Systemic and Local Modulation of the Immune Response to Allogeneic Cell Transplants

Immune rejection is a critical barrier to successful organ transplantation and stem cell therapies. In this project, I investigated the targeted modulation of the immune system to induce immune tolerance and alter the immune response to allogeneic grafts: 1) The first part of my Ph.D. project aimed to develop a mouse model that had functional human T cells for studying patient-specific allogeneic graft rejection. In the thymus, thymic epithelial cells can “educate” developing T lymphocytes and induce a specific tolerance for T cells to recognize self and non-self. Here, human pluripotent stem cells (PSCs) were in-vitro differentiated into thymic epithelial cell progenitors (TEPs) by mimicking a series of signal pathways important for embryonic thymus development. The upregulation of appropriate cell markers was detected at each differentiation stage; however, the expression of TEP markers FOXN1 and Cytokeratin (CK) 5 was not robust in the differentiated cells. The following in vivo functional assay indicated the TEP-like cell graft in a humanized mouse model was not functional and could not attract the lymphoid progenitors and could not further support T cell development. More optimization of TEP differentiation protocol is needed for future research and the clinical applications. 2) Learning from the immune regulation, I expressed a combination of immunomodulators (IMs) in allogeneic cells in order to induce local immune tolerance and prevent allogeneic immune rejection. The in-vitro cell interaction between human immune cells and IM-expressing cells (H1-FS-8IMs) derivatives showed suppressed immune proliferation and proinflammatory cytokine production. Immune profiling results also demonstrated the dynamic changes in human immune cells in the IM-expressing group. We observed the shift in the immune cell homeostasis, the weakened homing ability of naïve T cells and dendritic cells, indicating the expressed immunomodulators induced immune suppression. The in vivo evaluation is still in progress. A more robust immune response to the allogeneic teratoma tissue derived from human ESC without IMs expression was observed in the hu-PBL-NSG humanized mouse model. Further in vivo analysis is needed to assess the immune response and immune tolerance induced by H1-FS-8IMs-derived allogeneic cell grafts in a humanized mouse model.Ph.D.2021-11-15 00:00:0