Mechanism of action of combined short-term CTLA4Ig and anti-CD40 ligand in murine systemic lupus erythematosus.
Short-term combination therapy with the costimulatory antagonists CTLA4Ig and anti-CD40 ligand induces prolonged suppression of disease onset in New Zealand Black/New Zealand White F(1) systemic lupus erythematosus-prone mice. To determine the mechanism for this effect, 20- to 22-wk-old New Zealand Black/New Zealand White F(1) mice were treated with six doses each of CTLA4Ig and anti-CD40 ligand Ab over 2 wk. Combination-treated mice, but not mice treated with either agent alone, had prolonged survival and the production of pathogenic IgG anti-dsDNA Ab was suppressed. Twenty weeks after completion of treatment the frequency of activated B cells producing anti-dsDNA Ab was decreased, and the abnormal transition of T cells from the naive to the memory compartment was blocked. Combination treatment partially suppressed class switching and decreased the frequency of somatic mutations in the V(H)BW-16 gene, which is expressed by pathogenic anti-DNA Abs. Treated mice were still able to respond to the hapten oxazolone when it was given 8 wk after treatment initiation, and they mounted a somatically mutated IgG anti-oxazolone response that was noncross-reactive with dsDNA. Fifty to 60% of previously treated mice, but only 14% of previously untreated mice, responded within 2-3 wk to a second course of therapy given at the onset of fixed proteinuria and remained well for a further 3-4 mo. Although this treatment had no immediate effect on serum anti-dsDNA Abs or on the abnormal T cell activation observed in sick mice, 25% of treated mice lived for >18 mo compared with 5% of untreated controls. These results suggest that the effect of costimulatory blockade in remission induction must be mediated by a different mechanism than is demonstrated in the disease prevention studies.
Wang
Xiaobo
X
Departments of. Medicine and Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461.
Huang
Weiqing
W
Mihara
Masahiko
M
Sinha
Jayashree
J
Davidson
Anne
A
D000069594:Abatacept; D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D000974:Antibodies, Antinuclear / Q000096:biosynthesis / Q000235:genetics; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology*; D060908:CTLA-4 Antigen; D004247:DNA / Q000276:immunology; D006825:Hybridomas; D018796:Immunoconjugates; D017578:Immunoglobulin Class Switching; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007700:Kinetics; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000628:therapy; D051379:Mice; D008814:Mice, Inbred NZB; D008969:Molecular Sequence Data; D009154:Mutation; D010081:Oxazolone / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013154:Spleen / Q000276:immunology; D016896:Treatment Outcome
D000906:Antibodies; D000974:Antibodies, Antinuclear; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D011993:Recombinant Fusion Proteins; D023201:CD40 Ligand; D010081:Oxazolone; D000069594:Abatacept; D004247:DNA