This study investigated the role of tolerance induction in an inflammatory setting in regard to the early growth response genes Egr2 and Egr3. T cells robustly respond to pathogenic antigens during infection, but are tolerant to stimulation by self-antigens. The intrinsic mechanisms for self-tolerance in the periphery are still not clear. Egr2 and 3 are induced in tolerant T cells in response to antigen stimulation by NFAT-medicated tolerant signalling; however, their function in tolerant T cells is still unknown. The study demonstrated that Egr2 and 3, induced in tolerant T cells, are not directly involved in defective proliferation and IL-2 production, the hallmarks of T cell tolerance. However, they are essential for preventing inflammatory response of tolerant T cells. In the absence of Egr2 and 3, tolerant T cells show impaired proliferation and production of IL-2, but produce high levels of IFN-γ, a key inflammatory cytokine. This phenotype resembles CD4 T cells from autoimmune diseases such as lupus which show poor proliferative response, but hyper-inflammation. Our study demonstrated, for the first time, a distinctive mechanism to control inflammation from proliferative tolerance regulated by Egr2 and 3, which may be an important mechanism for the control of autoimmune diseases.

Ketamine and phencyclidine (PCP) are noncompetitive antagonists of the N-methyl-D-aspartate (NMDA) type of ligand-gated glutamate receptors. Both agents have high abuse liability, and may produce dependence. Tolerance to the reinforcing effects of drugs of abuse is widely regarded as a key component of the dependence process. Therefore, the present study was conducted to examine whether tolerance develops to the reinforcing effects of ketamine, and whether PCP and dizocilpine, a noncompetitive NMDA antagonist with negligible abuse liability, produce cross-tolerance to the reinforcing effects of ketamine. Further, identification of the neural mechanisms that underlie tolerance to the reinforcing effects of drugs may yield information regarding drug dependence.

Call number: LD2668 .T4 1938 L51

LD2668 .T4 1954 S25 / Master of Science

Call number: LD2668 .T4 1966 S761 / Master of Science

International Telemetering Conference Proceedings / October 25-28, 1999 / Riviera Hotel and Convention Center, Las Vegas, Nevada / This paper proposes a problem that the error tolerance property of spread spectrum sequence influences the performance of spread spectrum system. Then the relation is analyzed between the error tolerance property and the correlation property of binary sequence when correlation detection is proceeded, and the theoretical limitation of error tolerance is given. Finally, we investigate the relationship between the determination of the output decision threshold of correlation, the probability of correlation peak detection and the error tolerance of the spread spectrum sequence.

The administration of soluble antigenic peptides is known to be effective at inducing tolerance in naïve antigen-reactive CD4+ T cells. This observation forms the basis of antigen-based therapy, which offers the potential to specifically target the auto-reactive CD4+ T cells involved in driving autoimmune disease pathogenesis, whilst leaving the rest of the immune system intact. The prophylactic administration of soluble autoantigen-derived peptides has proven to be effective at inhibiting disease induction in various experimental models of autoimmune disease. However, the clinical requirement is to switch off the activated antigen-experienced CD4+ T cells that are present during an ongoing immune response. The effect of soluble peptide administration of antigenexperienced CD4+ T cells is poorly understood, and several clinical trials using peptides in multiple sclerosis patients had to be halted due to the exacerbation of disease. This thesis characterises the effect of soluble peptide administration on pathogenic antigen-experienced CD4+ T cells, using experimental autoimmune encephalomyelitis (EAE) as a model of autoimmune disease of the central nervous system. Using traceable myelin-reactive T cells from Tg4 mice, it was determined that soluble peptide administration induces substantial expansion of antigen-experienced CD4+ T cells. Despite the increase in number, these cells were no longer able to induce EAE. Production of effector cytokine was significantly decreased in peptide treated antigen-reactive CD4+ T cells, and this correlated with high level expression of the co-inhibitory molecule PD-1. The induction of tolerance in both naïve and antigen-experienced CD4+ T cells was found to be dependent upon PD-1 expression, whereby peptide treatment of naïve and antigen-experienced CD4+ T cells that were deficient in PD-1, did not inhibit disease induction. This thesis identifies a novel mechanism of peptide-induced tolerance in CD4+ T cells, and demonstrates that soluble peptide administration can induce tolerance in antigen-experienced T cells.

The aim of my project was to examine the extent to which endogenous expression of a largely renal-specific antigen influences the repertoire in adulthood of autoreactive T cells specific to that antigen. The renal-specific antigen, human α3(IV)NC1, is the target of autoimmune attack in Goodpasture’s disease. This protein was expressed and purified in recombinant (using bacterial and mammalian cell expression systems) and purified in native (extracted from human tissue) forms. Transgenic mice were generated that express HLA-DR15 (associated with Goodpasture’s disease) as their sole MHC class II molecule, and for which α3(IV)NC1 can be endogenous or exogenous. The CD4 T cell responses of these mice were then tested following immunisation with α3(IV)NC1. In mice with endogenous expression of α3(IV)NC1 there were no consistent detectable proliferative T cell responses to any α3(IV)NC1 peptides in a set of overlapping peptides representative of the entire sequence. In the mice lacking endogenous α3(IV)NC1 there were consistent responses to the peptide α3(IV)NC1 136-150. This contains part of the peptide recognised by the most abundant autoreactive T cells in patients with acute Goodpasture’s disease. Therefore, the T cell responses seen in man to an endogenous (auto)antigen have similar fine specificity to those seen in mice responding to the same protein as a foreign antigen. This is surprising as one might expect self-tolerance in man to be most secure to such dominantly presented and immunogenic (in HLA DR15 mice) self peptides. However, recent work suggests that the peptide most commonly presented in humans is normally destroyed during antigen processing, giving a possible explanation for the lack of tolerance. Future work should study why tolerance is ineffective to this particular peptide, whether tolerance can be reinforced, these questions could be addressed using a transgenic mouse model that develops Goodpasture-like pathology. In addition, how processing is defective in Goodpasture’s disease could be explored by making antigen presenting hybridomas from patient samples or from the transgenic mouse line described within this thesis.

No description available.

published_or_final_version / Mechanical Engineering / Doctoral / Doctor of Philosophy