Publications by authors named "Lloyd E King"

48 Publications

Cicatricial Alopecia Research Foundation meeting, May 2016: Progress towards the diagnosis, treatment and cure of primary cicatricial alopecias.

Exp Dermatol 2018 03;27(3):302-310

Department of Dermatology, Vanderbilt University Medical Center, Nashville, TN, USA.

Primary cicatricial alopecias (PCAs) are a group of skin diseases in which there is progressive and permanent destruction of hair follicles followed by replacement with fibrous tissue. Unfortunately, by the time patients seek clinical evaluation of their hair loss, the skin is already inflamed and/or scarred, so there is little hope for a return to their normal hair growth pattern. Clinical and basic science investigations are now focusing on three forms of human PCA: lichen planopilaris (LPP), frontal fibrosing alopecia (FFA) and central centrifugal cicatricial alopecia (CCCA). Transcriptome, lipidome and other new technologies are providing new insight into the pathogenesis of some of these diseases that are being validated and further investigated using spontaneous and genetically engineered mouse models.
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http://dx.doi.org/10.1111/exd.13495DOI Listing
March 2018

Alopecia areata.

Nat Rev Dis Primers 2017 Mar 16;3:17011. Epub 2017 Mar 16.

Department of Dermatology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Alopecia areata is an autoimmune disorder characterized by transient, non-scarring hair loss and preservation of the hair follicle. Hair loss can take many forms ranging from loss in well-defined patches to diffuse or total hair loss, which can affect all hair-bearing sites. Patchy alopecia areata affecting the scalp is the most common type. Alopecia areata affects nearly 2% of the general population at some point during their lifetime. Skin biopsies of affected skin show a lymphocytic infiltrate in and around the bulb or the lower part of the hair follicle in the anagen (hair growth) phase. A breakdown of immune privilege of the hair follicle is thought to be an important driver of alopecia areata. Genetic studies in patients and mouse models have shown that alopecia areata is a complex, polygenic disease. Several genetic susceptibility loci were identified to be associated with signalling pathways that are important to hair follicle cycling and development. Alopecia areata is usually diagnosed based on clinical manifestations, but dermoscopy and histopathology can be helpful. Alopecia areata is difficult to manage medically, but recent advances in understanding the molecular mechanisms have revealed new treatments and the possibility of remission in the near future.
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http://dx.doi.org/10.1038/nrdp.2017.11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5573125PMC
March 2017

DermO; an ontology for the description of dermatologic disease.

J Biomed Semantics 2016 Jun 13;7:38. Epub 2016 Jun 13.

Dept. of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK.

Background: There have been repeated initiatives to produce standard nosologies and terminologies for cutaneous disease, some dedicated to the domain and some part of bigger terminologies such as ICD-10. Recently, formally structured terminologies, ontologies, have been widely developed in many areas of biomedical research. Primarily, these address the aim of providing comprehensive working terminologies for domains of knowledge, but because of the knowledge contained in the relationships between terms they can also be used computationally for many purposes.

Results: We have developed an ontology of cutaneous disease, constructed manually by domain experts. With more than 3000 terms, DermO represents the most comprehensive formal dermatological disease terminology available. The disease entities are categorized in 20 upper level terms, which use a variety of features such as anatomical location, heritability, affected cell or tissue type, or etiology, as the features for classification, in line with professional practice and nosology in dermatology. Available in OBO flatfile and OWL 2 formats, it is integrated semantically with other ontologies and terminologies describing diseases and phenotypes. We demonstrate the application of DermO to text mining the biomedical literature and in the creation of a network describing the phenotypic relationships between cutaneous diseases.

Conclusions: DermO is an ontology with broad coverage of the domain of dermatologic disease and we demonstrate here its utility for text mining and investigation of phenotypic relationships between dermatologic disorders. We envision that in the future it may be applied to the creation and mining of electronic health records, clinical training and basic research, as it supports automated inference and reasoning, and for the broader integration of skin disease information with that from other domains.
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http://dx.doi.org/10.1186/s13326-016-0085-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4907256PMC
June 2016

Skin Diseases in Laboratory Mice: Approaches to Drug Target Identification and Efficacy Screening.

Methods Mol Biol 2016 ;1438:199-224

The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609-1500, USA.

A large variety of mouse models for human skin, hair, and nail diseases are readily available from investigators and vendors worldwide. Mouse skin is a simple organ to observe lesions and their response to therapy, but identifying and monitoring the progress of treatments of mouse skin diseases can still be challenging. This chapter provides an overview on how to use the laboratory mouse as a preclinical tool to evaluate efficacy of new compounds or test potential new uses for compounds approved for use for treating an unrelated disease. Basic approaches to handling mice, applying compounds, and quantifying effects of the treatment are presented.
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http://dx.doi.org/10.1007/978-1-4939-3661-8_12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5301944PMC
December 2017

Dermal lymphatic dilation in a mouse model of alopecia areata.

Exp Mol Pathol 2016 Apr 6;100(2):332-6. Epub 2016 Mar 6.

Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN, USA.

