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CTLA4Ig inhibits T cell–dependent B-cell maturation in murine systemic lupus erythematosus
Masahiko Mihara, … , Yun Gu, Anne Davidson
Masahiko Mihara, … , Yun Gu, Anne Davidson
Published January 1, 2000
Citation Information: J Clin Invest. 2000;106(1):91-101. https://doi.org/10.1172/JCI9244.
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Article

CTLA4Ig inhibits T cell–dependent B-cell maturation in murine systemic lupus erythematosus

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Abstract

Long-term administration of CTLA4Ig prevents the onset of disease in systemic lupus erythematosus–prone (SLE-prone) NZB/NZW F1 mice. To determine the mechanism of this effect, we engineered an adenovirus that expresses murine CTLA4Ig. Administration of a single high dose of this virus results in long-term expression of CTLA4Ig in the serum and absence of an immune response to the adenoviral vector. We administered Ad-CTLA4Ig to 19- to 22-week-old NZB/NZW F1 mice and evaluated the effect on anti-DNA antibody–producing B cells. We show that CTLA4Ig has a beneficial effect on murine SLE for as long as it is present in the serum. This effect is associated with decreased expansion of both the IgM and IgG autoreactive B-cell population, inhibition of immunoglobulin class switching, decreased frequency and altered pattern of somatic mutation, and a marked decrease in the numbers of activated CD4-positive T cells. In contrast, intrinsic B-cell hyperreactivity and the survival of plasma cells in the bone marrow, both of which are less dependent on T-cell help, appear to be unaffected by CTLA4Ig. High-dose CTLA4Ig did not induce permanent tolerance in this autoimmune disease model. Furthermore, although the mice survived in a conventional housing facility, treatment with Ad-CTLA4Ig was immunosuppressive.

Authors

Masahiko Mihara, Irene Tan, Yelena Chuzhin, Bhoompally Reddy, Lalbachan Budhai, Aton Holzer, Yun Gu, Anne Davidson

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Figure 2

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Cumulative percentage of mice in each group that developed fixed protein...
Cumulative percentage of mice in each group that developed fixed proteinuria (a) or died (b) at each time point. One mouse in each of the low- and high-dose groups died of a surgical complication at the age of 47 and 36 weeks, respectively, and was removed from the analysis. a: High-dose versus IgG2a or untreated control, P = 0.0001; b: high-dose versus IgG2a or untreated control, P = 0.0002.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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