Islet cell survival after transplantation to cure type 1 diabetes is limited primarily by immune-mediated rejection. Therefore, in situ monitoring of graft rejection in real time is critical for proper intervention. Current imaging modalities lack spatial and temporal resolution and consequently immune attack of the islets is only be detected once macroscopic graft damage has occurred. The long-term goal of this application is to establish a high resolution imaging approach where immune-mediated rejection of graft tissue in live recipients can be monitored noninvasively and studied in situ. This project aims to establish pancreatic islet transplantation into the murine anterior chamber of the eye as a model for two-photon fluorescence imaging of immune rejection of transplanted allogeneic islets. The anterior chamber of the eye provides a natural body window that allows noninvasive monitoring of the very same islets longitudinally. The hypothesis is that immune-mediated intraocular rejection of islet allografts occurs despite immune privilege and can be readily imaged noninvasively in real time. For the first time, this project will enable studying in vivo early rejection in real time. It will enable the study of cellular motility and dynamics during islet allograft rejection. Pilot data provided by the applicant revealed rejection of allogeneic islets and demonstrated the strength and feasibility of imaging intraocular islet function and rejection. These data showed for the first time in vivo recruitment of individual immune cells to the graft site and active infiltration of the islet grafts. The applicant proposes the following specific aims: (1) Establish intraocular transplantation as a rejection model for transplanted pancreatic islets. The working hypothesis is that islet rejection is mediated by early and persistent inflammation and ultimately by effector T lymphocytes;and (2) Identify the cellular mechanisms of intraocular rejection of islet allografts. The working hypothesis is that the rejection process requires the close association of inflammatory cells with allospecific effector T cells in the islet grafts. It is predicted that islet cell death occurs near these cell complexes. These studies will reveal the kinetics and dynamics of immunemediated intraocular rejection of islet allografts and will provide a platform to test and refine novel and existing therapeutic regimens aimed at enhancing islet survival and long-term acceptance of grafts. Being able to monitor the fate of islet grafts in real time would enable early intervention and will address the major limitation to pancreatic islet transplantation as a therapy to cure type 1 diabetes. This proposed project allows the early detection and study of rejection providing a better understanding of the process and the ability for a timely intervention to improve islet cell survival and long-term graft acceptance.
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| Shishido, A; Caicedo, A; Rodriguez-Diaz, R et al. (2016) Clinical intraocular islet transplantation is not a number issue. CellR4 Repair Replace Regen Reprogram 4: |
| Abdulreda, Midhat H; Rodriguez-Diaz, Rayner; Caicedo, Alejandro et al. (2016) Liraglutide Compromises Pancreatic ? Cell Function in a Humanized Mouse Model. Cell Metab 23:541-6 |
| Faleo, Gaetano; Berggren, Per-Olof; Pileggi, Antonello (2014) Intravital imaging of cytotoxic T lymphocytes. Methods Mol Biol 1186:121-9 |
| Kistler, Andreas D; Caicedo, Alejandro; Abdulreda, Midhat H et al. (2014) In vivo imaging of kidney glomeruli transplanted into the anterior chamber of the mouse eye. Sci Rep 4:3872 |
| Miska, Jason; Abdulreda, Midhat H; Devarajan, Priyadharshini et al. (2014) Real-time immune cell interactions in target tissue during autoimmune-induced damage and graft tolerance. J Exp Med 211:441-56 |
| Jaczewska, Justyna; Abdulreda, Midhat H; Yau, Chi Y et al. (2014) TNF-? and IFN-? promote lymphocyte adhesion to endothelial junctional regions facilitating transendothelial migration. J Leukoc Biol 95:265-74 |
| Tan, Y; Abdulreda, M H; Cruz-Guilloty, F et al. (2013) Role of T cell recruitment and chemokine-regulated intra-graft T cell motility patterns in corneal allograft rejection. Am J Transplant 13:1461-73 |
| Abdulreda, M H; Caicedo, A; Berggren, P-O (2013) A NATURAL BODY WINDOW TO STUDY HUMAN PANCREATIC ISLET CELL FUNCTION AND SURVIVAL. CellR4 Repair Replace Regen Reprogram 1:111-122 |
| Abdulreda, M H; Berggren, P-O (2013) Islet inflammation in plain sight. Diabetes Obes Metab 15 Suppl 3:105-16 |
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