Zsfassung in engl. Sprache. - Würzburg, Univ., Diss., 2008

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Being a Dissertation presented in fulfilment of the requirement governing the Degree of Master of Science in The School of Medicine, University of the Witwatersrand / Interleukin 1 (IL - 1) is a macrophage factor that exerts control over T cell activation. The experimental work presented in this dissertation consists of studies on IL - 1 production by monocytes which can be used as an in vitro correlate for monocyte function, as well as the effect of IL - 1 on immature T cells, that is, thymocytes. In accomplishing the studies presented in this dissertation, a two stage assay was employed. Firstly IL - 1 containing supernatants were produced by stimulated human peripheral blood adherent cells and secondly, the IL - 1 supernatants were assayed on mouse thymocyctes in which these supernatants caused mitogenesis. / IT2018

Despite the incorporation of the epidermal growth factor receptor (EGFR) inhibitor cetuximab into the clinical management of recurrent and metastatic (R/M) head and neck squamous cell carcinoma (HNSCC), only a small subset of patients responds to cetuximab, despite EGFR overexpression in virtually all of their tumors. At this time, there is a lack of validated predictive biomarkers to predict which patients will respond to cetuximab. Our previous work suggests that cetuximab activates the interleukin-1 (IL-1) pathway via tumor release of IL-1 alpha (IL-1α), although the implications of activating this pathway are unclear. The IL-1 pathway plays a central role in immune response and displays both pro-tumor and anti-tumor activities. IL-1 may promote tumor growth by upregulating the secretion of pro-inflammatory mediators involved in angiogenesis and metastasis. On the other hand, IL-1 signaling may promote antitumor immunity via enhancement of natural killer (NK)-cell mediated antibody-dependent cell-mediated cytotoxicity (ADCC) and T cell activity, which are important mechanisms of action of cetuximab. The goal of this work is to determine how modulation of the IL-1 pathway affects HNSCC tumor response to cetuximab and if IL-1 may serve as a predictive biomarker for patient response to cetuximab. Blockade of IL-1 signaling did not enhance the anti-tumor efficacy of cetuximab, while IL-1α overexpression and treatment with recombinant IL-1α and IL-1α nanoparticles increased HNSCC tumor response to cetuximab in immunodeficient and immunocompetent HNSCC mouse models. Mechanistically, these results appear to be due to activation of an anti-tumor NK and T cell-mediated immune response. Additionally, we found that both nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) and inducible nitric oxide synthase (iNOS) activity may be involved in the efficacy of IL-1-induced ADCC against cetuximab-coated HNSCC cells. Altogether, these results suggest that IL-1 signaling is necessary for HNSCC tumor response to cetuximab. Furthermore, we have shown that pre-treatment serum and tumor IL-1 ligands can predict progression-free survival of HNSCC patients treated with standard-of-care cetuximab and chemotherapy, cetuximab combined with other targeted therapies, and cetuximab monotherapy. Overall, we propose that IL-1α warrants further study as a novel therapeutic to enhance response to cetuximab and as a predictive biomarker for HNSCC response to cetuximab.

Bibliography: leaves 172-214. Interleukin-12 (IL-12) is a heterodimeric cytokine composed of two disulphide-linked subunits, p35 and p40, which form biologically active p70. IL-12 is able to induce IFN-y production from T and NK cells, and promote the proliferation of mitogen-activated T cells. It is thought that IL-12 may be an important cytokine in the initiation and progression of allograft destruction. This thesis describes the characterisation of ovine IL-12.

Erlangen, Nürnberg, University, Diss., 2007. / Enth. 1 Sonderabdr. aus: AIDS ; 19. 2005.