ORCID ID

https://orcid.org/0000-0003-2465-5872

Publication Date

2021-06-17

Document Type

Doctoral Dissertation

Academic Program

Millennium PhD

Department

Department of Dermatology

First Thesis Advisor

John Harris, MD, PhD

Keywords

Vitiligo, vitiligo surgery, melanocyte keratinocyte transplantation, MKTP, CD8+ T cells, lymphocytes, biomarkers, Ablative Laser Resurfacing, Fractional Laser Resurfacing, Er. Yag Laser

Abstract

The Melanocyte Keratinocyte Transplantation Procedure (MKTP) is an effective surgical replacement of lost melanocytes in recalcitrant vitiligo and pigmentary skin disorders. However, it is only effective in stable vitiligo lesions because active autoimmunity destroys the newly transplanted melanocytes. Despite careful selection of candidates based on the reported clinical stability, the success of the procedure is still unpredictable. MKTP candidates with non-segmental, segmental, and mixed vitiligo, as well as hypopigmented scars and Piebaldism patients were enrolled to our studies. Our aim was first, to investigate the possible immunological mechanisms responsible for the unpredictable post- transplantation outcomes, including T cell subsets and inflammatory chemokines, by correlating these biomarkers with clinical phenotypes, duration of stability, and surgical outcomes. We used suction blister biopsy, a minimally invasive technique that we developed to sample human skin. Moreover, we quantified transplanted melanocytes in the suspension using flow cytometry. Following MKTP, we corelated these biomarkers to the repigmentation score. We found that CD8+ T cells remain in some clinically stable vitiligo lesions, correlate negatively with the post-surgical score of repigmentation, and inversely impact the durability of the responses. Interestingly, the number of transplanted melanocytes in the suspension and the duration of stability do not have prognostic roles. Based on our findings and in a second group of patients, we suppressed the activity of T cells to enhance the outcomes of MKTP. We used Ruxolitinib, JAK1/2 inhibitor, in a triple blinded randomized controlled within subject study, in comparison with Tacrolimus (a calcineurin inhibitor and the standard of care treatment in vitiligo) as well as placebo control. We found lower T cell infiltrate, lower chemokines, and better skin repigmentation in lesions treated with MKTP plus Ruxolitinib or Tacrolimus than in lesions treated with MKTP plus placebo. Lastly, we compared two different types of laser in preparation of the recipient skin for MKTP - ablative versus fractional Er:YAG laser. We found that the ablative laser is combined with minimal CD8+ T cell epidermal infiltrate and superior repigmentation score in comparison to more infiltrate and lower repigmentation score with the fractional laser. Taken together, these results from our studies provide novel insight to predict the optimal surgical candidates and will improve surgical outcomes. It advances the treatment of vitiligo by uncovering the impact of autoimmunity on the success of repigmentation and discovering new approaches to optimize the surgical treatment options in patients with vitiligo and pigmentary skin disorders.

DOI

10.13028/8kf4-k664

Rights and Permissions

Copyright is held by the author, with all rights reserved.

Available for download on Thursday, June 29, 2023

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