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    John E Harris MD, PhD

    TitleAssociate Professor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentMedicine
    AddressUniversity of Massachusetts Medical School
    55 Lake Avenue North
    Worcester MA 01655
      Other Positions
      InstitutionUMMS - School of Medicine
      DepartmentMedicine
      DivisionDermatology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentImmunology and Virology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentInterdisciplinary Graduate Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentMD/PhD Program

        Overview 
        Narrative

        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-?-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.


        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.




        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Rashighi M, Harris JE. Sampling Serum in Patients With Vitiligo to Measure Disease Activity in the Skin. JAMA Dermatol. 2016 Nov 1; 152(11):1187-1188.
          View in: PubMed
        2. Strassner JP, Harris JE. Understanding mechanisms of autoimmunity through translational research in vitiligo. Curr Opin Immunol. 2016 Oct 17; 43:81-88.
          View in: PubMed
        3. Chong SZ, Evrard M, Devi S, Chen J, Lim JY, See P, Zhang Y, Adrover JM, Lee B, Tan L, Li JL, Liong KH, Phua C, Balachander A, Boey A, Liebl D, Tan SM, Chan JK, Balabanian K, Harris JE, Bianchini M, Weber C, Duchene J, Lum J, Poidinger M, Chen Q, Rénia L, Wang CI, Larbi A, Randolph GJ, Weninger W, Looney MR, Krummel MF, Biswas SK, Ginhoux F, Hidalgo A, Bachelerie F, Ng LG. CXCR4 identifies transitional bone marrow premonocytes that replenish the mature monocyte pool for peripheral responses. J Exp Med. 2016 Oct 17; 213(11):2293-2314.
          View in: PubMed
        4. Rork JF, Rashighi M, Harris JE. Understanding autoimmunity of vitiligo and alopecia areata. Curr Opin Pediatr. 2016 Aug; 28(4):463-9.
          View in: PubMed
        5. Strassner JP, Rashighi M, Harris JE. Melanocytes in psoriasis: convicted culprit or bullied bystander? Pigment Cell Melanoma Res. 2016 May; 29(3):261-3.
          View in: PubMed
        6. Li JL, Lim CH, Tay FW, Goh CC, Devi S, Malleret B, Lee B, Bakocevic N, Chong SZ, Evrard M, Tanizaki H, Lim HY, Russell B, Renia L, Zolezzi F, Poidinger M, Angeli V, St John AL, Harris JE, Tey HL, Tan SM, Kabashima K, Weninger W, Larbi A, Ng LG. Neutrophils Self-Regulate Immune Complex-Mediated Cutaneous Inflammation through CXCL2. J Invest Dermatol. 2016 Feb; 136(2):416-24.
          View in: PubMed
        7. Harris JE. Cellular stress and innate inflammation in organ-specific autoimmunity: lessons learned from vitiligo. Immunol Rev. 2016 Jan; 269(1):11-25.
          View in: PubMed
        8. Harris JE, Rashighi M, Nguyen N, Jabbari A, Ulerio G, Clynes R, Christiano AM, Mackay-Wiggan J. Rapid skin repigmentation on oral ruxolitinib in a patient with coexistent vitiligo and alopecia areata (AA). J Am Acad Dermatol. 2016 Feb; 74(2):370-1.
          View in: PubMed
        9. Rashighi M, Harris JE. Interfering with the IFN-?/CXCL10 pathway to develop new targeted treatments for vitiligo. Ann Transl Med. 2015 Dec; 3(21):343.
          View in: PubMed
        10. Harris JE. Melanocyte Regeneration in Vitiligo Requires WNT beneath their Wings. J Invest Dermatol. 2015 Dec; 135(12):2921-3.
          View in: PubMed
        11. Ezzedine K, Sheth V, Rodrigues M, Eleftheriadou V, Harris JE, Hamzavi IH, Pandya AG. Vitiligo is not a cosmetic disease. J Am Acad Dermatol. 2015 Nov; 73(5):883-5.
          View in: PubMed
        12. Zhang R, Borges CM, Fan MY, Harris JE, Turka LA. Requirement for CD28 in Effector Regulatory T Cell Differentiation, CCR6 Induction, and Skin Homing. J Immunol. 2015 Nov 1; 195(9):4154-61.
