High-Dose Post-Transplantation Cyclophosphamide to Induce Delayed Immune Tolerance After Reconstructive Transplantation
Technical Report,15 Sep 2017,14 Sep 2018
Johns Hopkins University Baltimore United States
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The overall objective of this project is to understand mechanisms of delayed transplant tolerance as they specifically relate to VCA, and establish a donor bone marrow and PTCy-based protocol for the induction of delayed tolerance with minimal or only transient immunosuppression after reconstructive transplantation. Our central hypothesis is that a vascularized intragraft BM stromal microenvironment combined with PTCy treatment will promote immunoregulatory mechanisms that allow for establishing delayed tolerance and ultimately immunosuppression-free graft survival. We aimed to first determine the optimal time point for the application of PTCy after VCA and secondly evaluate whether further transplantation of additional exogenous donor bone marrow can augment the outcome of allograft survival in the context of donor chimerism SPECIFIC AIM 1. The investigators were able to establish a reliable treatment protocol using rapamycin 5 mgkg combined with delayed PTCy in a mouse orthotopic hind limb transplantation model. The application of this treatment protocol leads to prolonged VCA survival 77.6 28.75 days and donor-specific mixed chimerism Avg 2.04 Range 0.1-6.49. Further in-vitro studies are geared towards the role of memory T cells in rejection of VCA after delayed PTCy and the use of additional donor bone marrow transplantation combined with delayed PTCy is ongoing.
- Medicine and Medical Research