Immunomodulatory effects of repository corticotropin injection (H.P. Acthar® gel) on the MRL/lpr model of lupus

Abstract Repository corticotropin injection (RCI) is indicated during exacerbations or as maintenance therapy for systemic lupus erythematosus (SLE), yet studies on the mechanisms of action have been limited. This study was performed to evaluate the effects of RCI on the MRL/lpr mouse model of lupus. Mice were administered RCI at 160, 400, and 800 U/kg s.c. every other day beginning on week 13 (after onset of clinical symptoms) until week 23. Urine and blood were collected for analysis of proteinuria and anti-dsDNA IgG antibody. In-life assessments were made weekly for lymphadenopathy and skin lesions. Kidneys and spleens were harvested for assessment of histopathology and leukocyte phenotyping performed by FACS. The results demonstrate that RCI at 400 and 800 U/kg significantly inhibited the development of proteinuria compared to placebo (p < 0.01, Friedman test). Development of lymphadenopathy (at 400 and 800 U/kg, p < 0.0001 and p < 0.001 Friedman test, respectively) and skin lesions (at 160 and 400 U/kg, p < 0.0001 and p < 0.05 Friedman test) were both reduced by drug treatment. RCI also significantly inhibited the generation of anti-dsDNA IgG antibodies at week 22 by 74%, 85%, and 90% at 160, 400 and 800 U/kg, respectively. Summed kidney histopathology scores were significantly reduced 67% and 74% at the 400 U/kg and 800 U/kg doses, respectively. Frequencies of specific spleen cell phenotypes were affected by RCI treatment. Immature B cells increased whereas transitional, marginal zone and germinal center B cells decreased. B220+ double negative T cell effector cells were also decreased. These results demonstrate the efficacy of RCI in the MRL/lpr lupus model and describe its immunomodulatory activity against specific lymphocyte subsets.