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Search Results to John E Harris MD, PhD

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Investigating contributions of both melanocytes and immune cells to vitiligo

John HarrisThe goal of my laboratory is to better understand what causes vitiligo in order to develop new treatments.

Vitiligo is an autoimmune disease that results in the appearance of white spots on the skin. It affects 0.5-2% of the population (about 1/100 people) regardless of race and gender, and can be psychologically devastating for patients due to its disfiguring appearance. The white spots are due to the destruction of melanocytes by T cells. As a physician-scientist, I treat patients with vitiligo and also manage a laboratory that is focused on studying the disease.

In the lab, we focus on two aspects of vitiligo:

VIT HandsFirst, we study how abnormal, “stressed” melanocytes alert the immune system to their presence. We believe that, once stressed, melanocytes produce signals that recruit T cells to the skin, which then find the melanocytes and kill them.

Second, we study how the T cells detect these signals, enter the skin, find the melanocytes, and kill them.

We use four major systems to answer these questions:

First, we use a mouse model of vitiligo that we developed, where the mice get spots of vitiligo on their ears, tails, feet and noses. Examining these mice from many angles, their disease looks very much like human vitiligo. The benefit of this system is the powerful tools available to study diseases in mice.
Second, we are developing humanized mouse models of vitiligo, where we transfer human T cells, or both T cells and skin, from vitiligo patients to immunosuppressed mice that permit the growth of human tissues. The benefit of this system is the ability to study human T cells and skin, and it has the potential to test new treatments on human tissues before attempting clinical trials.
Third, since I manage a specialty clinic in vitiligo, I regularly collect skin and blood from willing donors to study these processes directly. The benefit of this approach is that we can study the key cells that participate in vitiligo directly from patients, without variables that may change them, including their transfer into mice.
Fourth, we are conducting a clinical trial to test an investigational new drug as a treatment for vitiligo.

Using these systems, we have identified one of the critical pathways used by T cells to crawl into the skin and find melanocytes. The first signal in the pathway is IFN-g, a protein made by immune cells, which acts as a powerful master switch to turn on immune responses. IFN-g then turns on CXCL10, which is required for the ability of T cells to find melanocytes and kill them. Imagine an ant that has found a new piece of food on the ground. The ant then lays a chemical trail that others follow to the food. CXCL10 acts like that chemical trail, promoting both proper localization of T cells to “find” the melanocytes, and also increases their determination to kill them. There are existing drugs that have been developed by pharmaceutical companies that block the ability of CXCL10 to function in humans, and so they may be effective treatments in vitiligo. (See PDF of this article: Click Here)

We have also begun to identify the signals produced by stressed melanocytes that activate immune cells. We believe that studying the communication between stressed melanocytes and immune cells will tell us how vitiligo gets started in the first place, and how to better prevent its onset and spread. Also part of this project is better understanding how chemicals in the environment cause stress in melanocytes. Certain chemicals are well known to cause vitiligo and make it worse, and it is likely that there are many more that we come into contact with every day (in chemical dyes, cleaning products, etc). While we can guess at which chemicals do this based on their chemical structure, we are using our systems to definitively identify the chemicals, so that patients can avoid them and companies can change the ingredients of their products.
 

 

Rotation Projects

Rotations:

  1. Targeting the IFN-g-chemokine axis for treatment of vitiligo: We are using our newly developed mouse model and human tissues from patients with vitiligo to identify the cytokines and chemokines that are expressed within the depigmenting skin and which skin cells produce them. We are using genetically modified mouse strains (knockouts, conditional knockouts, fluorescent reporter strains), and cytokine and chemokine neutralizing antibodies to identify the key proteins required for disease. This data will permit us to rationally develop and test new therapeutic agents.
  2. Understanding the proinflammatory signals generated by melanocytes under cellular stress. Melanocytes from vitiligo patients have intrinsic abnormalities, including cellular stress evidenced by increased production of reactive oxygen species (ROS) and activation of the unfolded protein response (UPR). The immune system has evolved to recognize this stress as damage-associated molecular patterns (DAMPs), which activate innate immunity. We are using human cells and tissues to determine how cellular stress, innate immunity, and adaptive immunity cooperate to initiate and perpetuate depigmentation in vitiligo.
  3. Developing a humanized mouse model of immune-skin interactions to serve as a pre-clinical bridge to clinical studies: We are developing a humanized mouse model of skin disease that consists of an immunodeficient mouse strain as a host for an autologous human skin graft and immune reconstitution in order to study mechanisms of inflammation in the skin, including allergic contact dermatitis, response to infection, tumor immunotherapy, and autoimmunity, all within a fully human environment. This model system will act as a pre-clinical bridge between mouse models and human clinical trials, providing an opportunity to test new treatments on human cells and tissues prior to initiating trials on patients.
  4. Tracking autoreactive T cell interactions within the skin: We are using fluorescently tagged CD8 T cells to track their cellular interactions within the skin using confocal microscopy. Future studies will adapt this model to investigate real-time migration and other movements of these cells within compartments of the skin.
  5. Clinical trial to test a novel treatment for vitiligo: We recently completed a clinical trial based on insights developed from our animal data to test a novel drug for its ability to treat vitiligo.
Rotation Projects

Rotations:

