Tolerance Induction by the Blockade of CD40/CD154 Interaction in Pemphigus Vulgaris Mouse Model

Abstract

Pemphigus vulgaris (PV) is an autoimmune blistering disease caused by IgG autoantibodies against desmoglein 3 (Dsg3). We have recently developed an active disease mouse model for PV by adoptive transfer of splenocytes from Dsg3 À/À mice. The purpose of this study was to determine the role of CD40/CD154 interaction in the pathogenic antibody production and development of the disease in PV model mice. When anti-CD154 monoclonal antibody (mAb) was administered to recipient mice prior to adoptive transfer, anti-CD154 mAb almost completely blocked the anti-Dsg3 IgG production and prevented blister formation. The blockade of CD40/CD154 interaction induced tolerance against Dsg3 as the suppression of antibody production was observed through day 70, and it was maintained even after challenge by immunization with recombinant mouse Dsg3 or by adoptive transfer of immunized Dsg3 À/À splenocytes. Furthermore, the tolerance to Dsg3 was transferable because cotransfer of splenocytes from anti-CD154 mAb-treated mice and naı ¨ve Dsg3 À/À splenocytes significantly suppressed anti-Dsg3 IgG production in recipient mice. In contrast, when anti-CD154 mAb was injected after the mice had developed the PV phenotype, no significant suppression of the production of anti-Dsg3 IgG was observed. These findings indicate that the CD40/CD154 interaction is essential for the induction of pathogenic anti-Dsg3 IgG antibodies and that antigen-specific immune-regulatory cells induced by anti-CD154 mAb would hold a therapeutic option for autoimmune diseases.

Individual and epistatic effects of genetic polymorphisms of B-cell co-stimulatory molecules on susceptibility to pemphigus foliaceus

“…55 Besides, the blockade of the CD40-CD40L interaction by treatment with anti-CD40L monoclonal antibody inhibited the production of anti-Dsg3 IgG as well as the development of the pemphigus vulgaris disease phenotype in a mouse model. 6 In summary, our results reveal that CD40L, CD40 and BLYS are important genes modulating the susceptibility to endemic PF. Slight influence, like we saw for CD40À1C4T and BLYSÀ871C4T SNPs individually, is the rule in complex diseases.…”

“…In vivo blockade of CD40 or CD40L suppresses the induction of autoimmune diseases in murines (for a review, see Howard and Miller 5 ), including in pemphigus vulgaris model mice. 6 Therefore, blockade of the CD40-CD40L interaction has been considered an attractive immunoregulatory strategy for the suppression of antibody production in autoimmune diseases.…”

Increased Serum Levels of Circulating CD40 Ligand in Patients with Bullous Pemphigoid: Preliminary Results

“…Likewise, the blockade of the pathway by anti-CD40L antibodies has ameliorated the clinical and laboratory parameters of nephritis in both mice [17,18,19,20] and humans [21]. Furthermore, it is of note that anti-CD40L antibody has recently been proved to be effective in a mouse PV model [22]. …”

Bullous Pemphigoid, Mucous Membrane Pemphigoid and Pemphigus Vulgaris: An Update on Pathobiology

“…CD40L (CD154) binding on activated T cells with CD40 on B cells is considered critical to the interaction of activated T and B cells. It has also been shown that anti-CD154 mAb is capable of blocking this interaction between CD40 and CD154, resulting in the suppression of anti-Dsg3 IgG production [85]. Future investigations into autoreactive T-cell regulators of B-cell antibody production are needed to shed light on more targeted therapeutic interventions.…”