Optimization of Delayed Tolerance Induction in Swine: A Clinically Relevant Protocol for Immunosuppression-Free Vascularized Composite Allotransplantation
Abstract
Tolerance of kidney allografts has been achieved in nonhuman primates (NHPs) using a the delayed period protocol, i.e combination of post-transplant non-myeloablative conditioning and donor bone marrow transplantation four months later (DBMT). That results in transient mixed hematopoietic chimerism and then led transplant tolerance. A similar protocol has recently been successfully extended to human recipients of HLA-mismatched living-related renal allografts. Clearly, mixed chimerism represents a powerful and clinically relevant approach to tolerance induction. Unfortunately the reproducibility of such protocol constitutes a bottleneck because of the risk to develop an acute rejection (AR) episode during the delayed period. Any episode of AR sensitize le patient and then decrease the chance of bone marrow engraftment. In this protocol we want to perform the BMT the day of the surgery before any episode of acute rejection. Recently co-stimulatory blockade has gained considerable attention for its possible beneficial and critical effects in tolerance inducing regimens. However, unequivocal evidence demonstrates that CTLA4-Ig or belatacept on its own are not capable of inducing tolerance in either stringent rodent models, or in non-human primate solid organ transplantation. Thus, CTLA4-Ig needs to be combined with other strategies if tolerance is the ultimate goal. Concomitant administration of donor HSCs in the form of DBMT with CTLA4-Ig appears to be the most promising approach to induce tolerance as indicated in various small and large animal solid organ transplant models. This is particularly attractive for VCA due to the fact that many of these types of transplants already include a vascularized BM component. Moreover, recent evidence suggests that augmentation with CTLA4-Ig promotes engraftment following DBMT for the induction of stable mixed chimerism and thus transplantation tolerance, and helps overcome split tolerance of transplanted skin.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2021
- Accession Number
- AD1128320
Entities
People
- Curtis L. Cetrulo, Jr
Organizations
- Massachusetts General Hospital