          View in: PubMed
        13. Harris JE. IFN-? in Vitiligo, Is It the Fuel or the Fire? Acta Derm Venereol. 2015 Jul; 95(6):643-4.
          View in: PubMed
        14. Agarwal P, Rashighi M, Essien KI, Richmond JM, Randall L, Pazoki-Toroudi H, Hunter CA, Harris JE. Simvastatin prevents and reverses depigmentation in a mouse model of vitiligo. J Invest Dermatol. 2015 Apr; 135(4):1080-8.
          View in: PubMed
        15. Richmond JM, Harris JE. Immunology and skin in health and disease. Cold Spring Harb Perspect Med. 2014 Dec; 4(12):a015339.
          View in: PubMed
        16. Rashighi M, Agarwal P, Richmond JM, Harris TH, Dresser K, Su MW, Zhou Y, Deng A, Hunter CA, Luster AD, Harris JE. CXCL10 is critical for the progression and maintenance of depigmentation in a mouse model of vitiligo. Sci Transl Med. 2014 Feb 12; 6(223):223ra23.
          View in: PubMed
        17. Harris JE. Vitiligo and alopecia areata: apples and oranges? Exp Dermatol. 2013 Dec; 22(12):785-9.
          View in: PubMed
        18. Richmond JM, Frisoli ML, Harris JE. Innate immune mechanisms in vitiligo: danger from within. Curr Opin Immunol. 2013 Dec; 25(6):676-82.
          View in: PubMed
        19. Malhotra N, Narayan K, Cho OH, Sylvia KE, Yin C, Melichar H, Rashighi M, Lefebvre V, Harris JE, Berg LJ, Kang J. A network of high-mobility group box transcription factors programs innate interleukin-17 production. Immunity. 2013 Apr 18; 38(4):681-93.
          View in: PubMed
        20. Chin MS, Freniere BB, Fakhouri S, Harris JE, Lalikos JF, Crosby AJ. Cavitation rheology as a potential method for in vivo assessment of skin biomechanics. Plast Reconstr Surg. 2013 Feb; 131(2):303e-305e.
          View in: PubMed
        21. Harris JE, Harris TH, Weninger W, Wherry EJ, Hunter CA, Turka LA. A mouse model of vitiligo with focused epidermal depigmentation requires IFN-? for autoreactive CD8? T-cell accumulation in the skin. J Invest Dermatol. 2012 Jul; 132(7):1869-76.
          View in: PubMed
        22. Harris JE, Marshak-Rothstein A. Editorial: Interfering with B cell immunity. J Leukoc Biol. 2011 Jun; 89(6):805-6.
          View in: PubMed
        23. Ramón HE, Cejas PJ, LaRosa D, Rahman A, Harris JE, Zhang J, Hunter C, Choi Y, Turka LA. EGR-2 is not required for in vivo CD4 T cell mediated immune responses. PLoS One. 2010 Sep 23; 5(9):e12904.
          View in: PubMed
        24. Harris JE, Seykora JT, Lee RA. Renbok phenomenon and contact sensitization in a patient with alopecia universalis. Arch Dermatol. 2010 Apr; 146(4):422-5.
          View in: PubMed
        25. Bishop KD, Harris JE, Mordes JP, Greiner DL, Rossini AA, Czech MP, Phillips NE. Depletion of the programmed death-1 receptor completely reverses established clonal anergy in CD4(+) T lymphocytes via an interleukin-2-dependent mechanism. Cell Immunol. 2009; 256(1-2):86-91.
          View in: PubMed
        26. Harris JE, Sutton DA, Rubin A, Wickes B, De Hoog GS, Kovarik C. Exophiala spinifera as a cause of cutaneous phaeohyphomycosis: case study and review of the literature. Med Mycol. 2009 Feb; 47(1):87-93.
          View in: PubMed
        27. Harris JE, Bishop KD, Phillips NE, Mordes JP, Greiner DL, Rossini AA, Czech MP. Early growth response gene-2, a zinc-finger transcription factor, is required for full induction of clonal anergy in CD4+ T cells. J Immunol. 2004 Dec 15; 173(12):7331-8.
          View in: PubMed
        28. Hemavathy K, Guru SC, Harris J, Chen JD, Ip YT. Human Slug is a repressor that localizes to sites of active transcription. Mol Cell Biol. 2000 Jul; 20(14):5087-95.
          View in: PubMed
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