title: Combination treatment of mice with CRx-153 (nortriptyline and desloratadine) decreases the severity of experimental autoimmune encephalomyelitis.
abstract: 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-γ) 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 PLP(139-151)-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 PLP(139-151) primed mice decreases the level of IFN-γ and IL-17 secreted via a decrease in both the number of cells secreting and the amount of cytokine secreted per cell following PLP(139-151) 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-γ and IL-17 produced by naive CD4(+) T cells activated in the presence of Th1 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.
authors.affiliation: Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Podojil
authors.forename: Mahesh V
authors.initials: MV
authors.lastname: Padval
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Miller
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D005260:Female; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D015847:Interleukin-4 / Q000096:biosynthesis; D017336:Loratadine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D051379:Mice; D008822:Mice, Transgenic; D018991:Myelin Proteolipid Protein / Q000235:genetics / Q000276:immunology; D009661:Nortriptyline / Q000008:administration & dosage*; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology
chemical_list: D007166:Immunosuppressive Agents; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments; C435023:myelin proteolipid protein (139-151); D015847:Interleukin-4; D017336:Loratadine; D009661:Nortriptyline; C121345:desloratadine