Thesis (M.S.)--Marshall University, 2003. / Title from document title page. Document formatted into pages; contains vi, 74 p. including illustrations. Includes bibliographical references (p. 71-74).

Thesis (Ph. D.)--University of Queensland, 2002. / Includes bibliographical references.

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The use of rhIL-2 to augment antitumour immunity was seen as having great potential for the treatment of neoplasia, but the efficacy of immunotherapy has remained poor despite encouraging experimental data. A reason for this could be active immunosuppression by the tumour mediated by the secretion of suppressor factors. Suramin is a polyanionic drug which blocks and inhibits a range of growth factors and cytokines. This project investigates the potential of suramin to act as an adjunct to rhIL-2 based immunotherapy by acting as a blockade to suppressor factors. In vitro studies showed that rhIL-2 generation of LAK cells resulted in an increase in expression of activation associated antigens, a proliferation of cytotoxic T cells and natural killer cells and augmentation of cytolytic activity. These parameters could be suppressed by factors released from the colorectal cell line LoVo, but co-culture with suramin reversed the suppression in cells isolated from normal individuals. A suramin induced fall in the percentage of cells expressing CD4 was shown to be due to CD4 modulation and not the apoptotic death of CD4+ve cells. CD4 modulation could be reversed by the removal of suramin and could be influenced by tyrosine kinase inhibitors, though direct tyrosine phosphorylation of CD4 did not occur. The CBHlCBi Hooded rat was used as an in vivo model to study the potential of suramin and rhIL-2 in controlling induced liver metastasis from the syngeneic HSN sarcoma cell line. A toxicology study showed suramin side effects to include a reduction in total body weight gain and an increase in lymph node and spleen weights. Enlargement of kidneys and reduction in liver size were also seen. Haematologically, a suramin induced basophilia and thrombocytopenia were recorded as well as a rhIL-2 induced eosinophilia. In vivo CD4 modulation was also seen. Finally a combined suramin and rhIL-2 therapy regimen was found to be more effective than either agent alone in reducing both hepatic tumour mass and numbers after the induction of metastases in these animals. It was concluded that suramin can be used as an adjunct to rhIL-2 based immunotherapy.

The proliferation dynamics in vitro of the obligate intracellular protozoan parasite Leishmania donovani was studied for 14 days in resting monolayers of peritoneal macrophages of C57BL/6 $(Lsh sp{ rm s})$ mice inoculated with 5, 50, or 500 promastigotes/cell. Irrespective of the inoculum, only 50 to 65% of the cells became infected initially; only 3 to 6 amastigotes were present in each macrophage initially, suggesting a limited number of parasite ligands on the host cell. The amastigotes did not divide in the first 3 or 4 days after infection and then they actively proliferated from day 5 to day 8; the number of parasites was then reduced. Infection with L. donovani down-regulates immunity and parasite clearance by macrophages, but IL-2-stimulated splenocytes activate leishmanicidal action in vitro in infected peritoneal macrophages and in vivo in C57BL/6 (Lsh$ sp{ rm s})$ mice. IL-2-stimulated splenocytes were most effective when used in the non-proliferating phase of the infection, whereas the anti-leishmanial drug Pentostam was most effective when used during the proliferative phase. Immunochemotherapy was more effective than either treatment alone. Infection with L. donovani abolishes the ability of macrophages to produce the superoxide and INO microbicidal responses; curative treatment with IL-2-stimulated splenocytes restores the ability of infected macrophages to secrete inorganic nitrogen oxides, but not to produce a superoxide response. Pentostam had no effect to stimulate either microbicidal mechanism in infected cells; the drug is, therefore, probably directly toxic to the parasite. These studies have indicated, among other things, that IL-2-stimulated splenocytes rescue infected cells and infected animal from the immunological deficit which L. donovani induces, allowing the re-establishment of those mechanisms that make the macrophage an essential component of the host's protective immune system.

This thesis evaluated the role of rIL-2 in patients with advanced colorectal cancer and also, as a perioperative regime, in patients with localized colorectal cancer undergoing surgical resection. Twenty patients with advanced colorectal cancer received up to six cycles of chemoimmunotherapy, each consisting of 5-fluorouracil, levamisole and rIL-2 at 18x10<SUP>6</SUP>IU/m<SUP>2</SUP>/24 for 120 hours. Responding patients were found to have significantly lower pre-treatment serum IL-6 and soluble IL-2 receptor levels, compared with non-responders. Differential patterns of host cytokine release were also identified. Haemodynamic monitoring found that indices of rIL-2-mediated toxicity, e.g. weight gain correlated with alterations in serum cytokine concentrations. In a separate study, eighteen patients, undergoing curative surgery for localized colorectal cancer, were randomized to receive placebo or bolus low-dose subcutaneous rIL-2 for three days preoperatively. rIL-2 was found to significantly enhance host antitumour natural cytotoxicity, monocyte activity and immune cell surface activation marker expression (e.g. CD25). Circulating levels of key host cytokines (e.g. interleukin-6, soluble interleukin-2 receptor) were elevated in the immediate postoperative period in these patients. Mesenteric release of key cytokines was determined in patients undergoing resection for benign and malignant colorectal disease through portal sampling at surgery. Higher patterns of release were found in patients with malignancy suggesting local modulation of immune activity. rIL-2 has been found to beneficially enhance host immune reactivity in patients with localized and advanced colorectal cancer. The nephrotoxic potential of rIL-2 therapy was determined through urinary enzyme release, plasma renin and standard blood biochemistry measurements. RIL-2, when administered carefully, may form the basis of further adjuvant immunotherapy in both the peri-operative period and in patients with advanced colorectal cancer.

Copies of author's previously published article inserted onto back cover. / Bibliography: leaves 164-187. / xxii, 187, [87] leaves, [18] leaves of plates : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Confirms the value of DHBV infection in ducks as a model to evaluate the protective and therapeutic efficacy of DNA vaccines against hepadnavirus infection. The possibility that this model could be explored further to evaluate various combinations of antigens and cytokines 'cocktail' DNA vaccines that elicit the most effective humoral and effective CMI responses for prevention and treatment of HBV infection is discussed. / Thesis (Ph.D.)--University of Adelaide, Dept. of Microbiology and Immunology, 1999

Copies of author's previously published article inserted onto back cover. / Bibliography: leaves 164-187. / xxii, 187, [87] leaves, [18] leaves of plates : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Confirms the value of DHBV infection in ducks as a model to evaluate the protective and therapeutic efficacy of DNA vaccines against hepadnavirus infection. The possibility that this model could be explored further to evaluate various combinations of antigens and cytokines 'cocktail' DNA vaccines that elicit the most effective humoral and effective CMI responses for prevention and treatment of HBV infection is discussed. / Thesis (Ph.D.)--University of Adelaide, Dept. of Microbiology and Immunology, 1999

Thesis (Ph. D.)--University of Adelaide, Dept. of Microbiology and Immunology, 1999. / Copies of author's previously published article inserted onto back cover. Includes bibliographical references (leaves 164-187).

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2006. / Härtill 4 uppsatser.