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Study of the mechanisms of melanocyte destruction in melanoma, halo nevi and vitiligo

Reinhart Speeckaert UGent (2012)
abstract
In this thesis we investigated the different aspects of the in vivo immune responses against benign and malignant melanocytes. The aim of this research project was to gain more insights into an adequate skin immunosurveillance of melanocytes. Therefore, we chose distinct models that reflect a depressed (melanoma), an efficient (halo nevi) and an overactive (vitiligo) immune response against melanocytes. In chapter 4.1 we assessed the role of indoleamine 2,3-dioxygenase (IDO) and Forkhead Box P3 (Foxp3) - both factors associated with immunosuppression - in the sentinel nodes of melanoma patients. High IDO expression was an independent prognostic factor of worse outcome in our study. This effect was more pronounced in sentinel negative patients, which suggests that a deficient immune response develops early in the disease process. An associated network of immunosuppression was confirmed by an enhanced percentage of Foxp3+ cells in sentinel nodes expressing IDO and higher CTLA-4 levels in the circulating regulatory T-cells of these patients. In chapter 4.2 we describe a patient with a history of melanoma and the dysplastic nevus syndrome who showed regression of almost all nevi. As the patient did not receive systemic therapy, this was most likely a spontaneous phenomenon. We found both in the regressing nevus as in the blood Gp100+ CD8+ T-cells, confirming the presence of an anti-melanocyte immune response. These findings substantiate the hypothesis that regressing nevi may be a sign of efficient immunosurveillance. In chapter 4.3 we investigated whether in analogy to melanoma-associated leukoderma, patients with multiple halo nevi show additional depigmentations not corresponding to classic vitiligo. We observed indeed in a subpopulation of halo nevi patients remarkable limited depigmentations, which developed at the same time of the halo nevi and did not progress over time. This phenomenon is most likely due to a subgroup of circulating melanocyte-specific T cells, which become active during the halo process for example due to release of oxidative factors (such as H2O2). Oxidative stress has earlier been shown to play a crucial role in the development of depigmentation by inducing a process of haptenation that elicits strong immune responses. In chapter 4.4 we developed an in vivo model to investigate koebner-induced depigmentation in vitiligo patients. This model lends itself to investigate the pathophysiological aspects of koebner-induced vitiligo and to assess the efficacy of therapeutic strategies. The results were reproducibly showing depigmentation after all 3 koebner induction methods, which could be prevented by anti-inflammatory treatment. Our pilot study pointed to tacrolimus and corticosteroids as significantly better inhibitors of the koebner process compared to pimecrolimus. In chapter 4.5 we investigated the clinical significance of Koebner’s phenomenon in vitiligo patients. Patients with Koebner’s phenomenon had more active vitiligo. They displayed a younger age of onset and had a higher affected body surface area. These patients were more susceptible for further depigmentation despite treatment. Moreover, patients with Koebner’s phenomenon due to friction had a marked enhanced frequency of thyroid disease. In conclusion, we believe this work contributes to the insights into the development of immune reactions against benign and malignant melanocytes. Therefore, it has implications both for melanoma, halo nevi and vitiligo.
Please use this url to cite or link to this publication:
author
promoter
UGent and UGent
organization
year
type
dissertation (monograph)
subject
pages
236 pages
publisher
Ghent University. Faculty of Medicine and Health Sciences
place of publication
Ghent, Belgium
defense location
Gent : UZ (auditorium C)
defense date
2012-07-09 17:30
language
English
UGent publication?
yes
classification
D1
additional info
dissertation consists of copyrighted material
copyright statement
I have transferred the copyright for this publication to the publisher
id
3002748
handle
http://hdl.handle.net/1854/LU-3002748
date created
2012-10-01 08:48:54
date last changed
2012-11-14 10:14:22
@phdthesis{3002748,
  abstract     = {In this thesis we investigated the different aspects of the in vivo immune responses against benign and malignant melanocytes. The aim of this research project was to gain more insights into an adequate skin immunosurveillance of melanocytes. Therefore, we chose distinct models that reflect a depressed (melanoma), an efficient (halo nevi) and an overactive (vitiligo) immune response against melanocytes.
