Thesis (PhD)--University of South Australia, 2000

Includes copies of articles co-authored by the author during the preparation of this thesis, in back pocket. / Errata attached to back flyleaf. / Includes bibliographical references (leaves 127-139). / 139 leaves : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / The results presented lend further evidence to previous work suggesting that cold shock domain factors function to repress granulocyte macrophage-colony stimulating factor transcription via DNA binding to single stranded regions across the proximal promoter. / Thesis (Ph.D.)--Adelaide University, Dept. of Medicine, 2001

The activation and effector function of CD4+ T cells are critical points of regulation during an antigen specific T cell response. Dysregulation of these processes can lead to the development of human diseases, encompassing both immunodeficiency and autoimmunity. Members of the TNF superfamily have recently emerged as important regulators of T cell responses, with their overexpression causing autoimmune inflammation in animal models. As overproduction of the novel TNF superfamily ligand BAFF is associated with several autoimmune conditions, we sought to examine the potential role of BAFF as a regulator of T cell activation and effector function. We initially demonstrated BAFF costimulation of T cell activation in vitro. Generation of specific monoclonal antibodies identified BAFF-R as the only BAFF receptor present on T cells, and showed that it was expressed in an activation-dependent and subset-specific manner. Impaired BAFF costimulation in BAFF-R deficient mice indicated that BAFF-R was crucial for mediating BAFF effects in T cells. Analysis of T cell responses in vivo revealed that BAFF transgenic mice have increased T cell priming and recall responses to protein antigens, and showed a corresponding increase in the DTH model of Th1 cell-dependent inflammation. In addition, Th2-dependent allergic airway responses are suppressed in BAFF transgenic mice. Crossing to a B cell deficient background revealed that the proinflammatory effects of BAFF on T cell priming and DTH rely on the presence of B cells, while the suppressive effects during allergic airway inflammation are B cell independent. These data demonstrated that BAFF regulated the outcome of T cell responses in vivo and identified BAFF dependent crosstalk between T and B cells. Stimulation of B cells with BAFF induced the upregulation of MHC class II and ICOS-L both in vitro and in vivo. Induction of these cell surface molecules was associated with an increased capacity to induce T cell proliferation, however this effect was independent of ICOS-L expression. Thus it was demonstrated that BAFF regulated T cell activation and effector function both directly, via stimulation of BAFF-R, and indirectly, by altering the function of B cells. These data suggest that BAFF dependent alterations in T cell function may be an additional causative factor in the association between elevated BAFF levels and the generation of autoimmunity.

Spiral ganglion neurons (SGNs) within the cochlea degenerate following the loss of the auditory sensory epithelium, the auditory hair cells. Since these neurons are the target cells of the cochlear implant, which bypasses damaged or lost hair cells to stimulate the SGNs directly, enhanced SGN number and integrity may provide enhanced outcomes for cochlear implant patients. Improved contact between the cochlear implant electrode array and the auditory nerve fibres is also likely to enhance the benefits received by cochlear implant patients. Therefore, the identification of molecules with the capacity to support SGN survival and stimulate axonal growth has significant clinical implications. Based on their roles in the development and maintenance of the auditory system, some neurotrophic factors are expected to play an important role in enhancing the survival of auditory elements following deafening. This thesis investigates various molecules for their capacity to stimulate and guide the growth of SGN axons, and also investigates the survival-promoting effects of specific neurotrophic factors on SGN survival in clinically relevant animal models of deafness. Two neurotrophic factors were identified specifically to stimulate axonal growth from SGNs in an in vitro model of deafness.

The activation and effector function of CD4+ T cells are critical points of regulation during an antigen specific T cell response. Dysregulation of these processes can lead to the development of human diseases, encompassing both immunodeficiency and autoimmunity. Members of the TNF superfamily have recently emerged as important regulators of T cell responses, with their overexpression causing autoimmune inflammation in animal models. As overproduction of the novel TNF superfamily ligand BAFF is associated with several autoimmune conditions, we sought to examine the potential role of BAFF as a regulator of T cell activation and effector function. We initially demonstrated BAFF costimulation of T cell activation in vitro. Generation of specific monoclonal antibodies identified BAFF-R as the only BAFF receptor present on T cells, and showed that it was expressed in an activation-dependent and subset-specific manner. Impaired BAFF costimulation in BAFF-R deficient mice indicated that BAFF-R was crucial for mediating BAFF effects in T cells. Analysis of T cell responses in vivo revealed that BAFF transgenic mice have increased T cell priming and recall responses to protein antigens, and showed a corresponding increase in the DTH model of Th1 cell-dependent inflammation. In addition, Th2-dependent allergic airway responses are suppressed in BAFF transgenic mice. Crossing to a B cell deficient background revealed that the proinflammatory effects of BAFF on T cell priming and DTH rely on the presence of B cells, while the suppressive effects during allergic airway inflammation are B cell independent. These data demonstrated that BAFF regulated the outcome of T cell responses in vivo and identified BAFF dependent crosstalk between T and B cells. Stimulation of B cells with BAFF induced the upregulation of MHC class II and ICOS-L both in vitro and in vivo. Induction of these cell surface molecules was associated with an increased capacity to induce T cell proliferation, however this effect was independent of ICOS-L expression. Thus it was demonstrated that BAFF regulated T cell activation and effector function both directly, via stimulation of BAFF-R, and indirectly, by altering the function of B cells. These data suggest that BAFF dependent alterations in T cell function may be an additional causative factor in the association between elevated BAFF levels and the generation of autoimmunity.

Thesis (M. P. H.)--University of Hong Kong, 2006. / Also available in print.

Diss. (sammanfattning) Uppsala : Univ., 2003. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 4 uppsatser.

Thesis (Ph. D.)--Dept. of Medicine, University of Adelaide, 1990. / Typescript (Photocopy). Includes bibliographical references (leaves 202-281).