Proinflammatory Cytokines and Their Receptors

Proinflammatory cytokines, such as TNF-a and interleukin (IL)-12, are produced in increasing quantities in peripheral blood cells of MS patients prior to relapse, and protein and mRNA of proinflammatory cytokines are found in MS plaques. Increased levels of TNF-a have also been found in the CSFof MS patients, and IL-2 receptors are expressed on the surface of activated lymphocytes.

Anti-TNF-a therapies are approved for the treatment of RA and Crohn's disease. However, monoclonal antibodies against TNF-a induce SLE, and lead to increased and prolonged exacerbations in MS patients. Further, there is some clinical trial evidence that etanercept, a soluble recombinant TNF receptor Fc protein, designed as a TNF-a inhibitor, may actually lead to the upregulation of TNF-a expression in some MG patients - leading to worsening of the disease.

Monoclonal antibodies against IL-12 are currently being tested in clinical trials for MS and Crohn's disease. A monoclonal antibody to the IL-2 receptor daclizumab functions as an IL-2 antagonist. Daclizumab inhibits IL-2-mediated stimulation of lymphocytes, is approved for use in kidney transplant patients, and is being tested in clinical trials as a therapy for RRMS.

The monoclonal antibody antagonist of the cytokine BLyS can also be included in this category (see below).

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