CTLA4Ig inhibits T cell-dependent B-cell maturation in murine systemic lupus erythematosus.
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.
Mihara
M
M
Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA.
Tan
I
I
Chuzhin
Y
Y
Reddy
B
B
Budhai
L
L
Holzer
A
A
Gu
Y
Y
Davidson
A
A
D000069594:Abatacept; D000256:Adenoviridae / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis; D000914:Antibodies, Viral / Q000097:blood; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000097:blood / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000502:physiology*; D001483:Base Sequence; D060908:CTLA-4 Antigen; D002460:Cell Line; D005260:Female; D006825:Hybridomas / Q000276:immunology; D018796:Immunoconjugates; D007136:Immunoglobulins / Q000096:biosynthesis; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007668:Kidney / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008814:Mice, Inbred NZB; D008969:Molecular Sequence Data; D013601:T-Lymphocytes / Q000502:physiology*
D000974:Antibodies, Antinuclear; D000914:Antibodies, Viral; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007136:Immunoglobulins; D007166:Immunosuppressive Agents; D000069594:Abatacept