Primary Investigators: Dr. Maria Siemionow, MD
Institution: The University of Illinois at Chicago
Funding began in 2016.
The aim of this study was to establish an innovative, less-toxic stem cell-based therapy, which will extend allograft survival without the need for life-long immunosuppression. We have developed and tested two alternative therapies of CD90+/CD90+ and CD90+/MSC Di-Chimeric Cells (DCC) for induction of tolerance in Vascularized Composite Allograft (VCA) and Heart transplantation. DCC present both the donor and recipient characteristics and diverse molecular and secretion profiles, which determine their intercellular cross-talk, and as such may elicit different tolerogenic properties when applied as the supportive therapy in the context of VCA or solid organ- heart transplantation. Under Aim 1 of this grant application, we evaluated the molecular profile of DCC of hematopoietic CD90+ cells and mesenchymal stem cells (MSC) origin and determined their pro-tolerogenic cytokine mRNA expression profiles following cell fusion. The bone marrow of ACI and Lewis rats was used for the selection of CD90+ HSC and MSC isolation. Next, the parent cell lines were assessed for: cell lines purity, surface markers expression, and cell viability. The in vitro T-cell suppression and regulatory T-cell (Treg) induction assays were assessed by flow cytometry. Cytokine mRNA expression profiles were assessed in real time-PCR. Under Aim 2, we assessed in vivo the tolerogenic effect of the supportive DCC therapy using a new generation of created hematopoietic and MSC Di-Chimeric Cells in VCA and heart allograft transplant models. The outcomes measures included evaluation of VCA and heart allograft survival up to 100 days, assessment of heart allograft histology at day 7, and day 100 post-transplant. At the study end-point, the peripheral blood, lymphoid organs, and liver were harvested for assessment of chimerism by flow cytometry. Confirmation of the DCC engraftment combined with ex vivo assessment of cytokine expression and in vivo monitoring of allograft survival would allow determining a preferential DCC therapy for the potential clinical application for tolerance induction in VCA and solid organ transplantation
Specific Aim 1: To evaluate molecular and secretion profiles of CD90+/CD90+ DCC and CD90+/MSC DCC and to determine pro-tolerogenic cytokine secretion profiles following cell fusion.
Specific Aim 2: To assess in vivo the tolerogenic effect of the supportive therapy of new generation of CD90+/CD90+ DCC and CD90+/MSC DCC in the VCA and heart transplantation models
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