Efficacy of intravenous immunoglobulin (IVIG) affinity-purified anti-desmoglein anti-idiotypic antibodies in the treatment of an experimental model of pemphigus vulgaris.
Pemphigus vulgaris is a rare life-threatening autoimmune bullous disease caused by immunoglobulin G (IgG) autoantibodies directed against desmogleins 1 and 3. Previously, we showed that intravenous immunoglobulin (IVIG) ameliorates anti-desmoglein-induced experimental pemphigus vulgaris in newborn naive mice. The aim of this study was to examine the efficacy of anti-anti-desmoglein-specific IVIG in a similar model. Pemphigus-vulgaris-specific IVIG (PV-sIVIG) was affinity-purified from IVIG on a column of single-chain variable fragment (scFv) anti-desmogleins 1 and 3. The anti-idiotypic activity of PV-sIVIG was confirmed by enzyme-linked immunosorbent assay, inhibition assay. After induction of pemphigus by injection of anti-desmogleins 1 and 3 scFv to newborn mice, the animals were treated with PV-sIVIG, IVIG (low or high dose) or IgG from a healthy donor (n = 10 each). The skin was examined 24-48 h later, and samples of affected areas were analysed by histology and immunofluorescence. In vitro study showed that PV-sIVIG significantly inhibited anti-desmogleins 1 and 3 scFv binding to recombinant desmoglein-3 in a dose-dependent manner. Specificity was confirmed by inhibition assay. In vivo analysis revealed cutaneous lesions of pemphigus vulgaris in mice injected with normal IgG (nine of 10 mice) or low-dose IVIG (nine of 10 mice), but not in mice treated with PV-sIVIG (none of 10) or high-dose IVIG (none of 10). On immunopathological study, PV-sIVIG and regular IVIG prevented the formation of acantholysis and deposition of IgG in intercellular spaces. In conclusion, the PV-sIVIG preparation is more effective than native IVIG in inhibiting anti-desmoglein-induced pemphigus vulgaris in mice and might serve as a future therapy in patients with the clinical disease.
Mimouni
D
D
Department of Medicine B and Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel Hashomer, Israel.
Blank
M
M
Payne
A S
AS
Anhalt
G J
GJ
Avivi
C
C
Barshack
I
I
David
M
M
Shoenfeld
Y
Y
D000051:Acantholysis / Q000517:prevention & control; D000818:Animals; D000831:Animals, Newborn; D000888:Antibodies, Anti-Idiotypic / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology / Q000302:isolation & purification; D001323:Autoantibodies / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D051183:Desmoglein 1 / Q000276:immunology; D051184:Desmoglein 3 / Q000276:immunology; D004195:Disease Models, Animal; D000939:Epitopes; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology / Q000302:isolation & purification; D051379:Mice; D008810:Mice, Inbred C57BL; D010392:Pemphigus / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D015202:Protein Engineering; D057127:Single-Chain Antibodies / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D000888:Antibodies, Anti-Idiotypic; D001323:Autoantibodies; D051183:Desmoglein 1; D051184:Desmoglein 3; D000939:Epitopes; D016756:Immunoglobulins, Intravenous; D057127:Single-Chain Antibodies