Because of the skin's accessibility, autoimmune diseases of the epidermis, such as vitiligo, are amenable to study using minimally invasive techniques. In addition, potential therapeutic agents can be tested locally. The long-term goal of this project is to develop a novel fusion protein useful for treating autoimmune disorders of the epidermis. Activated T cells, which cause autoimmune destruction, express an immunosuppressive receptor on their surface called Programmed Death-1 (PD-1). PD-Ligand 1 (PD-L1) binds to the PD-1 receptor to generate signals that inactivate T cells. This pathway is important in many physiologic systems, including maintenance of chronic viral infections, tumor immune evasion, and normal tolerance in the prevention of autoimmunity. We have developed a potentially therapeutic molecule consisting of the extracellular domain of PD-L1 that is fused to a non-pathogenic antibody against desmoglein 3 (Dsg3). Because Dsg3 is constitutively expressed on mouse and human keratinocytes, intradermal or intravenous injection of this fusion protein targets the epidermis. By targeting delivery of the immunosuppressive protein PD-L1 to the epidermis, we will determine if we can suppress T cell activation in the epidermis and halt progression of epidermal inflammation or prevent its initial triggering. To test this hypothesis, we will first determine if the fusion protein suppresses a human allogeneic T cell response to cultured primary keratinocytes in vitro. Then, we will test whether local or systemic administration of this fusion protein can arrest onset or progression of disease in a mouse model of vitiligo. Finally, we will confirm that the fusion protein targets human keratinocytes in human skin xenografts on mice. This research has the potential to impact clinical care for patients with autoimmune disorders involving the epidermis and other epithelia. The project will provide preliminary results for an NIH K-award or new investigator RO1 application.

Public Health Relevance

If successful, this project will lead to a new approach to therapy of many epidermal autoimmune diseases, and consequently, a fertile field of research in immunodermatology. The nature of this delivery method also allows for simple and rapid screening of potentially immunosuppressive proteins for effective immunomodulation in epidermal inflammation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Center Core Grants (P30)
Project #
5P30AR057217-05
Application #
8499269
Study Section
Special Emphasis Panel (ZAR1-KM-D)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$24,967
Indirect Cost
$9,362
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Ellebrecht, Christoph T; Bhoj, Vijay G; Nace, Arben et al. (2016) Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. Science 353:179-84
Lo, Agnes S; Mao, Xuming; Mukherjee, Eric M et al. (2016) Pathogenicity and Epitope Characteristics Do Not Differ in IgG Subclass-Switched Anti-Desmoglein 3 IgG1 and IgG4 Autoantibodies in Pemphigus Vulgaris. PLoS One 11:e0156800
Cho, Michael Jeffrey; Ellebrecht, Christoph T; Hammers, Christoph M et al. (2016) Determinants of VH1-46 Cross-Reactivity to Pemphigus Vulgaris Autoantigen Desmoglein 3 and Rotavirus Antigen VP6. J Immunol 197:1065-73
Billings, Paul C; Sanzari, Jenine K; Kennedy, Ann R et al. (2015) Comparative analysis of colorimetric staining in skin using open-source software. Exp Dermatol 24:157-9
Suzuki, Daisuke; Sahu, Raju; Leu, N Adrian et al. (2015) The carboxy-terminus of p63 links cell cycle control and the proliferative potential of epidermal progenitor cells. Development 142:282-90
Gay, Denise L; Yang, Chao-Chun; Plikus, Maksim V et al. (2015) CD133 expression correlates with membrane beta-catenin and E-cadherin loss from human hair follicle placodes during morphogenesis. J Invest Dermatol 135:45-55
Ortiz, Myrna L; Kumar, Vinit; Martner, Anna et al. (2015) Immature myeloid cells directly contribute to skin tumor development by recruiting IL-17-producing CD4+ T cells. J Exp Med 212:351-67
Agarwal, Priti; Rashighi, Mehdi; Essien, Kingsley I et al. (2015) Simvastatin prevents and reverses depigmentation in a mouse model of vitiligo. J Invest Dermatol 135:1080-8
Wong, Waihay J; Richardson, Theresa; Seykora, John T et al. (2015) Hypoxia-inducible factors regulate filaggrin expression and epidermal barrier function. J Invest Dermatol 135:454-61
Hammers, Christoph M; Chen, Jing; Lin, Chenyan et al. (2015) Persistence of anti-desmoglein 3 IgG(+) B-cell clones in pemphigus patients over years. J Invest Dermatol 135:742-9

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