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Use of autoantigen-knockout mice in developing an active autoimmune disease model for pemphigus.

ABSTRACT: The development of experimental models of active autoimmune diseases can be difficult due to tolerance of autoantigens, but knockout mice, which fail to acquire tolerance to the defective gene product, provide a useful tool for this purpose. Using knockout mice lacking desmoglein 3 (Dsg3), the target antigen of pemphigus vulgaris (PV), we have generated an active disease model for this autoantibody-mediated disease. Dsg3(-/-) mice, but not Dsg3(+/-) littermates, produced anti-Dsg3 IgG that binds native Dsg3, when immunized with recombinant mouse Dsg3. Splenocytes from the immunized Dsg3(-/-) mice were then adoptively transferred into Rag-2(-/-) immunodeficient mice expressing Dsg3. Anti-Dsg3 IgG was stably produced in the recipient mice for more than 6 months without further boosting. This IgG bound to Dsg3 in vivo and disrupted the cell-cell adhesion of keratinocytes. Consequently, the recipient mice developed erosions in their oral mucous membranes with typical histologic findings of PV. In addition, the recipient mice showed telogen hair loss, as found in Dsg3(-/-) mice. Collectively, the recipient mice developed the phenotype of PV due to the pathogenic anti-Dsg3 IgG. This model will be valuable for developing novel therapeutic strategies. Furthermore, our approach can be applied broadly for the development of various autoimmune disease models.

SUBMITTER: Amagai M

PROVIDER: S-EPMC292455 | biostudies-literature | 2000 Mar

REPOSITORIES: biostudies-literature

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Use of autoantigen-knockout mice in developing an active autoimmune disease model for pemphigus.

Amagai M M Tsunoda K K Suzuki H H Nishifuji K K Koyasu S S Nishikawa T T

The Journal of clinical investigation 20000301 5

The development of experimental models of active autoimmune diseases can be difficult due to tolerance of autoantigens, but knockout mice, which fail to acquire tolerance to the defective gene product, provide a useful tool for this purpose. Using knockout mice lacking desmoglein 3 (Dsg3), the target antigen of pemphigus vulgaris (PV), we have generated an active disease model for this autoantibody-mediated disease. Dsg3(-/-) mice, but not Dsg3(+/-) littermates, produced anti-Dsg3 IgG that binds ...[more]

PMID: 10712434

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Project description:BACKGROUND:Introduction and diffusion of new disease management programs in healthcare is usually slow, but active theory-driven implementation seems to outperform other implementation strategies. However, we have only scarce evidence on the feasibility and real effect of such strategies in complex primary care settings where municipalities, general practitioners and hospitals should work together. The Central Denmark Region recently implemented a disease management program for chronic obstructive pulmonary disease (COPD) which presented an opportunity to test an active implementation model against the usual implementation model. The aim of the present paper is to describe the development of an active implementation model using the Medical Research Council's model for complex interventions and the Chronic Care Model. METHODS:We used the Medical Research Council's five-stage model for developing complex interventions to design an implementation model for a disease management program for COPD. First, literature on implementing change in general practice was scrutinised and empirical knowledge was assessed for suitability. In phase I, the intervention was developed; and in phases II and III, it was tested in a block- and cluster-randomised study. In phase IV, we evaluated the feasibility for others to use our active implementation model. RESULTS:The Chronic Care Model was identified as a model for designing efficient implementation elements. These elements were combined into a multifaceted intervention, and a timeline for the trial in a randomised study was decided upon in accordance with the five stages in the Medical Research Council's model; this was captured in a PaTPlot, which allowed us to focus on the structure and the timing of the intervention. The implementation strategies identified as efficient were use of the Breakthrough Series, academic detailing, provision of patient material and meetings between providers. The active implementation model was tested in a randomised trial (results reported elsewhere). CONCLUSION:The combination of the theoretical model for complex interventions and the Chronic Care Model and the chosen specific implementation strategies proved feasible for a practice-based active implementation model for a chronic-disease-management-program for COPD. Using the Medical Research Council's model added transparency to the design phase which further facilitated the process of implementing the program. TRIAL REGISTRATION:http://www.clinicaltrials.gov/(NCT01228708).

Dataset Information

Use of autoantigen-knockout mice in developing an active autoimmune disease model for pemphigus.

Publications

Use of autoantigen-knockout mice in developing an active autoimmune disease model for pemphigus.

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