  1. Targeting the IFN-?-chemokine axis for treatment of vitiligo: We are using our newly developed mouse model and human tissues from patients with vitiligo to identify the cytokines and chemokines that are expressed within the depigmenting skin and which skin cells produce them. We are using genetically modified mouse strains (knockouts, conditional knockouts, fluorescent reporter strains), and cytokine and chemokine neutralizing antibodies to identify the key proteins required for disease. This data will permit us to rationally develop and test new therapeutic agents.
  2. Understanding the proinflammatory signals generated by melanocytes under cellular stress. Melanocytes from vitiligo patients have intrinsic abnormalities, including cellular stress evidenced by increased production of reactive oxygen species (ROS) and activation of the unfolded protein response (UPR). The immune system has evolved to recognize this stress as damage-associated molecular patterns (DAMPs), which activate innate immunity. We are using human cells and tissues to determine how cellular stress, innate immunity, and adaptive immunity cooperate to initiate and perpetuate depigmentation in vitiligo.
  3. Developing a humanized mouse model of immune-skin interactions to serve as a pre-clinical bridge to clinical studies: We are developing a humanized mouse model of skin disease that consists of an immunodeficient mouse strain as a host for an autologous human skin graft and immune reconstitution in order to study mechanisms of inflammation in the skin, including allergic contact dermatitis, response to infection, tumor immunotherapy, and autoimmunity, all within a fully human environment. This model system will act as a pre-clinical bridge between mouse models and human clinical trials, providing an opportunity to test new treatments on human cells and tissues prior to initiating trials on patients.
  4. Tracking real-time autoreactive T cell migration and interactions within the skin: We are using fluorescently/bioluminescently tagged CD8 T cells to track their movements and interactions within the skin in live mice, using real-time confocal microscopy and bioluminescent imaging. Initial studies will focus on the role of cytokines and chemokines in T cell migration within the skin.
  5. Clinical trial to test a novel treatment for vitiligo: We are in the early stages of developing a clinical trial based on insights developed from our animal data to test a novel drug for its ability to treat vitiligo.

One or more keywords matched the following items that are connected to Harris, John

Item TypeName
Academic Article A mouse model of vitiligo with focused epidermal depigmentation requires IFN-? for autoreactive CD8? T-cell accumulation in the skin.
Concept Vitiligo
Academic Article CXCL10 is critical for the progression and maintenance of depigmentation in a mouse model of vitiligo.
Academic Article Innate immune mechanisms in vitiligo: danger from within.
Academic Article Vitiligo and alopecia areata: apples and oranges?
Academic Article Simvastatin prevents and reverses depigmentation in a mouse model of vitiligo.
Academic Article Melanocyte Regeneration in Vitiligo Requires WNT beneath their Wings.
Academic Article Cellular stress and innate inflammation in organ-specific autoimmunity: lessons learned from vitiligo.
Academic Article Interfering with the IFN-?/CXCL10 pathway to develop new targeted treatments for vitiligo.
Academic Article Rapid skin repigmentation on oral ruxolitinib in a patient with coexistent vitiligo and alopecia areata (AA).
Academic Article Vitiligo is not a cosmetic disease.
Academic Article Understanding autoimmunity of vitiligo and alopecia areata.
Academic Article IFN-? in Vitiligo, Is It the Fuel or the Fire?
Academic Article Understanding mechanisms of autoimmunity through translational research in vitiligo.
Academic Article Sampling Serum in Patients With Vitiligo to Measure Disease Activity in the Skin.
Academic Article Keratinocyte-Derived Chemokines Orchestrate T-Cell Positioning in the Epidermis during Vitiligo and May Serve as Biomarkers of Disease.
Academic Article A double-blind, placebo-controlled, phase-II clinical trial to evaluate oral simvastatin as a treatment for vitiligo.
Academic Article CXCR3 Depleting Antibodies Prevent and Reverse Vitiligo in Mice.
Academic Article The Vitiligo Working Group recommendations for narrowband ultraviolet B light phototherapy treatment of vitiligo.
Academic Article Suction blistering the lesional skin of vitiligo patients reveals useful biomarkers of disease activity.
Academic Article Chemical-Induced Vitiligo.
Academic Article Vitiligo Pathogenesis and Emerging Treatments.
Academic Article Optimizing Vitiligo Management: Past, Present, and Future.
Academic Article Current and emerging treatments for vitiligo.
Academic Article New discoveries in the pathogenesis and classification of vitiligo.
Academic Article Vitiligo.
Academic Article Antibody blockade of IL-15 signaling has the potential to durably reverse vitiligo.
Academic Article Vitiligo-like depigmentation in patients receiving programmed cell death-1 inhibitor reflects active vitiligo.
Academic Article Repigmentation in vitiligo using the Janus kinase inhibitor tofacitinib may require concomitant light exposure.
Academic Article Treatment with Modified Heat Shock Protein Repigments Vitiligo Lesions in Sinclair Swine.
Academic Article Resident memory and recirculating memory T cells cooperate to maintain disease in a mouse model of vitiligo.
Academic Article Mouse Model for Human Vitiligo.
Academic Article Use of permanent hair dyes and risk of vitiligo in women.
Academic Article Vitiligo: Mechanistic insights lead to novel treatments.
Academic Article Patient satisfaction and physician productivity in shared medical appointments for vitiligo.
Academic Article Validation of a Physicians Global Assessment (PGA) tool for vitiligo extent: results of an international vitiligo expert meeting.
Academic Article The Role of Memory CD8+ T Cells in Vitiligo.
Academic Article Standardizing serial photography for assessing and monitoring vitiligo: a core set of international recommendations for essential clinical and technical specifications.
Academic Article Proceeding Report of the Second Vitiligo International Symposium (VIS)- November 9-10, 2018, Detroit, Michigan, USA.
Academic Article Vitiligo: Mechanisms of Pathogenesis and Treatment.
Academic Article JAK inhibitors reverse vitiligo in mice but do not deplete skin resident memory T cells.
Academic Article Ruxolitinib cream for treatment of vitiligo: a randomised, controlled, phase 2 trial.
Academic Article Type I interferon signaling limits viral vector priming of CD8+ T cells during initiation of vitiligo and melanoma immunotherapy.

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