Sharief, Mohammad Kassim; (1992) The importance of interleukin-2 and its soluble receptor in patients with multiple sclerosis and other inflammatory diseases of the central nervous system. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Interleukin-2 (IL-2) was originally identified in 1976 as a growth factor for T lymphocytes. Since that time it has become an important mediator of immune functions through its effects on the growth, development, and activity of T and B lymphocytes, natural killer cells, and lymphokine-activated killer cells. Although the role of IL-2 in the systemic immune response is well-established, the importance of IL-2 and soluble IL-2 receptor (sIL-2R) in the intrathecal immune response is still unclear, probably due to the lack of sensitive and standardised methods to detect these cytokines in body fluids. Another factor may be the shortage of longitudinal studies that correlate the local release of IL-2 and sIL-2R with other pathological and clinical features of inflammatory disorders of the central nervous system (CNS). This study describes a sensitive method that detects IL-2 and sIL-2R in human cerebrospinal fluid (CSF) and serum samples, and is able to evaluate intrathecal synthesis of these cytokines in vivo. Using this method, intrathecal release of IL-2 and sIL-2R was evaluated in 148 patients with clinically definite multiple sclerosis (MS), 28 patients with other inflammatory neurologic diseases, 36 patients with post-polio syndrome, and 128 neurologic controls and normal subjects. Intrathecal synthesis of IL-2 and sIL-2R was predominantly found in patients with relapsing-remitting MS and other inflammatory CNS diseases. No evidence of in vivo antagonism was detected between IL-2 and sIL-2R. Detection of IL-2 and sIL-2R in CSF provided an objective indicator of poliovirus activation in post-polio syndrome. Intrathecal levels of IL-2 and sIL-2R in MS correlated with local CNS synthesis of IgD and IgM, indicating that these cytokines are involved in the intrathecal humoral immune response in MS. Furthermore, IL-2 and sIL-2R demonstrated an outstanding predictive value for subsequent development of MS in 45 patients with acute isolated brainstem or spinal cord syndromes, who were prospectively followed-up for 30 months. High IL-2 and sIL-2R levels correlated with the degree of blood- brain barrier damage in patients with MS, primarily through the release of tumour necrosis factor-α. Moreover, the degree of disability and overall disease activity of MS correlated with high intrathecal levels of IL-2 and sIL-2R. This study demonstrates that IL-2 and sIL-2R are valuable indicators of intrathecal immune activation, and that in vivo evaluation of these cytokines is imperative in understanding the pathogenesis of some CNS inflammatory diseases.

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