CD137 costimulatory T cell receptor engagement reverses acute disease in lupus-prone NZB x NZW F1 mice.
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.
Department of Surgery and Emory Vaccine Center, School of Medicine, School of Public Health, Emory University, Atlanta, Georgia, USA.
Juergen
J
Foell
Simona
S
Strahotin
Shawn P
SP
O'Neil
Megan M
MM
McCausland
Carolyn
C
Suwyn
Michael
M
Haber
Praveen N
PN
Chander
Abhijit S
AS
Bapat
Xiao-Jie
XJ
Yan
Nicholas
N
Chiorazzi
Michael K
MK
Hoffmann
Robert S
RS
Mittler
D000208:Acute Disease; D019264:Adoptive Transfer; D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000917:Antibody Formation / Q000187:drug effects; D015703:Antigens, CD; D001323:Autoantibodies / Q000097:blood / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D002908:Chronic Disease; D003433:Crosses, Genetic; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation; D004195:Disease Models, Animal; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D007376:Interleukin-2 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008814:Mice, Inbred NZB; D008815:Mice, Inbred Strains; D011507:Proteinuria / Q000517:prevention & control; D017475:Receptors, Nerve Growth Factor / Q000037:antagonists & inhibitors* / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors* / Q000276:immunology; D016896:Treatment Outcome; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D001323:Autoantibodies; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007376:Interleukin-2; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C505715:Tnfrsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D015847:Interleukin-4