My career goal is to better understand the mechanisms of autoimmunity in vitiligo, develop new treatments using animal models, and translate these treatments to human patients. The time and support provided by this award will be critical for me to learn the skills necessary to generate a humanized mouse model of vitiligo, test anti-human cytokine and chemokine blocking antibodies as novel treatments, and gain an understanding of clinical and translational research strategies for future studies. Observations made in my vitiligo clinic prompted me to hypothesize that skin-derived signals recruit T cells to lesional skin. Using a new mouse model of vitiligo developed during my postdoctoral training, I discovered that IFN-3-dependent chemokines were critical for depigmentation and T cell recruitment to the skin. Based on these studies, I hypothesize that IFN-3 and downstream chemokines are required for the development of human vitiligo and that the IFN-3-chemokine axis is an ideal target for new treatments. Animal models do not always reflect human disease mechanisms. A vitiligo model with human tissues is needed to bridge the gap between basic studies in mice and clinical trials in patients. My primary mentor, Dr. Dale Greiner, is the pioneer of a humanized mouse with a functional human immune system. Human skin grafted onto this host will complete a fully human immune-skin axis in which to investigate skin immunity. We hypothesize that this humanized mouse will provide a functional immune-skin axis in which potential new therapies for skin diseases can be tested prior to clinical studies. My research strategy is as follows:
Specific Aim 1 : Generate and validate a humanized mouse model for skin-immune system functional interactions. Immunodeficient mice will receive autologous human skin and peripheral blood lymphocytes. The functionality of the immune-skin axis will be validated by skin-specific immune challenges.
Specific Aim 2 : Test neutralizing antibodies against human IFN-3, CXCL9, CXCL10, and CXCR3 as new treatments for vitiligo induced in the humanized mouse system. Vitiligo will be induced in humanized mice. Members of the human IFN-3-chemokine axis will be neutralized with blocking antibodies to determine if they are effective treatments for vitiligo. Future studies will test these antibodies in clinical trials. The training plan in this proposal takes advantage of coursework and a strong mentoring team (Drs. Greiner, Harlan, Turka, Rothstein, and Le Poole) with broad expertise (humanized mouse models, models of autoimmunity, translational/clinical research in autoimmunity, controlling T cell responses in vivo, and basic/translational research in vitiligo) to fill key gaps in my previous training to advance my career goals. This proposal will introduce the first mouse model with a fully immune-skin axis, providing a system to investigate human immune-skin interactions and test new treatments for vitiligo in a human environment. Future studies will focus on translating these findings to clinical studies in order to treat patients with this devastating disease.

Public Health Relevance

Inflammatory skin diseases affect over 600 million people in the United States and cost the healthcare industry over $27 billion annually. Much of the research that is currently performed to better understand these conditions and develop new treatments is done on animal models of skin disease because human studies are expensive, time-consuming, and potentially harmful. Because studies using animals do not always fully represent human disease, we will establish a mouse model of inflammatory skin diseases that consists of human skin and immune cells, and use this novel humanized system to directly test new treatments for vitiligo, a psychologically devastating skin disease.

Agency
National Institute of Health (NIH)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AR061437-04
Application #
8707973
Study Section
Special Emphasis Panel (ZAR1)
Program Officer
Cibotti, Ricardo
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Worcester
State
MA
Country
United States
Zip Code
01655
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Rashighi, Mehdi; Agarwal, Priti; Richmond, Jillian M et al. (2014) CXCL10 is critical for the progression and maintenance of depigmentation in a mouse model of vitiligo. Sci Transl Med 6:223ra23
Harris, John E (2013) Vitiligo and alopecia areata: apples and oranges? Exp Dermatol 22:785-9
Malhotra, Nidhi; Narayan, Kavitha; Cho, Ok Hyun et al. (2013) A network of high-mobility group box transcription factors programs innate interleukin-17 production. Immunity 38:681-93
Chin, Michael S; Freniere, Brian B; Fakhouri, Sami et al. (2013) Cavitation rheology as a potential method for in vivo assessment of skin biomechanics. Plast Reconstr Surg 131:303e-305e
Richmond, Jillian M; Frisoli, Michael L; Harris, John E (2013) Innate immune mechanisms in vitiligo: danger from within. Curr Opin Immunol 25:676-82
Harris, John E; Harris, Tajie H; Weninger, Wolfgang et al. (2012) A mouse model of vitiligo with focused epidermal depigmentation requires IFN-ýý for autoreactive CD8ýýý T-cell accumulation in the skin. J Invest Dermatol 132:1869-76