Adult Tissue-Derived Stem Cells and Tolerance Induction in Nonhuman Primates for Vascularized Composite Allograft Transplantation
Technical Report,30 Sep 2016,29 Sep 2017
Henry M Jackson Foundation for the Advancement of Military Medicine Bethesda United States
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Amputations and unsalvageable injuries with devastating tissue loss are common in the combat wounded. Reconstructive transplantation in the civilian setting using vascular composite allotransplants VCA composed of multiple tissues skin, muscle, nerve, bone in combination with long-term multidrug immunosuppression has been encouraging. However, skin rejection remains a critical complication. We have demonstrated in a murine skin allograft transplantation model that human adipose-derived stromal cells ASC when used in concert with immunological conditioning support engraftment of limited numbers of donor bone marrow cells dBMCs across major histocompatibility complex MHC barriers, and lead to stable multilineage mixed-chimerism and skin allograft tolerance without the need for long-term immunosuppression. Focus Areas Immune Rejection-understanding mechanisms of immune rejection, immunomodulation approaches and mechanisms e.g., tolerance induction, chimerism, and optimizing immunosuppressive drug regimens. ObjectivesHypothesis We realize that the implications and potential clinical benefit of the tolerance induction protocol to shown efficacy in a mouse model can only be validated mechanistically in established non-human primate models of allograft transplantation with long-term observations and evaluations. We hypothesize that ASCsdBMC therapy may be a pro-tolerogenic cellular therapeutic displaying clinical efficacy for vascular composite allograft VCA, solid organ, and hematopoietic stem cell transplant applications. This combination would allow for long term graft survival without the need for chronic immunosuppression and the resulting multitude of adverse effects associated with such agents. Specific Aims 1 To investigate whether ASCs augment chimerism and promote long-term VCA graft survival and 2 To determine whether ASC therapy allows for immunosuppression minimization and development of immunologic tolerance to VCA.
- Medicine and Medical Research
- Anatomy and Physiology