Defective regulation of IFNγ and IL-12 by endogenous IL-10 in progressive MS

Konstantin Balashov, M. Comabella, T. Ohashi, S. J. Khoury, H. L. Weiner

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Abstract

Background: MS is a chronic inflammatory disease of the CNS postulated to be a Th1 type cell-mediated autoimmune disease. There is increased interferon-γ (IFNγ) secretion in MS, and IFNγ administration induces exacerbations of disease. IFNγ expression is closely regulated by a number of cytokines produced by different cells of the immune system. Interleukin-12 (IL-12) is a major factor leading to Th1-type responses, including IFNγ secretion, and there is increased secretion of IL-12 in MS. IL-10 is a potent inhibitor of both IL-12 and IFNγ expression. Methods: The authors investigated cytokine production and proliferative responses of peripheral blood mononuclear cells stimulated with soluble anti-CD3 in healthy controls and patients with stable relapsing-remitting MS or progressive MS. Results: The authors found that T cell receptor-mediated IFNγ and IL-10 secretion were increased in progressive MS, whereas IL-4 and IL-2 secretion and lymphocyte proliferative responses were normal. Anti-IL-12 antibody suppressed raised IFNγ in progressive MS but did not affect raised IL-10. In addition, neutralization of endogenous IL-10 upregulated IFNγ in controls but not progressive MS. IL-10 was produced by CD4+ cells whereas IFNγ was produced by both CD4+ and CD8+ cells. There were no differences in IL-10 receptor expression in MS patients. Conclusions: These abnormalities in IL-10 regulation were not seen in the relapsing-remitting form of MS. Thus, the defect in regulation of both IL-12 and IFNγ production by endogenous IL-10 in progressive MS could be an important factor involved in the transition of MS from the relapsing to the progressive stage and has implications for treating MS patients with exogenous IL-10.

Original languageEnglish (US)
Pages (from-to)192-198
Number of pages7
JournalNeurology
Volume55
Issue number2
DOIs
StatePublished - Jul 25 2000

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Interleukin-12
Interleukin-10
Interferons
Interleukin-10 Receptors
Cytokines
Th1 Cells
T-Cell Antigen Receptor
Interleukin-4
Autoimmune Diseases
Interleukin-2
Disease Progression
Immune System
Blood Cells
Chronic Disease
Lymphocytes
Antibodies

All Science Journal Classification (ASJC) codes

  • Clinical Neurology

Cite this

Balashov, Konstantin ; Comabella, M. ; Ohashi, T. ; Khoury, S. J. ; Weiner, H. L. / Defective regulation of IFNγ and IL-12 by endogenous IL-10 in progressive MS. In: Neurology. 2000 ; Vol. 55, No. 2. pp. 192-198.
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abstract = "Background: MS is a chronic inflammatory disease of the CNS postulated to be a Th1 type cell-mediated autoimmune disease. There is increased interferon-γ (IFNγ) secretion in MS, and IFNγ administration induces exacerbations of disease. IFNγ expression is closely regulated by a number of cytokines produced by different cells of the immune system. Interleukin-12 (IL-12) is a major factor leading to Th1-type responses, including IFNγ secretion, and there is increased secretion of IL-12 in MS. IL-10 is a potent inhibitor of both IL-12 and IFNγ expression. Methods: The authors investigated cytokine production and proliferative responses of peripheral blood mononuclear cells stimulated with soluble anti-CD3 in healthy controls and patients with stable relapsing-remitting MS or progressive MS. Results: The authors found that T cell receptor-mediated IFNγ and IL-10 secretion were increased in progressive MS, whereas IL-4 and IL-2 secretion and lymphocyte proliferative responses were normal. Anti-IL-12 antibody suppressed raised IFNγ in progressive MS but did not affect raised IL-10. In addition, neutralization of endogenous IL-10 upregulated IFNγ in controls but not progressive MS. IL-10 was produced by CD4+ cells whereas IFNγ was produced by both CD4+ and CD8+ cells. There were no differences in IL-10 receptor expression in MS patients. Conclusions: These abnormalities in IL-10 regulation were not seen in the relapsing-remitting form of MS. Thus, the defect in regulation of both IL-12 and IFNγ production by endogenous IL-10 in progressive MS could be an important factor involved in the transition of MS from the relapsing to the progressive stage and has implications for treating MS patients with exogenous IL-10.",
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Balashov, K, Comabella, M, Ohashi, T, Khoury, SJ & Weiner, HL 2000, 'Defective regulation of IFNγ and IL-12 by endogenous IL-10 in progressive MS', Neurology, vol. 55, no. 2, pp. 192-198. https://doi.org/10.1212/WNL.55.2.192

Defective regulation of IFNγ and IL-12 by endogenous IL-10 in progressive MS. / Balashov, Konstantin; Comabella, M.; Ohashi, T.; Khoury, S. J.; Weiner, H. L.

