Immunomodulatory effects of H.P. Acthar Gel on B cell development in the NZB/W F1 mouse model of systemic lupus erythematosus

Abstract

H.P. Acthar Gel® (Acthar) is a highly purified repository gel preparation of adrenocorticotropic hormone (ACTH1-39), a melanocortin peptide that can bind and activate specific receptors expressed on a range of systemic lupus erythematosus (SLE)-relevant target cells and tissues. This study was performed to evaluate the effects of Acthar in a mouse model of SLE, using an F1 hybrid of the New Zealand Black and New Zealand White strains (NZB/W F1). Twenty-eight week old NZB/W F1 mice with established autoimmune disease were treated with Acthar, Placebo Gel (Placebo), or prednisolone and monitored for 19 weeks. Outcomes assessed included disease severity (severe proteinuria, ≥ 20% body weight loss, or prostration), measurement of serial serum autoantibody titers, terminal spleen immunophenotyping, and evaluation of renal histopathology. Acthar treatment was linked with evidence of altered B cell differentiation and development, manifested by a significant reduction in splenic B cell follicular and germinal center cells, and decreased levels of circulating total and anti-double-stranded DNA (IgM, IgG, and IgG2a) autoantibodies as compared with Placebo. Additionally, Acthar treatment resulted in a significant decrease of proteinuria, reduced renal lymphocyte infiltration, and attenuation of glomerular immune complex deposition. These data suggest that Acthar diminished pathogenic autoimmune responses in the spleen, peripheral blood, and kidney of NZB/W F1 mice. This is the first preclinical evidence demonstrating Acthar's potential immunomodulatory activity and efficacy in a murine model of systemic lupus erythematosus.

Efficacy and tolerability of repository corticotropin injection in patients with persistently active SLE: results of a phase 4, randomised, controlled pilot study

“…Acthar Gel, Mallinckrodt ARD, Ellicott City, Maryland, USA) contains a highly purified porcine ACTH analogue formulated to allow prolonged release after intramuscular or subcutaneous injection, and is approved by the US Food and Drug Administration for use during exacerbations and as maintenance therapy in selected patients with SLE 8. In a murine model of SLE, this preparation has been shown to reduce B-cell differentiation and development, and to decrease circulating autoantibodies, proteinuria, renal lymphocyte infiltration and glomerular immune complex deposition 9. Similarly, other investigators demonstrated that α-MSH attenuated manifestations of pristane-induced lupus in mice 10.…”

Model Roles of the Hypothalamo-Neurohypophysial System in Neuroscience Study

“…Thus, the HPA axis and the HNS form a complex feedback loop while functioning collaboratively in responses to immunologic challenges. Consistently, the central inhibition of VP on the proliferative response of splenic T-cells could be due to VP activation of HPA axis in the brain that directly inhibits splenic responses to pathologic challenges [103]. Nevertheless, it remains to explore the subtle interactions between these immune-associated neuropeptide systems.…”

Generation and characterization of highly purified canine Schwann cells from spinal nerve dorsal roots as potential new candidates for transplantation strategies

“…After detachment of the cells from the microtitre plates by administration of cold PBS − supplemented with 1% penicillin/streptomycin and accutase, cells were centrifuged at 200× g for 5 min at 4 °C, resuspended in complete medium and washed once with PBS − supplemented with FCS (1%; Sigma‐Aldrich) and sodium acid (0.01%; Sigma‐Aldrich) (membrane immunofluorescence buffer; MIF‐buffer). Human TrueStain (FcX; BioLegend, San Diego, CA, USA) was added to the cell suspension after centrifugation (200× g for 6 min at 10 °C) for blocking non‐specific antibody binding at Fc receptors (Decker et al, ). Mouse immunoglobulin G1 (MCA 928; Serotec, MorphoSys AbD, Düsseldorf, Germany) (isotype control) (Stein et al, ) and anti‐p75 NTR antibodies (1:5) were added to the cells and incubated for 30 min at 4 °C.…”