1. Antagonism of histamine H4 receptors exacerbates clinical and pathological signs of experimental autoimmune encephalomyelitis.
- Author
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Ballerini C, Aldinucci A, Luccarini I, Galante A, Manuelli C, Blandina P, Katebe M, Chazot PL, Masini E, and Passani MB
- Subjects
- Animals, Antibody Formation, Cytokines metabolism, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Female, Flow Cytometry, Gene Expression Regulation drug effects, Indoles pharmacology, Inflammation physiopathology, Mice, Mice, Inbred C57BL, Myelin-Oligodendrocyte Glycoprotein administration & dosage, Piperazines pharmacology, RNA, Messenger metabolism, Receptors, G-Protein-Coupled metabolism, Receptors, Histamine metabolism, Receptors, Histamine H4, Severity of Illness Index, T-Lymphocytes drug effects, T-Lymphocytes metabolism, Encephalomyelitis, Autoimmune, Experimental physiopathology, Histamine Antagonists pharmacology, Multiple Sclerosis physiopathology, Receptors, G-Protein-Coupled antagonists & inhibitors
- Abstract
Background and Purpose: The histamine H4 receptor has a primary role in inflammatory functions, making it an attractive target for the treatment of asthma and refractory inflammation. These observations suggested a facilitating action on autoimmune diseases. Here we have assessed the role of H4 receptors in experimental autoimmune encephalomyelitis (EAE) a model of multiple sclerosis (MS)., Experimental Approach: We induced EAE with myelin oligodendrocyte glycoprotein (MOG35-55 ) in C57BL/6 female mice as a model of MS. The histamine H4 receptor antagonist 5-chloro-2-[(4-methylpiperazin-1-yl)carbonyl]-1H-indole (JNJ7777120) was injected i.p. daily starting at day 10 post-immunization (D10 p.i.). Disease severity was monitored by clinical and histopathological evaluation of inflammatory cells infiltrating into the spinal cord, anti-MOG35-55 antibody production, assay of T-cell proliferation by [(3) H]-thymidine incorporation, mononucleate cell phenotype by flow cytometry, cytokine production by elisa assay and transcription factor quantification of mRNA expression., Key Results: Treatment with JNJ7777120 exacerbated EAE, increased inflammation and demyelination in the spinal cord of EAE mice and increased IFN-γ expression in lymph nodes, whereas it suppressed IL-4 and IL-10, and augmented expression of the transcription factors Tbet, FOXP3 and IL-17 mRNA in lymphocytes. JNJ7777120 did not affect proliferation of anti-MOG35-55 T-cells, anti-MOG35-55 antibody production or mononucleate cell phenotype., Conclusions and Implications: H4 receptor blockade was detrimental in EAE. Given the interest in the development of H4 receptor antagonists as anti-inflammatory compounds, it is important to understand the role of H4 receptors in immune diseases to anticipate clinical benefits and also predict possible detrimental effects., (© 2013 The British Pharmacological Society.)
- Published
- 2013
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