Combination treatment of mice with crx-153 (nortriptyline and desloratadine) decreases the severity of experimental autoimmune encephalomyelitis

Pro-inflammatory CD4(+) T cell-mediated autoimmune diseases, such as multiple sclerosis, are hypothesized to be initiated and maintained by self-reactive interferon-gamma (IFN-gamma) and interleukin-17 (IL-17) producing CD4(+) T cells. Previous studies have shown moderate to significant alterations in inflammatory T cell responses and potentially treatment of autoimmune disease by administration of antihistamine or tricyclic antidepressants alone. The goal of the present study was to determine if treatment of PLP139-151-induced relapsing-remitting experimental autoimmune encephalomyelitis (R-EAE) in SJL/J mice with a combination of two FDA approved drugs for other indications could decrease R-EAE disease. The findings show that combination treatment with desloratadine and nortriptyline decreases the mean clinical score, disease relapse frequency, and number of CD4(+). T cells infiltrating into the CNS. In addition, combination treatment of PLP139-151 primed mice decreases the level of IFN-gamma and IL-17 secreted via a decrease in both the number of cells secreting and the amount of cytokine secreted per cell following PLP139-151 reactivation ex vivo. This is in contrast to an increase in the level of IL-4 produced and the number of IL-4 secreting cells. The data also show that combination treatment with desloratadine and nortriptyline inhibits the production of IFN-gamma and IL-17 produced by naive CD4(+) T cells activated in the presence of Thl cell- and Th17 cell-promoting conditions, while increasing the level of IL-4 produced by naive CD4(+). T cells activated in the presence of Th2 cell-promoting conditions. The present findings suggest a novel method for the development of a putative autoimmune therapy. (C) 2011 Elsevier Inc. All rights reserved.