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(American Journal of Pathology. 2004;164:883-892.)
© 2004 American Society for Investigative Pathology

Attenuation of Th1 Effector Cell Responses and Susceptibility to Experimental Allergic Encephalomyelitis in Histamine H₂ Receptor Knockout Mice Is Due to Dysregulation of Cytokine Production by Antigen-Presenting Cells

Cory Teuscher^*, Matthew E. Poynter^*, Halina Offner, Alex Zamora, Takeshi Watanabe, Parley D. Fillmore, James F. Zachary and Elizabeth P. Blankenhorn^¶

From the Department of Medicine,^*University of Vermont School of Medicine, Burlington, Vermont; the Department of Neurology,Oregon Health and Science University and Neuroimmunology Research, Veterans Affairs Medical Center, Portland, Oregon; the Department of Veterinary Pathobiology,University of Illinois at Urbana–Champaign, Urbana, Illinois; the Department of Microbiology and Immunology,^¶Drexel University College of Medicine, Philadelphia, Pennsylvania; and the Medical Institute of Bioregulation,Kyushu University, Fukuoka, Japan

Histamine, a biogenic amine with both neurotransmitter and vasoactive properties, is well recognized as an immunomodulatory agent in allergic and inflammatory reactions. It also plays a regulatory role in the development of antigen-specific immune responses. CD4⁺ T-cells from histamine H₁ receptor (H1R)-deficient (H1RKO) mice produce significantly less interferon- and more interleukin (IL)-4 in in vitro recall assays compared to wild-type controls. H1RKO mice are also less susceptible to acute early-phase experimental allergic encephalomyelitis indicating that H1R signaling in CD4⁺ T cells plays a central role in regulating pathogenic T-cell responses. In this study, we show that mice lacking histamine H₂ receptor (H2RKO) are similar to H1RKO mice in that they develop encephalitogen-specific T-cell responses as assessed by proliferation and IL-2 production and present with less severe acute early-phase experimental allergic encephalomyelitis. However, unlike T cells from H1RKO mice, which exhibit a strong Th2 bias, T cells from H2RKO mice do not. Rather, they are uniquely characterized by a significant inhibition of Th1 effector cell responses. Given that both histamine and adjuvants such as pertussis toxin modulate antigen-presenting cell (APC) maturation and function, including T-cell-polarizing activity, we analyzed the cytokines/chemokines secreted by APCs from wild-type, H1RKO, and H2RKO mice. Significant differences in cytokine/chemokine production by APCs from unimmunized and immunized mice were delineated. APCs from H2RKO mice produce significantly less IL-12 and IL-6 and markedly greater amounts of MCP-1 compared to wild-type and H1RKO mice. Because MCP-1 is known to inhibit IL-12 production, the failure of H2RKO mice to generate encephalitogenic Th1 effector cell responses is consistent with inhibition of negative regulation of MCP-1 secretion by H2R signaling in APCs.

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