However, which, if any, of these signalling mechanisms is necessary or sufficient for acantholysis, their exact involvement in causing acantholysis, or whether they are activated as a result of acantholysis, remains to be determined. In order to reduce anti-desmoglein selleck inhibitor 3 autoantibody synthesis, only agents that are known to suppress antibody production, alter antibody action, inhibit antibody binding to antigen or encourage antibody catabolism have a rational basis for therapeutic use in PV. However, only a limited number of drugs have this effect, and none is restricted to desmoglein autoantibodies. Several uncontrolled clinical studies [49,50] and a recent well-designed

double-blind placebo-controlled study [26] have demonstrated the efficacy of IVIG in patients with moderate to severe pemphigus disease. The influence of IVIG was correlated strongly with the clinical status and the reduction of desmogleins 1 and 3 titres [51,52]. This treatment is limited, however, by the low cost-efficiency ratio of IgG and the extremely problematic worldwide shortage in plasma. We speculated that the manipulation of the idiotypic network by anti-idiotypic antibodies contained in IVIG [13,14,53] selleck may

be the main mechanism of action of the drug in the treatment of pemphigus, and that owing to the relatively low amount of specific anti-idiotypic antibodies in commercial IVIG preparations, isolating

pathogenic autoantibodies of PV might be more effective. Our premise was based on earlier studies by Blank et al. [54–56], which showed that this approach was very effective in an experimental model of anti-phospholipid syndrome and systemic lupus erythematosus. Other groups reported greater benefit for IVIG specific to anti-acetylcholin receptor than native IVIG in the treatment of rats with Fossariinae myasthenia gravis [57]. Moreover, our earlier work showed that F(ab)2 fragments were as efficient as the native antibodies in treating experimental PV, whereas Fc fragments were ineffective [27]. In the present study, we prepared polyclonal anti-desmogleins 1 and 3 anti-idiotypic antibodies by affinity-purifying commercial IVIG on a column constructed of scFv against desmogleins 1 and 3, and then tested the efficacy of this preparation in the most frequently used animal model of pemphigus. Our preparation was able to suppress the autoantibody response (no intercellular IgG deposition, no acantholysis) and the development of blisters and erosions using a 66-fold lower IgG dose than commercial IVIG. The same low dose of IVIG had no effect. Theoretically, the configuration of IVIG anti-idiotypic antibodies may resemble the structure of the antigen itself and induce the disease. We ruled out this hypothesis by showing that injection of PV-sIVIG did not induce the disease.