In chapter 4.1 we assessed the role of indoleamine 2,3-dioxygenase (IDO) and Forkhead Box P3 (Foxp3) - both factors associated with immunosuppression - in the sentinel nodes of melanoma patients. High IDO expression was an independent prognostic factor of worse outcome in our study. This effect was more pronounced in sentinel negative patients, which suggests that a deficient immune response develops early in the disease process. An associated network of immunosuppression was confirmed by an enhanced percentage of Foxp3+ cells in sentinel nodes expressing IDO and higher CTLA-4 levels in the circulating regulatory T-cells of these patients.
In chapter 4.2 we describe a patient with a history of melanoma and the dysplastic nevus syndrome who showed regression of almost all nevi. As the patient did not receive systemic therapy, this was most likely a spontaneous phenomenon. We found both in the regressing nevus as in the blood Gp100+ CD8+ T-cells, confirming the presence of an anti-melanocyte immune response. These findings substantiate the hypothesis that regressing nevi may be a sign of efficient immunosurveillance.
In chapter 4.3 we investigated whether in analogy to melanoma-associated leukoderma, patients with multiple halo nevi show additional depigmentations not corresponding to classic vitiligo. We observed indeed in a subpopulation of halo nevi patients remarkable limited depigmentations, which developed at the same time of the halo nevi and did not progress over time. This phenomenon is most likely due to a subgroup of circulating melanocyte-specific T cells, which become active during the halo process for example due to release of oxidative factors (such as H2O2). Oxidative stress has earlier been shown to play a crucial role in the development of depigmentation by inducing a process of haptenation that elicits strong immune responses.
In chapter 4.4 we developed an in vivo model to investigate koebner-induced depigmentation in vitiligo patients. This model lends itself to investigate the pathophysiological aspects of koebner-induced vitiligo and to assess the efficacy of therapeutic strategies. The results were reproducibly showing depigmentation after all 3 koebner induction methods, which could be prevented by anti-inflammatory treatment. Our pilot study pointed to tacrolimus and corticosteroids as significantly better inhibitors of the koebner process compared to pimecrolimus.
In chapter 4.5 we investigated the clinical significance of Koebner{\textquoteright}s phenomenon in vitiligo patients. Patients with Koebner{\textquoteright}s phenomenon had more active vitiligo. They displayed a younger age of onset and had a higher affected body surface area. These patients were more susceptible for further depigmentation despite treatment. Moreover, patients with Koebner{\textquoteright}s phenomenon due to friction had a marked enhanced frequency of thyroid disease. 
In conclusion, we believe this work contributes to the insights into the development of immune reactions against  benign and malignant melanocytes. Therefore, it has implications both for melanoma, halo nevi and vitiligo.},
  author       = {Speeckaert, Reinhart},
  language     = {eng},
  pages        = {236},
  publisher    = {Ghent University. Faculty of Medicine and Health Sciences},
  school       = {Ghent University},
  title        = {Study of the mechanisms of melanocyte destruction in melanoma, halo nevi and vitiligo},
  year         = {2012},
}

Chicago
Speeckaert, Reinhart. 2012. “Study of the Mechanisms of Melanocyte Destruction in Melanoma, Halo Nevi and Vitiligo”. Ghent, Belgium: Ghent University. Faculty of Medicine and Health Sciences.
APA
Speeckaert, R. (2012). Study of the mechanisms of melanocyte destruction in melanoma, halo nevi and vitiligo. Ghent University. Faculty of Medicine and Health Sciences, Ghent, Belgium.
Vancouver
1.
Speeckaert R. Study of the mechanisms of melanocyte destruction in melanoma, halo nevi and vitiligo. [Ghent, Belgium]: Ghent University. Faculty of Medicine and Health Sciences; 2012.
MLA
Speeckaert, Reinhart. “Study of the Mechanisms of Melanocyte Destruction in Melanoma, Halo Nevi and Vitiligo.” 2012 : n. pag. Print.