Background and purpose. The histamine H4 receptor has a primary role in inflammatory functions that has made it an attractive target for the treatment of asthma and refractory inflammation. These observations suggested a facilitating action on autoimmune diseases. However, little is known about the role of the H4 receptor in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). Experimental approach. We used EAE induced by myelin oligodendrocyte glycoprotein (MOG35-55) in C57BL/6 female mice, as a model of multiple sclerosis. The histamine H4 receptor antagonist 5-chloro-2-[(4-methylpiperazin-1-yl)carbonyl]-1Hindole (JNJ7777120) was injected i.p. daily starting at day 10 post-immunisation (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 [3H]-thymidine incorporation, mononucleate cells phenotype by flow cytometry, cytokine production by ELISA assay, transcription factors quantification of mRNA expression. Key results. Treatment with JNJ7777120 worsened the severity of EAE, increased inflammation and demyelination in the spinal cord of EAE mice, it 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 neither affect proliferation of anti-MOG35-55 T cells, anti-MOG35-55 antibody production, nor mononucleate cell phenotype. Conclusions and Implications. Our data show a detrimental effect of H4 receptor blockade in EAE. Given the interest in the development of H4 receptor antagonists as anti-inflammatory compounds, it is important to understand the role of the H4 receptor in immune diseases to anticipate clinical benefits and also predict possible detrimental effects.

Antagonism of histamine H4 receptors exacerbates clinical and pathological signs of experimental autoimmune encephalomyelitis / C Ballerini; A Aldinucci; I Luccarini; A Galante; C Manuelli; P Blandina; M Katebe; PL Chazot; E Masini; MB Passani. - In: BRITISH JOURNAL OF PHARMACOLOGY. - ISSN 0007-1188. - ELETTRONICO. - 170:(2013), pp. 167-177. [10.1111/bph.12263]

Antagonism of histamine H4 receptors exacerbates clinical and pathological signs of experimental autoimmune encephalomyelitis.

BALLERINI, CLARA;ALDINUCCI, ALESSANDRA;LUCCARINI, ILARIA;MANUELLI, CINZIA;BLANDINA, PATRIZIO;MASINI, EMANUELA;PASSANI, MARIA BEATRICE
2013

Abstract

Background and purpose. The histamine H4 receptor has a primary role in inflammatory functions that has made it an attractive target for the treatment of asthma and refractory inflammation. These observations suggested a facilitating action on autoimmune diseases. However, little is known about the role of the H4 receptor in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). Experimental approach. We used EAE induced by myelin oligodendrocyte glycoprotein (MOG35-55) in C57BL/6 female mice, as a model of multiple sclerosis. The histamine H4 receptor antagonist 5-chloro-2-[(4-methylpiperazin-1-yl)carbonyl]-1Hindole (JNJ7777120) was injected i.p. daily starting at day 10 post-immunisation (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 [3H]-thymidine incorporation, mononucleate cells phenotype by flow cytometry, cytokine production by ELISA assay, transcription factors quantification of mRNA expression. Key results. Treatment with JNJ7777120 worsened the severity of EAE, increased inflammation and demyelination in the spinal cord of EAE mice, it 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 neither affect proliferation of anti-MOG35-55 T cells, anti-MOG35-55 antibody production, nor mononucleate cell phenotype. Conclusions and Implications. Our data show a detrimental effect of H4 receptor blockade in EAE. Given the interest in the development of H4 receptor antagonists as anti-inflammatory compounds, it is important to understand the role of the H4 receptor in immune diseases to anticipate clinical benefits and also predict possible detrimental effects.
170
167
177
C Ballerini; A Aldinucci; I Luccarini; A Galante; C Manuelli; P Blandina; M Katebe; PL Chazot; E Masini; MB Passani
File in questo prodotto:
File Dimensione Formato  
26. BJP Ballerini.pdf

Accesso chiuso

Tipologia: Pdf editoriale (Version of record)
Licenza: DRM non definito
Dimensione 1.82 MB
Formato Adobe PDF
1.82 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in FLORE sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2158/946335
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 29
  • ???jsp.display-item.citation.isi??? 27
social impact