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, Elizabeth P. Blankenhorn

Research output: Contribution to journalArticle

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Abstract

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 H 1 receptor (H1R)-deficient (H1RKO) mice produce significantly less interferon-γ 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.

Original languageEnglish (US)
Pages (from-to)883-892
Number of pages10
JournalAmerican Journal of Pathology
Volume164
Issue number3
StatePublished - Mar 2004

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Histamine H2 Receptors
Th1 Cells
Autoimmune Experimental Encephalomyelitis
Antigen-Presenting Cells
Knockout Mice
Cytokines
T-Lymphocytes
Histamine
Interleukin-12
Chemokines
Biogenic Amines
Histocompatibility Antigens Class II
Pertussis Toxin
Interleukin-4
Interferons
Interleukin-2
Neurotransmitter Agents
Interleukin-6
Hypersensitivity

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

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. / Teuscher, Cory; Poynter, Matthew E.; Offner, Halina; Zamora, Alex; Watanabe, Takeshi; Fillmore, Parley D.; Zachary, James F.; Blankenhorn, Elizabeth P.

In: American Journal of Pathology, Vol. 164, No. 3, 03.2004, p. 883-892.

Research output: Contribution to journalArticle

Teuscher, Cory ; Poynter, Matthew E. ; Offner, Halina ; Zamora, Alex ; Watanabe, Takeshi ; Fillmore, Parley D. ; Zachary, James F. ; Blankenhorn, Elizabeth P. / 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. In: American Journal of Pathology. 2004 ; Vol. 164, No. 3. pp. 883-892.
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abstract = "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 H 1 receptor (H1R)-deficient (H1RKO) mice produce significantly less interferon-γ 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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