Estrogen potentiates treatment with T-cell receptor protein of female mice with experimental encephalomyelitis
Halina Offner, Kirsten Adlard, Alex Zamora, Arthur A. Vandenbark
Halina Offner, Kirsten Adlard, Alex Zamora, Arthur A. Vandenbark
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Estrogen potentiates treatment with T-cell receptor protein of female mice with experimental encephalomyelitis

Abstract

Transgenic mice expressing the BV8S2 chain, which is specific for the myelin basic protein determinant Ac1-11, possess a naturally induced set of regulatory T cells directed against BV8S2. Further activation of anti-BV8S2 T cells in male mice with recombinant BV8S2 protein can inhibit IFN-γ release by Ac1-11–specific T cells through a cytokine-driven mechanism and prevent induction of experimental autoimmune encephalomyelitis (EAE). In contrast, naive female mice possess fewer anti-BV8S2–reactive T cells, and treatment with BV8S2 delayed but did not prevent EAE. We here demonstrate that combining T-cell receptor (TCR) vaccination with supplemental estrus doses of estrogen potentiated IL-10 production by anti-BV8S2–reactive T cells and induced Ac1-11–specific T cells to produce IL-10 and TGF-β. This combined treatment resulted in full protection against EAE, which was not observed with either therapy alone. These findings imply that supplemental estrogen can enhance the efficacy of TCR-based immunotherapy for autoimmune diseases that predominate in females.

Authors

Halina Offner, Kirsten Adlard, Alex Zamora, Arthur A. Vandenbark

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T-cell and antibody responses in treated and control Tg mice challenged ...
T-cell and antibody responses in treated and control Tg mice challenged to develop EAE. (a) Proliferation responses of lymph node cells to Ac1-11 and BV8S2 protein in naive male and female Tg mice. Note decreased female response to BV8S2 protein. (b) Proliferation and cytokine responses to Ac1-11 of splenocytes from control and treated Tg females sampled at the peak of EAE (day 15). Note striking increase in production of IL-10 and TGF-β in mice treated with both BV8S2 protein and estrus levels of estrogen. (c) Proliferation and cytokine responses to BV8S2 protein of splenocytes from control and treated Tg females sampled at the peak of EAE (day 15). Note increased production of IL-10 in mice treated with BV8S2 protein, estrus levels of estrogen, or both agents. (d) Serum antibody responses to Ac1-11 in control and treated Tg females (day 29). Note decreased IgG2a antibody in estrogen or combined treatment groups. (a) Composite data from 14 mice per group. (b, c, and d) Representative of two to four separate experiments. ASignificant difference between control and experimental (P < 0.0001); Bsignificant difference between control and experimental (P < 0.01).