Approximately 7% of the US population suffers from diabetes, a chronic disease with significant morbidity and mortality. Pancreatic islet-cell transplantation poses an ideal therapy that would relinquish dependence on daily insulin injection and blood glucose monitoring, and would prevent the devastating consequences of diabetes. The discovery that dendritic cells (DC) can tolerize an immune response heralded the potential therapeutic value of DC rendered maturation resistant (MR) in islet-cell allograft transplantation. This proposal aims to use adoptively transferred vitamin D3 generated MRDC to indefinitely prolong islet-cell allograft survival, and to determine the effect of MRDC therapy on naive and memory CD4 and CD8 T cell alloresponses through the direct (T cells recognize donor MHC) and indirect (T cells recognize self-MHC presenting donor allopeptide) pathways of allorecognition. Further, this proposal aims to investigate the fate of adoptively transferred donor DC, elucidate the mechanism(s) by which donor DC are reprocessed by recipient APC into alloantigen (Ag), and determine the duration of alloAg presentation that results. Finally, it aims to study the role that the inhibitory mediators programmed cell death ligand 1 and indoleamine 2,3- dioxygenase play in inducing allograft tolerance. This study utilizes numerous types of genetically modified mice to definitively investigate the above stated aims, including TCRtg mice whose CD4 or CD8 T cells are specific for alloAg. Techniques to be used include but are not limited to flow cytometry, immunofluorescent staining and fluorescent microscopy, cell culture, ELISA, in vivo proliferation assay and islet-cell transplantation. The proposed study will allow for evaluation of DC therapy clinical utility over other cellular therapies, and for design of protocols using DC therapy in conjunction with sub-therapeutic immunosuppressive agents to indefinitely prolong islet-cell allograft survival. Further, it will elucidate the mechanism(s) of in vivo tolerance induction, an important area of research in the setting of transplantation and autoimmunity.
Diabetes is a devastating chronic disease for which the only currently available cure is islet-cell transplantation. The lack of success of islet-cell transplantation is largely attributable to the toxicity of immunosuppressive agents used to prevent allograft rejection. Therefore, the development of cellular based therapies that prolong islet-cell transplant survival by inducing donor-specific tolerance without side effects is clearly advantageous.
| Liu, Quan; Rojas-Canales, Darling M; Divito, Sherrie J et al. (2016) Donor dendritic cell-derived exosomes promote allograft-targeting immune response. J Clin Invest 126:2805-20 |
| Montecalvo, Angela; Larregina, Adriana T; Shufesky, William J et al. (2012) Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes. Blood 119:756-66 |
| Wang, Z; Divito, S J; Shufesky, W J et al. (2012) Dendritic cell therapies in transplantation revisited: deletion of recipient DCs deters the effect of therapeutic DCs. Am J Transplant 12:1398-408 |
| Divito, Sherrie J; Wang, Zhiliang; Shufesky, William J et al. (2010) Endogenous dendritic cells mediate the effects of intravenously injected therapeutic immunosuppressive dendritic cells in transplantation. Blood 116:2694-705 |
