Direct effects of HP Acthar Gel on human B lymphocyte activation in vitro.
BACKGROUND
Both clinical experience and experimental evidence have suggested that Adrenocorticotropic hormone (ACTH) might directly exert immunomodulatory effects not dependent on adrenal steroidogenesis.


METHODS
The direct effects of H.P. Acthar Gel (Acthar), a repository preparation containing a porcine ACTH analogue, on human B lymphocyte function were studied in vitro using peripheral blood B cells isolated using anti-CD19 coated magnetic beads and activated by interleukin 4 (IL-4) and CD40 ligand (CD40L). Analysis of expression of messenger RNA (mRNA) encoding activation-induced cytidine deaminase (AICDA) was carried out by quantitative real-time polymerase chain reaction (PCR). Cellular proliferation was assessed by a flow cytometric technique using intracellular staining with carboxyfluorescein succinimidyl ester (CFSE). Immunoglobulin G (IgG) production was measured in cell supernatants using an immunoassay.


RESULTS
Acthar was found to exert acute, dose-dependent inhibitory effects on IL-4/CD40L-mediated induction of the expression of activation-induced cytidine deaminase (AICDA) after 24 hours, as well as sustained inhibition of B cell proliferation and IgG production during five more days of culture, without deleterious effects on B cell viability.


CONCLUSIONS
These experiments demonstrate that Acthar can exert direct effects on the humoral immune system independent of any role in the regulation of adrenal steroidogenesis. Although the impact of these findings on clinical disease was not evaluated in this study, these data support the therapeutic potential of Acthar for the management of autoimmune diseases characterized by B cell activation and aberrant humoral immune function.
Division of Rheumatology, The Pennsylvania State University, College of Medicine, 500 University Drive, Hershey, 17033, PA, USA. nolsen@hmc.psu.edu.
Nancy J
NJ
Olsen
Autoimmune and Rare Diseases Business, Mallinckrodt Pharmaceuticals, 6011 University Boulevard, Ellicott City, 21043, MD, USA. Dima.Decker@mallinckrodt.com.
Dima A
DA
Decker
Autoimmune and Rare Diseases Business, Mallinckrodt Pharmaceuticals, 6011 University Boulevard, Ellicott City, 21043, MD, USA. Paul.Higgins@mallinckrodt.com.
Paul
P
Higgins
Autoimmune and Rare Diseases Business, Mallinckrodt Pharmaceuticals, 6011 University Boulevard, Ellicott City, 21043, MD, USA. Patrice.Becker@mallinckrodt.com.
Patrice M
PM
Becker
Division of Rheumatology, The Pennsylvania State University, College of Medicine, 500 University Drive, Hershey, 17033, PA, USA. cmcaloose@hmc.psu.edu.
Carl A
CA
McAloose
Division of Endocrinology, Diabetes, and Metabolism, The Pennsylvania State University, College of Medicine, 500 University Drive, Hershey, PA, 17033, USA. abenko@hmc.psu.edu.
Ann L
AL
Benko
Division of Endocrinology, Diabetes, and Metabolism, The Pennsylvania State University, College of Medicine, 500 University Drive, Hershey, PA, 17033, USA. wkovacs@hmc.psu.edu.
William J
WJ
Kovacs
D000324:Adrenocorticotropic Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000328:Adult; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects; D003564:Cytidine Deaminase / Q000096:biosynthesis; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007118:Immunoassay; D066298:In Vitro Techniques; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013552:Swine; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D000324:Adrenocorticotropic Hormone; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase