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

J Clin Invest. 2000 Jul;106(1):91-101. doi: 10.1172/JCI9244.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abatacept
  • Adenoviridae / immunology
  • Amino Acid Sequence
  • Animals
  • Antibodies, Antinuclear / biosynthesis
  • Antibodies, Viral / blood
  • Antigens, CD
  • Antigens, Differentiation / blood
  • Antigens, Differentiation / therapeutic use*
  • B-Lymphocytes / physiology*
  • Base Sequence
  • CTLA-4 Antigen
  • Cell Line
  • Female
  • Hybridomas / immunology
  • Immunoconjugates*
  • Immunoglobulins / biosynthesis
  • Immunosuppressive Agents / therapeutic use*
  • Kidney / pathology
  • Lupus Erythematosus, Systemic / drug therapy*
  • Lupus Erythematosus, Systemic / immunology
  • Lupus Erythematosus, Systemic / pathology
  • Mice
  • Mice, Inbred NZB
  • Molecular Sequence Data
  • T-Lymphocytes / physiology*


  • Antibodies, Antinuclear
  • Antibodies, Viral
  • Antigens, CD
  • Antigens, Differentiation
  • CTLA-4 Antigen
  • Ctla4 protein, mouse
  • Immunoconjugates
  • Immunoglobulins
  • Immunosuppressive Agents
  • Abatacept