs which could be used clinically and low doses of irradiation. Our results demonstrated that donor-specific Treg cells acquired from tolerant mice after in vitro expansion generate stable chimerism and lead to acceptance of intestinal allograft. Increased intragraft Treg cells and clonal deletion contribute to the development of SBT tolerance.
Highlights
For patients with end-stage bowel failure, small bowel transplantation (SBT) is recognized as a definitive therapy [1]
Numerous in vitro and in vivo studies have suggested the critical role of rapamycin in expanding naturally occurring CD4+CD25+Foxp3+ (donor-specific) regulatory T cells (Treg) cells that are normally found in the naïve splenic CD4+ T-cell compartment, as well as in maintaining their suppressive function in vitro [19,20,21]
After 14 days stimulation, we found that donorspecific Treg (DSTreg) and fresh Treg cells could be expanded stably in vitro, and the combination of rapamycin plus IL-2 resulted in greatest expansion of fresh CD4+CD25+ Treg cells (23.7 ± 1.8-fold) and DSTreg cells (31.5 ± 2.1-fold) (Figure 1B)
Summary
For patients with end-stage bowel failure, small bowel transplantation (SBT) is recognized as a definitive therapy [1]. The intestine carries the largest population of lymphoid cells of any transplanted solid organ, which are the least tolerogenic cells in any organ and they have the potential risk of inducing graft-versus-host reaction [2]. Both acute and chronic rejection after SBT is still a great challenge to overcome, which leads to the inferior overall outcome of SBT when compared. Combining Treg cell therapy with co-stimulation blockade and rapamycin has been tested to promote full MHC-mismatched mixed chimerism, and the results are encouraging [8, 9]. Whether recipient DSTreg cells could lead to intestinal allograft acceptance after establishment of mixed chimerism has not been fully elucidated
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