Hewson, Adrian Kenneth; (1998) Regulation of susceptibility and resistance to experimental allergic encephalomyelitis by neuroendocrine and immune factors. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Susceptibility to the induction of the T-cell mediated autoimmune disease experimental allergic encephalomyelitis (EAE) in Lewis rats is attributed to the decreased production of corticosterone compared to the histocompatible EAE-resistant Fischer rat. This hypo-responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis appears to be caused by a defect in hypothalamic corticotrophin-releasing factor-41 (CRF) secretion, possibly a consequence of abnormal signal transduction in the CRF neuron. Activation of the HPA axis with either bacterial endotoxin (lipopolysaccharide, LPS), interleukin (IL)-1beta or tumour necrosis factor (TNF)-alpha increased plasma corticosterone levels up to 10-fold greater in Fischer rats than in Lewis rats. However, second messenger and neurotransmitter production in the paraventricular nucleus of the hypothalamus in response to LPS was greater in the Lewis rat suggesting that the Lewis CRF neuron requires greater stimulation and/or must increase production of second messengers to precipitate a steroid response which is substantially smaller than that observed in the Fischer rat. In contrast, changes in hypothalamic cyclic adenosine monophosphate, prostaglandin E2 and noradrenaline following administration of IL-1beta were similar in both strains and were not as great as those seen following LPS. It is possible that cytokines produced following LPS administration (e.g. IL-1beta], TNF-alpha) may act synergistically to activate the systems measured in this study or that IL-1β stimulates alternative pathways which lead to adrenocortical activation. Recovery from transfer EAE in intact Lewis rats was associated with increased numbers of apoptotic T lymphocytes (32%, 7 days post transfer) in the spinal cord at the time of the expected increase in plasma corticosterone levels; intact Fischer rats displayed reduced T cell numbers in the spinal cord, increased T cell apoptosis (44%, 7 d.p.t.) and milder disease. Adrenalectomised Lewis and Fischer rats developed severe and often fatal EAE and had low numbers of apoptotic T cells (max. 8.5 %) in the spinal cord. Glucocorticoid mediated apoptosis of T cells, the initiator cell type for the induction of EAE, appears to be an effective and important mechanism for recovery from EAE and perhaps contributes to disease resistance. Induction of EAE is dependent on secretion of T helper 1 (Th1) cytokines while recovery is associated with a switch to a Th2 cytokine profile which may underlie the subsequent refractoriness to re-induction of disease. Increased corticosterone secretion in Fischer rats may suppress the development of a Th1 response and may be a contributory factor in conferring resistance. The incidence of EAE but not the severity was increased in Fischer rats following administration of IL-12 whereas Lewis rats developed severe EAE with rapid onset, the likely result of increased Th1 cytokine production and macrophage activation. Peripheral administration of IL-12 to Lewis rats up to one week after full recovery from paralysis resulted in clinical relapse when EAE was induced by active immunisation, whilst co-administration of myelin basic protein with IL-12 was required to elicit relapse following recovery from transfer EAE, suggesting IL-12 (re)-activates antigen specific T-cells peripherally, triggering a secondary wave of cellular infiltration and disease relapse. Disease exacerbation and re-induction was accompanied by extensive up-regulation of inducible nitric oxide synthase immunoreactivity, microglial activation and a predominance of macrophages in CNS lesions. These studies highlight the importance of CNS control of the HPA axis in determining resistance and recovery from EAE through corticosterone-mediated mechanism(s) and also suggest a role for the Th1-cell-inducing cytokine, IL-12, in mediating disease relapse by promoting macrophage-mediated pathology.

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