Bullous pemphigoid (BP), the most common autoimmune blistering disease, is caused by autoantibodies against type XVII collagen (COL17). To establish an active stable BP animal model that demonstrates the persistent inflammatory skin lesions initiated by the anti-human COL17 Abs, we used COL17-humanized (COL17m−/−,h+) mice that we recently produced. First, we generated immunodeficient Rag-2−/−/COL17–humanized mice by crossing Rag-2−/− mice with COL17-humanized mice. Then, splenocytes from wild-type mice that had been immunized by grafting of human COL17-transgenic mouse skin were transferred into Rag-2−/−/COL17–humanized mice. The recipient mice continuously produced anti-human COL17 IgG Abs in vivo and developed blisters and erosions corresponding to clinical, histological, and immunopathological features of BP, although eosinophil infiltration, one of the characteristic histological findings observed in BP patients, was not detected in the recipients. Although the depletion of CD8+ T cells from the immunized splenocytes was found to produce no effects in the recipients, the depletion of CD4+ T cells as well as CD45R+ B cells was found to inhibit the production of anti-human COL17 IgG Abs in the recipients, resulting in no apparent clinical phenotype. Furthermore, we demonstrated that cyclosporin A significantly suppressed the production of anti-human COL17 IgG Abs and prevented the development of the BP phenotype in the treated recipients. Although this model in an immunodeficient mouse does not exactly reproduce the induction mechanism of BP in human patients, this unique experimental system targeting humanized pathogenic Ag allows us to investigate ongoing autoimmune responses to human molecules in experimental animal models.

Activation of the complement cascade via the classical pathway is required for the development of tissue injury in many autoantibody-mediated diseases. It therefore makes sense to block the pathological action of autoantibodies by preventing complement activation through inhibition of autoantibody binding to the corresponding pathogenic autoantigen using targeted Fab antibody fragments. To achieve this, we use bullous pemphigoid (BP) as an example of a typical autoimmune disease. Recombinant Fabs against the non-collagenous 16th-A domain of type XVII collagen , the main pathogenic epitope for autoantibodies in BP , were generated from antibody repertoires of BP patients by phage display. Two Fabs , Fab-B4 and Fab-19 , showed marked ability to inhibit the binding of BP autoantibodies and subsequent complement activation in vitro. In the in vivo experiments using type XVII collagen humanized BP model mice , these Fabs protected mice against BP autoantibody-induced blistering disease. Thus , the blocking of pathogenic epitopes using engineered Fabs appears to demonstrate efficacy and may lead to disease-specific treatments for antibody-mediated autoimmune diseases.

Oral lichen planus (LP) is a severe, painful form of LP, and is often resistant to topical corticosteroid therapy. Recently, open trials demonstrated that topical tacrolimus therapy was effective for the treatment of chronic erosive oral LP. We report two cases with severe recalcitrant erosive oral LP, who dramatically benefited from topical tacrolimus therapy. In case 1, a 64-year-old man presented with a 5-month history of painful erosions on his entire lower lip and buccal mucosa. Physical and histological examination confirmed a diagnosis of LP. He experienced rapid relief from pain and a dramatic improvement was obtained within 5 weeks of topical tacrolimus treatment. No significant irritation was observed and blood tacrolimus level was kept within a safe level (2.5 ng/mL). In case 2, a 68-year-old man developed painful erosions on his right lower lip and buccal mucosa 2 months before his arrival at our hospital. Histopathological analysis confirmed a diagnosis of oral LP. He experienced a rapid dramatic improvement of both lesions within 4 weeks of the start of tacrolimus application. No significant irritation or recurrence was observed. Thus, topical tacrolimus is suggested as a well-tolerated, effective therapy for oral LP.

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