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Purpose
The mixed chimerism approach has outstanding potency in the induction of donor-specific tolerance in both preclinical animal models and clinical pilot trials. However, some chimeras develop a state of “split tolerance”, an incompletely understood phenomenon. Cardiac allograft vasculopathy (CAV) and skin graft rejection were observed in chimeric animals that are tolerant to donor antigen in vitro. We hypothesized that Tregs therapy is able to prevent “split tolerance” and chronic rejection.
Methods and Materials
Groups of B6 mice received 2x107 unseparated Balb/c BMC (d0, iv) and costimulation blockade consisting of antiCD40LmAb (1mg, d0) and CTLA4Ig (0.5mg, d2). Control groups received 3 GyTBI to facilitate BM engraftment, whereas the “Treg protocol” received 5x106 Tregs (d0) and a short course of rapamycin (0.1mg/mouse, d-1/d0/d2). Multilineage chimerism was followed by flowcytometry, heterotopic heart transplantation was used to assess donor-specific tolerance.
Results
Treg therapy reliably induced longterm multilineage chimerism without the need for recipient TBI (8/8 chimeras Treg protocol vs 13/18 control group, p=0.28). Heart allografts survived longterm in both groups (>100 days, Treg group n=4; control group n=7), whereas third-party allografts were promptly rejected. Histological examination of donor heart allografts revealed that Treg treatment potently avoids CAV (all grafts were scored with ISHLT grade 0 or 1; 0: n=2, 1: n=2). In the control group 4/7 mice were classified with a rejection rate 2 or higher (0: n=1, 1: n=2, 2:n=2, 3:n=2).
Conclusions
In this study we demonstrate that Treg treatment enhances the potency of the mixed chimerism approach for the induction of donor-specific tolerance. Treg treatment obviates the need for cytoreductive recipient pretreatment and prevents CAV. Thus, both efficiency and safety of the mixed chimerism approach are improved. We think that these results will have significant impact on the development of new protocols for tolerance induction in cardiac transplantation.
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Identification
Copyright
© 2013 Published by Elsevier Inc.
