Previous work has shown that many Ags recognized on melanomas by patient-derived T lymphocytes are derived from differentiation proteins expressed in melanocytes (MDP). T cells directed against MDP-derived Ags have also been found in the skin of patients with autoimmune vitiligo, and vitiligo often accompanies spontaneous or immunotherapy based melanoma regression. Thus, self-tolerance to MDP is incomplete, and the mechanisms that regulate it are relevant to both autoimmune vitiligo development and effective melanoma immunity. We have developed animal and cellular reagents to analyze self-tolerance and autoimmunity to a model MDP derived from murine tyrosinase (Tyr369) that is highly homologous to its human counterpart. Using recently developed Tyr369-specific TCR transgenic mice we have established that self- tolerance to this Ag is based on peripheral, not central, deletion. However, the localization of this process and the nature of the cells presenting Tyr369 are different from those in any other current model. Despite the occurrence of self-tolerance, the animals also develop neonatal depigmentation that shows both regional localization and bilateral symmetry, followed by a progressive delocalized process in adults. This pattern shows similarities to autoimmune vitiligo in humans, and is without precedent in other experimental models. The primary goal of this application is to use this unique model to investigate the cells and molecules that control the development of self-tolerance and autoimmunity to this endogenous melanocyte Ag. The primary hypothesis driving all aspects of the work is that autoimmunity and self-tolerance in this model are determined by changes in the quality of T cell activation and/or control of T cell access to the epidermis and hair follicle.
Our aims are: 1) To identify the APC that present Tyr369 and are responsible for deletional self-tolerance and autoimmune vitiligo;2) To distinguish the skin-associated factors that promote development of localized neonatal/epidermal vitiligo and disseminated/hair follicle adult vitiligo in FH TCR transgenic mice;3) To identify the mechanisms that tip the balance from tolerance to vitiligo after adoptive transfer of IL-2 supported Tyr369 specific T cells into sublethally irradiated recipients. The knowledge gained will provide insight into factors that control the development of vitiligo, and that distinguish it from other autoimmune diseases of the skin.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI068836-03
Application #
7640786
Study Section
Special Emphasis Panel (ZRG1-IMM-H (02))
Program Officer
Rothermel, Annette L
Project Start
2007-07-01
Project End
2012-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
3
Fiscal Year
2009
Total Cost
$575,287
Indirect Cost
Name
University of Virginia
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Rouhani, Sherin J; Eccles, Jacob D; Riccardi, Priscila et al. (2015) Roles of lymphatic endothelial cells expressing peripheral tissue antigens in CD4 T-cell tolerance induction. Nat Commun 6:6771
Rouhani, Sherin J; Eccles, Jacob D; Tewalt, Eric F et al. (2014) Regulation of T-cell Tolerance by Lymphatic Endothelial Cells. J Clin Cell Immunol 5:
Cohen, Jarish N; Tewalt, Eric F; Rouhani, Sherin J et al. (2014) Tolerogenic properties of lymphatic endothelial cells are controlled by the lymph node microenvironment. PLoS One 9:e87740
Henrich, Timothy J; Kuritzkes, Daniel R (2013) HIV-1 entry inhibitors: recent development and clinical use. Curr Opin Virol 3:51-7
Brinkman, C Colin; Rouhani, Sherin J; Srinivasan, Nithya et al. (2013) Peripheral tissue homing receptors enable T cell entry into lymph nodes and affect the anatomical distribution of memory cells. J Immunol 191:2412-25
Tewalt, Eric F; Cohen, Jarish N; Rouhani, Sherin J et al. (2012) Lymphatic endothelial cells - key players in regulation of tolerance and immunity. Front Immunol 3:305
Tewalt, Eric F; Cohen, Jarish N; Rouhani, Sherin J et al. (2012) Lymphatic endothelial cells induce tolerance via PD-L1 and lack of costimulation leading to high-level PD-1 expression on CD8 T cells. Blood 120:4772-82
Cohen, Jarish N; Guidi, Cynthia J; Tewalt, Eric F et al. (2010) Lymph node-resident lymphatic endothelial cells mediate peripheral tolerance via Aire-independent direct antigen presentation. J Exp Med 207:681-8
Gregg, Randal K; Nichols, Lisa; Chen, Yiming et al. (2010) Mechanisms of spatial and temporal development of autoimmune vitiligo in tyrosinase-specific TCR transgenic mice. J Immunol 184:1909-17
Kuritzkes, Daniel R (2009) HIV-1 entry inhibitors: an overview. Curr Opin HIV AIDS 4:82-7

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