Effect of in vivo Hydroxychloroquine and ex vivo Anti-BDCA2 mAb Treatment on pDC IFNα Production From Patients Affected With Cutaneous Lupus Erythematosus

Abstract

Objective: Plasmacytoid dendritic cells (pDCs) are a major source of Type-I Interferon (IFN-I), a key driver in cutaneous lupus erythematosus (CLE). Currently evaluated in Phase II clinical trial, 24F4A (BIIB059) is an antibody targeting BDCA2, an inhibitory receptor expressed on pDCs. Given that Hydroxychloroquine (HCQ), a widely-used CLE therapy, and 24F4A are both able to inhibit pDC-derived IFN-I production; this study aimed to determine whether 24F4A would show an additional inhibitory effect on pDC response after ex vivo or in vivo treatment with HCQ. Methods: The effect of 24F4A on pDC-derived IFNα was measured from peripheral blood mononuclear cells (PBMC) either from healthy donors in presence or absence of HCQ or from CLE patients clinically exposed to various levels of HCQ. TLR7, TLR7/8, and TLR9 agonists (ssRNA, R848, and CpG-A) were used for pDC stimulation. Results: PDCs were the only producers of IFNα in response to CpG-A, R848, and ssRNA stimulation in PBMC cultures. CLE patients with higher levels of blood HCQ showed lower ex vivo pDC responses to CpG-A, but not R848 or ssRNA. In contrast, 24F4A reduced the amount of IFNα produced by pDCs from CLE patients in response to all TLR agonists, irrespective of the blood HCQ level. Conclusion: Our findings reveal that clinically-relevant HCQ concentrations partially inhibit the pDC response to TLR9 and weakly affect the response to TLR7/8 stimulation. 24F4A robustly inhibits pDC responses even in the presence of HCQ, highlighting its unique potential to disrupt pDC disease relevant biology, which could provide additional therapeutic benefit for CLE patients.

Neue Erkenntnisse zur Pathogenese des SLE und ihre Auswirkungen auf die Entwicklung neuer Therapie-Konzepte

“…Glucocorticoide in hohen Dosen sind in der Lage, die Typ-I Interferon-Signatur auszulöschen [29]. Der therapeutische Effekt der Antimalaria-Mittel Chloroquin und Hydroxychloroquin ist zumindest teilweise auf eine Hemmung der Typ-I Interferon-Freisetzung durch pDC über ihre antagonistische Wirkung auf die Toll-like Rezeptoren TLR7 und 9 zurückzuführen [30,31]. Auch Proteasom-Inhibitoren scheinen über die TLR-Blockade die Typ-I Interferon-Freisetzung zu hemmen [13,32].…”

“…Auch Proteasom-Inhibitoren scheinen über die TLR-Blockade die Typ-I Interferon-Freisetzung zu hemmen [13,32]. pDC exprimieren den Rezeptor BDCA2, deren Ligation mit einem monoklonalen Antikörper die Freisetzung von Typ-I Interferonen blockieren kann [30,33].…”

Current Paradigms of Tolerogenic Dendritic Cells and Clinical Implications for Systemic Lupus Erythematosus

“…BCDA-2 is a specific marker of pDCs that plays a role in antigen internalization and presentation [178]. Targeting BCDA-2 on pDCs from SLE and cutaneous lupus erythematous patients, respectively, restored the tolerogenic state of pDCs by limiting type I IFN production which may enhance the clinical efficacy of SLE treatments [162,163,164]. In addition, activation of CXCR4 on pDCs by a small molecule, IT1t, stimulated immunoregulatory signaling in pDCs and prevented glomerulonephritis in a pristine-induced lupus-like model [165].…”

Azithromycin and glucosamine may amplify the type 1 interferon response to RNA viruses in a complementary fashion

“…It should be noted that hydroxychloroquine’s impact on endosomes may lessen the efficacy of the viral RNA-induced, TLR7-mediated endosomal pathway of type 1 interferon induction. [ 32 , 33 ] (Indeed, enhanced TLR7-mediated signaling triggered by endosomal uptake autoantibody/RNA complexes in plasmacytoid dendritic cells may be a key driver of systemic lupus erythematosus, and hydroxychloroquine’s down-regulatory impact on this may help to rationalize its efficacy in this disorder [ [34] , [35] , [36] ].) For which reason, azithromycin’s (and glucosamine’s) up-regulatory impact on interferon induction by cytosolic double-stranded RNA receptors may provide compensation for a flaw in hydroxychloroquine’s anti-viral activity – a fact which may well be pertinent to the complementarity of these two drugs in COVID-19 therapy.…”