In: Neurology, Vol. 55, No. 2, 25.07.2000, p. 192-198.

Research output: Contribution to journalArticle

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T1 - Defective regulation of IFNγ and IL-12 by endogenous IL-10 in progressive MS

AU - Balashov, Konstantin

AU - Comabella, M.

AU - Ohashi, T.

AU - Khoury, S. J.

AU - Weiner, H. L.

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N2 - Background: MS is a chronic inflammatory disease of the CNS postulated to be a Th1 type cell-mediated autoimmune disease. There is increased interferon-γ (IFNγ) secretion in MS, and IFNγ administration induces exacerbations of disease. IFNγ expression is closely regulated by a number of cytokines produced by different cells of the immune system. Interleukin-12 (IL-12) is a major factor leading to Th1-type responses, including IFNγ secretion, and there is increased secretion of IL-12 in MS. IL-10 is a potent inhibitor of both IL-12 and IFNγ expression. Methods: The authors investigated cytokine production and proliferative responses of peripheral blood mononuclear cells stimulated with soluble anti-CD3 in healthy controls and patients with stable relapsing-remitting MS or progressive MS. Results: The authors found that T cell receptor-mediated IFNγ and IL-10 secretion were increased in progressive MS, whereas IL-4 and IL-2 secretion and lymphocyte proliferative responses were normal. Anti-IL-12 antibody suppressed raised IFNγ in progressive MS but did not affect raised IL-10. In addition, neutralization of endogenous IL-10 upregulated IFNγ in controls but not progressive MS. IL-10 was produced by CD4+ cells whereas IFNγ was produced by both CD4+ and CD8+ cells. There were no differences in IL-10 receptor expression in MS patients. Conclusions: These abnormalities in IL-10 regulation were not seen in the relapsing-remitting form of MS. Thus, the defect in regulation of both IL-12 and IFNγ production by endogenous IL-10 in progressive MS could be an important factor involved in the transition of MS from the relapsing to the progressive stage and has implications for treating MS patients with exogenous IL-10.

AB - Background: MS is a chronic inflammatory disease of the CNS postulated to be a Th1 type cell-mediated autoimmune disease. There is increased interferon-γ (IFNγ) secretion in MS, and IFNγ administration induces exacerbations of disease. IFNγ expression is closely regulated by a number of cytokines produced by different cells of the immune system. Interleukin-12 (IL-12) is a major factor leading to Th1-type responses, including IFNγ secretion, and there is increased secretion of IL-12 in MS. IL-10 is a potent inhibitor of both IL-12 and IFNγ expression. Methods: The authors investigated cytokine production and proliferative responses of peripheral blood mononuclear cells stimulated with soluble anti-CD3 in healthy controls and patients with stable relapsing-remitting MS or progressive MS. Results: The authors found that T cell receptor-mediated IFNγ and IL-10 secretion were increased in progressive MS, whereas IL-4 and IL-2 secretion and lymphocyte proliferative responses were normal. Anti-IL-12 antibody suppressed raised IFNγ in progressive MS but did not affect raised IL-10. In addition, neutralization of endogenous IL-10 upregulated IFNγ in controls but not progressive MS. IL-10 was produced by CD4+ cells whereas IFNγ was produced by both CD4+ and CD8+ cells. There were no differences in IL-10 receptor expression in MS patients. Conclusions: These abnormalities in IL-10 regulation were not seen in the relapsing-remitting form of MS. Thus, the defect in regulation of both IL-12 and IFNγ production by endogenous IL-10 in progressive MS could be an important factor involved in the transition of MS from the relapsing to the progressive stage and has implications for treating MS patients with exogenous IL-10.

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