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CD137 costimulatory T cell receptor engagement reverses acute disease in lupus-prone NZB x NZW F1 mice.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2003 May; Vol. 111 (10), pp. 1505-18. - Publication Year :
- 2003
-
Abstract
- Systemic lupus erythematosus (SLE) is a CD4(+) T cell-dependent, immune complex-mediated, autoimmune disease that primarily affects women of childbearing age. Generation of high-titer affinity-matured IgG autoantibodies, specific for double-stranded DNA and other nuclear antigens, coincides with disease progression. Current forms of treatment of SLE including glucocorticosteroids are often inadequate and induce severe side effects. Immunological approaches for treating SLE in mice using anti-CD4 mAb's or CTLA4-Ig and anti-CD154 mAb's have proven to be effective. However, like steroid treatment, these regimens induce global immunosuppression, and their withdrawal allows for disease progression. In this report we show that lupus-prone NZB x NZW F(1) mice given three injections of anti-CD137 (4-1BB) mAb's between 26 and 35 weeks of age reversed acute disease, blocked chronic disease, and extended the mice's lifespan from 10 months to more than 2 years. Autoantibody production in recipients was rapidly suppressed without inducing immunosuppression. Successful treatment could be traced to the fact that NZB x NZW F(1) mice, regardless of their age or disease status, could not maintain pathogenic IgG autoantibody production in the absence of continuous CD4(+) T cell help. Our data support the hypothesis that CD137-mediated signaling anergized CD4(+) T cells during priming at the DC interface.
- Subjects :
- Acute Disease
Adoptive Transfer
Animals
Antibodies, Antinuclear blood
Antibody Formation drug effects
Antigens, CD
Autoantibodies blood
Autoantibodies drug effects
B-Lymphocytes drug effects
B-Lymphocytes immunology
CD4-Positive T-Lymphocytes drug effects
CD4-Positive T-Lymphocytes immunology
CD4-Positive T-Lymphocytes metabolism
CD4-Positive T-Lymphocytes transplantation
Chronic Disease
Crosses, Genetic
Dendritic Cells immunology
Dendritic Cells transplantation
Disease Models, Animal
Immunoglobulin G blood
Immunoglobulin M blood
Interleukin-2 biosynthesis
Interleukin-4 biosynthesis
Lupus Erythematosus, Systemic blood
Lupus Erythematosus, Systemic immunology
Mice
Mice, Inbred BALB C
Mice, Inbred NZB
Mice, Inbred Strains
Proteinuria prevention & control
Receptors, Nerve Growth Factor immunology
Receptors, Tumor Necrosis Factor immunology
Treatment Outcome
Tumor Necrosis Factor Receptor Superfamily, Member 9
Antibodies, Monoclonal therapeutic use
Lupus Erythematosus, Systemic drug therapy
Receptors, Nerve Growth Factor antagonists & inhibitors
Receptors, Tumor Necrosis Factor antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9738
- Volume :
- 111
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 12750400
- Full Text :
- https://doi.org/10.1172/JCI17662