Core A will perform all pathology tissue studies in this program project. The Core will be led by Robert B. Colvin, M.D., who is the Benjamin Castleman Distinguished Professor of Pathology at Harvard/Massachusetts General Hospital. He is an internationally recognized investigator in transplantation pathology and has collaborated extensively in the past with the other investigators. He will be joined in this effort by R. Neal Smith, Associate Professor of Pathology, who has expertise in islet transplantation pathology and Sandro Alessandrini, Assistant Professor of Surgery (Immunology), who has experience with endothelial activation pathways, Treg and dendritic cells. The studies will be performed in the Immunopathology Research Laboratory at the Massachusetts General Hospital (Thier 8). No embryonic stem cells will be used. The techniques that will be utilized include routine histology, immunohistochemistry, immunofluorescence, and electron microscopy. Immunoperoxidase techniques with a panel of mAbs will distinguish the infiltrating cell types (Teff, Treg, Breg, et al), adhesion and cytokine molecules and receptors, complement deposition (C4d), and endothelial activation markers (e.g., pERK). Analysis ofthe in situ processes will be enhanced by whole slide digital scans and morphometry. The pathology results will be correlated with functional and molecular studies done in the projects. In addition, complete necropsies will be done on all animals, with samples from all major organs analyzed by routine and special techniques as indicated.
The pathology studies in Core A are essential to evaluate the status of the allografts and the effects of the intervention to reduce inflammation and parenchymal injury. The studies are critical to determine the nature and location of the cells infiltrating the graft, the role of antibodies in rejection and systemic toxicity of treatment. The primary role is to document and characterize: 1) The status of the kidney and islet grafts (nature of infiltrate, presence of acute or chronic rejection, including a humoral component;quantitation of lesions, presence of transplanted islet cells in liver of beneath the kidney capsule 2) Systemic effects ofthe protocols (toxicity, complications, BK viral infection, PTLD) 3) Intragraft markers that predict acceptance vs. rejection 4) Mechanisms by which intragraft cells may promote rejection or acceptance
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