jnj-7777120 and Multiple-Sclerosis

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).. 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.. 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.. 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.

Topics: Animals; Antibody Formation; Cytokines; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Gene Expression Regulation; Histamine Antagonists; Indoles; Inflammation; Mice; Mice, Inbred C57BL; Multiple Sclerosis; Myelin-Oligodendrocyte Glycoprotein; Piperazines; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; RNA, Messenger; Severity of Illness Index; T-Lymphocytes