CONTRIBUTION OF DEFECTIVE CYTOTOXICITY TO DEVELOPMENT OF CANINE HEMOPHAGOCYTIC HISTIOCYTIC SARCOMA

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CONTRIBUTION OF DEFECTIVE CYTOTOXICITY TO DEVELOPMENT OF CANINE HEMOPHAGOCYTIC HISTIOCYTIC SARCOMA

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Title: CONTRIBUTION OF DEFECTIVE CYTOTOXICITY TO DEVELOPMENT OF CANINE HEMOPHAGOCYTIC HISTIOCYTIC SARCOMA
Author: Neta, Michal
Department: Department of Pathobiology
Program: Pathobiology
Advisor: Jacobs, Robert
Abstract: Canine Hemophagocytic Histiocytic Sarcoma (CHHS) is an aggressive neoplasm of macrophages with local lymphocytic reaction. Similarities exist between CHHS and Familial Hemophagocytic Lymphohistiocytosis (FHL), a complex of histiocytic diseases in children, which is attributable to various defects in granule dependent killing (GDK). This led to the hypothesis that defective GDK compromises lymphocyte homeostasis and anti-tumor immunity which results in CHHS. The sequence of canine perforin, a key effector molecule of GDK, was determined by RT-PCR and RACE. Genomic DNA from healthy and CHHS-affected dogs was sequenced and analyzed, but mutations with functional implications were not identified. Subsequently, tumor infiltrating lymphocytes (TIL) of CHHS were examined for GDK functionality. CHHS-TIL were compared to their functional counterparts in canine cutaneous histiocytoma (CCH), a benign histiocytic tumor in dogs, known to regress via lymphocytic reaction. To facilitate such comparison, functionality of CCH-TIL was studied by immunohistochemistry and confocal microscopy and quantified by image analysis applications. This provided novel insights regarding the physiology of TIL in tumor microenvironment and further characterizing CCH as a model for anti-tumor immunity. The comparison revealed a clear, and highly significant structural difference in polarization and degranulation of CHHS-TIL which likely hampers GDK. This defect is similar to several variants of FHL, an association further supported by comparison of clinical and laboratory manifestations of CHHS and FHL. This study suggests that CHHS is a promising natural model for investigating the pathogenesis of FHL, for studying granule polarization and degranulation and assessing the role of TIL in anti-cancer immunity.
URI: http://hdl.handle.net/10214/3006
Date: 2011-09-15


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