Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose: The histamine H4 receptor (H4R) has been shown to drive inflammatory responses in models of asthma, colitis and dermatitis and in these models it appears to impact both innate and adaptive immune responses. In this study we utilized both H4R-deficient mice and specific H4R antagonists, to investigate the involvement of the H4R in mouse arthritis models and in toll-like receptor (TLR) driven events in vitro and in vivo.
Methods: H4R-deficient mice and wild-type mice administered the H4R antagonist, JNJ 28307474, were studied in models of collagen antibody-induced arthritis (CAIA) and collagen-induced arthritis (CIA). The impact on Th17 cells was assessed by restimulation of inguinal lymphocytes in the disease or immunization models and upon in vitro stimulation of whole blood. The impact of H4R antagonists, JNJ 7777120 and 28307474, on innate immunity were also examined in LPS challenge of mice, and of in vitro mast cells and dendritic cells.
Results: Both H4R-deficient mice and mice treated with the H4R antagonist exhibited reduced arthritis disease severity in both CAIA and CIA models. This was evident from the reduction in disease score and in joint histology. In the CIA model treatment with the H4R antagonist reduced the number of IL-17 positive cells in the lymph node and the total production of IL-17. Th17 cell development in vivo was reduced in H4R-deficient mice or in mice treated with an H4R antagonist. In human blood an H4R antagonist reduced the production of IL-17 when cells were stimulated in vitro. Additionally, H4R antagonists were able to inhibit TNF production in response to LPS challenge in mice, and to decrease IL-6 and multiple cytokine and chemokine production from TLR stimulated mast cells and dendritic cells, respectively
Conclusion: These results implicate the H4R in disease progression in arthritis, in innate driven, proarthritic inflammatory events and in the production of IL-17 from Th17 cells. This work supports future clinical exploration of H4R antagonists for the treatment of rheumatoid arthritis and other autoimmune diseases.
Disclosure:
P. J. Dunford,
Johnson & Johnson,
3,
Johnson & Johnson,
1;
J. Cowden,
Johnson & Johnson,
3;
F. Yu,
Johnson & Johnson,
3;
H. Banie,
Johnson & Johnson,
3;
M. Farahani,
Johnson & Johnson,
3;
P. Ling,
Johnson & Johnson,
3;
S. Nguyen,
Johnson & Johnson,
3;
J. Riley,
Johnson & Johnson,
3;
M. Zhang,
None;
J. Zhu,
Johnson & Johnson,
3;
R. L. Thurmond,
Johnson & Johnson,
1,
Johnson & Johnson,
3.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-histamine-h4-receptor-drives-inflammation-in-preclinical-models-of-arthritis/