A new, spontaneous mouse model for autoimmune vitiligo has been created by introducing a human T cell receptor to human tyrosinase (h3T) into mice, combined with transgenic expression of the associated human HLA-A*0201 molecule. Resulting h3TA2 mice develop rapid, symmetrical and progressive depigmentation of the pelage during adolescence, and cytotoxicity of circulating mouse T cells towards pigment cells, including human HLA-A2+ melanocytes and melanoma cells, is independent of CD4 or CD8 expression. This model is very suited to devise means of interfering with an ongoing immune response to melanocytes. The hypothesis to be tested within the current proposal is that encouraging a regulatory T cell response while interfering with a contribution for inflammatory Th17 in actively depigmenting mice can halt the progression of vitiligo. Preliminary data show that regulatory T cells, important to prevent autoimmune responses, are virtually lacking from the skin of human vitiligo patients. Likewise, in the mouse model, a reduced number of Treg was detectable in the circulation of actively depigmenting mice. The first objective of the current proposal is to further characterize and optimize the new mouse model with reference to the development and abundance of CD4+ T cell subsets and regulatory responses, and by further 'humanizing'the model by crossbreeding the h3TA2 model to mice that express melanocytes in the epidermis as a consequence of SCF expression under the k14 promotor. Next it is proposed to increase the abundance of Treg in depigmenting mice by adoptive transfer of traceable FoxP3-EGFP+ Treg, and by driving the development of naive T cells towards a regulatory phenotype and function by creating a favorable cytokine environment primarily under increased TGF-beta and reduced IL-6 concentrations, which will be addressed both in culture, and within the mouse model. Under the 3rd and final aim, regulatory T cells will be redirected towards the skin by overexpressing relevant skin homing receptors including but not limited to CCR-8 and CLA and/or chemokines such as CCL-1, in order to favor immune inhibition there where depigmentation is taking place.

Public Health Relevance

The project entitled 'modulating tolerance in a spontaneous mouse model of autoimmune vitiligo'addresses the lack of a regulatory T cell response in vitiligo by elevating Treg concentrations and supporting their skin homing properties while interfering with inflammatory Th17 within a newly generated mouse model that encompasses a human transgenic T cell receptor reactive with a tyrosinase peptide recognized in the context of HLA-A2: the h3T-A2 mouse.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR057643-04
Application #
8457139
Study Section
Special Emphasis Panel (ZRG1-MOSS-A (02))
Program Officer
Cibotti, Ricardo
Project Start
2010-09-01
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
4
Fiscal Year
2013
Total Cost
$305,132
Indirect Cost
$60,944
Name
Loyola University Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153
Eby, Jonathan M; Kang, Hee-Kap; Klarquist, Jared et al. (2014) Immune responses in a mouse model of vitiligo with spontaneous epidermal de- and repigmentation. Pigment Cell Melanoma Res 27:1075-85
Webb, Kirsten C; Eby, Jonathan M; Hariharan, Vidhya et al. (2014) Enhanced bleaching treatment: opportunities for immune-assisted melanocyte suicide in vitiligo. Exp Dermatol 23:529-33
Kesarwani, Pravin; Al-Khami, Amir A; Scurti, Gina et al. (2014) Promoting thiol expression increases the durability of antitumor T-cell functions. Cancer Res 74:6036-47
Husain, Shahid; Abdul, Yasir; Webster, Christine et al. (2014) Interferon-gamma (IFN-?)-mediated retinal ganglion cell death in human tyrosinase T cell receptor transgenic mouse. PLoS One 9:e89392
Iuga, Aurel O; McGuire, Maura J (2014) Adherence and health care costs. Risk Manag Healthc Policy 7:35-44
Chatterjee, Shilpak; Eby, Jonathan M; Al-Khami, Amir A et al. (2014) A quantitative increase in regulatory T cells controls development of vitiligo. J Invest Dermatol 134:1285-94
Keerthivasan, Shilpa; Suleiman, Reem; Lawlor, Rebecca et al. (2011) Notch signaling regulates mouse and human Th17 differentiation. J Immunol 187:692-701