Pathology - Theses
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ItemThe role of TNF-related apoptosis-inducing ligand in immune function( 2004)Tumor necrosis factor (TNF)-related apoptosis-inducing ligand [TRAIL or Apo-2 ligand (L)] is a member of the TNF superfamily of ligands that can induce cellular responses such as activation, proliferation, differentiation, migration and apoptosis. Recombinant (r) soluble TRAIL is currently being developed as a most promising natural immune molecule for trial in cancer patients since it selectively induces apoptosis in transformed or stressed cells, but not in most normal cells. Unlike TNF and FasL (CD95L), that both exert significant systemic toxicities, rTRAIL has been shown to be relatively non-toxic and to exert potent anti-tumor functions when administered in vivo to tumor-bearing mice and non-human primates. Moreover, whilst radiation and most deoxy ribonucleic acid (DNA)-damaging chemotherapeutic drugs induce tumor cell apoptosis in a p53-dependent manner, TRAIL-mediated apoptosis is p53-independent. Treatment with rTRAIL might therefore be expected to circumvent resistance to conventional chemotherapy and radiotherapy in cancer patients lacking p53 function. Despite great interest in TRAIL as a cancer therapeutic, either as a sole agent or in combination with irradiation or chemotherapeutic drugs, what has undeniably been lacking is an in depth understanding of the natural physiological role of TRAIL. This knowledge is fundamental if TRAIL is to be used safely and with efficacy in the clinic. Very recently, constitutive TRAIL expression has been identified on a small subset of liver natural killer (NK) cells in adult mice. TRAIL expression can also be induced on interferon (IFN)-α-stimulated peripheral blood T cells, IFN-stimulated human monocytes and dendritic cells (DCs), and NK cells stimulated with interleukin (IL)-2, IFNs or IL-15. We and others have reported that TRAIL-expressing liver NK cells play a role in suppression of TRAIL-sensitive liver tumor metastasis in vivo, suggesting that TRAIL might play a role in tumor surveillance. In a small number of preliminary studies, TRAIL has also been identified to suppress autoimmune disease induction. The focus of this thesis has been to help elucidate the roles of endogenous host TRAIL in disease. The research described herein provides the first detailed evidence of the leukocyte expression and function of mouse TRAIL. We describe the initial characterization of TRAIL-deficient mice generated by gene-targeting, and use these mice to (I) identify TRAIL as a marker of NK cell differentiation, (2) determine the role for TRAIL in regulation of tumor development, (3) determine the role for TRAIL in T cell development and homeostasis, and (4) determine the importance of TRAIL in controlling the induction of experimental autoimmune encephalomyelitis (EAE).