High-Dose Post-Transplantation Cyclophosphamide to Induce Delayed Immune Tolerance After Reconstructive Transplantation
Abstract
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 PT/Cy-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 PT/Cy 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 PT/Cy 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 mg/kg) combined with delayed PT/Cy 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 PT/Cy and the use of additional donor bone marrow transplantation combined with delayed PT/Cy is ongoing.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2018
- Accession Number
- AD1094793
Entities
People
- Georg Furtmller
- Gerald Brandacher
- Leo Luznik
Organizations
- Johns Hopkins University