Mouse models of various types of inflammatory skin disease are often accompanied by increased dermal angiogenesis. The C3H/HeJ inbred strain spontaneously develops alopecia areata (AA), a cell mediated autoimmune disorder that can be controllably expanded using full thickness skin grafts to young unaffected mice. This provides a reproducible and progressive model for AA in which the vascularization of the skin can be examined. Mice receiving skin grafts from AA or normal mice were evaluated at 5, 10, 15, and 20 weeks after engraftment. Lymphatics are often overlooked as they are small slit-like structures above the hair follicle that resemble artifact-like separation of collagen bundles with some fixatives. Lymphatics are easily detected using lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1) by immunohistochemistry to label their endothelial cells. Using LYVE1, there were no changes in distribution or numbers of lymphatics although they were more prominent (dilated) in the mice with AA. Lyve1 transcripts were not significantly upregulated except at 10 weeks after skin grafting when clinical signs of AA first become apparent. Other genes involved with vascular growth and dilation or movement of immune cells were dysregulated, mostly upregulated. These findings emphasize aspects of AA not commonly considered and provide potential targets for therapeutic intervention.
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http://dx.doi.org/10.1016/j.yexmp.2016.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4823156PMC
April 2016

Excavating the Genome: Large-Scale Mutagenesis Screening for the Discovery of New Mouse Models.

J Investig Dermatol Symp Proc 2015 Nov;17(2):27-9

Department of Genetic Resources Science, The Jackson Laboratory, Bar Harbor, Maine, USA.

Technology now exists for rapid screening of mutated laboratory mice to identify phenotypes associated with specific genetic mutations. Large repositories exist for spontaneous mutants and those induced by chemical mutagenesis, many of which have never been fully studied or comprehensively evaluated. To supplement these resources, a variety of techniques have been consolidated in an international effort to create mutations in all known protein coding genes in the mouse. With targeted embryonic stem cell lines now available for almost all protein coding genes and more recently CRISPR/Cas9 technology, large-scale efforts are underway to create further novel mutant mouse strains and to characterize their phenotypes. However, accurate diagnosis of skin, hair, and nail diseases still relies on careful gross and histological analysis, and while not automated to the level of the physiological phenotyping, histopathology still provides the most direct and accurate diagnosis and correlation with human diseases. As a result of these efforts, many new mouse dermatological disease models are being characterized and developed.
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http://dx.doi.org/10.1038/jidsymp.2015.36DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4734626PMC
November 2015

Animal Models for Alopecia Areata: What and Where?

J Investig Dermatol Symp Proc 2015 Nov;17(2):23-6

Department of Medicine, Division of Dermatology, Vanderbilt University, Nashville, Tennessee, USA.

Disease is not limited to humans. Rather, humans are but another mammal in a continuum, and as such, often share similar if not identical diseases with other mammalian species. Alopecia areata (AA) is such a disease. Natural disease occurs in humans, nonhuman primates, many domestic animals, and laboratory rodents. However, to be useful as models of human disease, affected animals need to be readily available to the research community, closely resemble the human disease, be easy to work with, and provide reproducible data. To date, the laboratory mouse (most if not all of the C3H substrains) and the Dundee experimental bald rat fit these criteria. Manipulations using full-thickness skin grafts or specific immune cell transfers have improved the models. New mouse models that carry a variety of genetic-based immunodeficiencies can now be used to recapitulate the human immune system and allow for human full-thickness skin grafts onto mice to investigate human-specific mechanistic and therapeutic questions. These models are summarized here including where they can currently be obtained from public access repositories.
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http://dx.doi.org/10.1038/jidsymp.2015.35DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4722955PMC
November 2015

Resolution of chronic ocular sarcoidosis with antimycobacterial therapy.

Case Rep Intern Med 2014 ;1(2)

Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, United States ; Division of Infectious Diseases/Department of Medicine, Vanderbilt University Medical School, Nashville, United States.

Ocular and cutaneous sarcoidosis is a chronic manifestation of sarcoidosis that remains difficult to treat. Recent investigations demonstrating efficacy with antimicrobial therapy in pulmonary and cutaneous sarcoidosis have been reported. Here, we report dual clinical improvement in cutaneous and ocular sarcoidosis following administration of oral antimycobacterial therapy.
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http://dx.doi.org/10.5430/crim.v1n2p216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4286311PMC
January 2014

Crisp1 and alopecia areata in C3H/HeJ mice.

Exp Mol Pathol 2014 Dec 29;97(3):525-8. Epub 2014 Oct 29.

Department of Environmental Toxicology, University of California, Davis, CA, United States.

Alopecia areata (AA), a cell mediated autoimmune disease, is the second most common form of hair loss in humans. While the autoimmune disease is responsible for the underlying pathogenesis, the alopecia phenotype is ultimately due to hair shaft fragility and breakage associated with structural deficits. Quantitative trait genetic analyses using the C3H/HeJ mouse AA model identified cysteine-rich secretory protein 1 (Crisp1), a hair shaft structural protein, as a candidate gene within the major AA locus. Crisp1 transcripts in the skin at various times during disease development were barely detectable. In situ hybridization identified Crisp1 expression within the medulla of hair shafts from clinically normal strains of mice but not C3H/HeJ mice with AA. Follow-up work with 5-day-old C3H/HeJ mice with normal hair also had essentially no expression of Crisp1. Other non-inflammatory based follicular dystrophy mouse models with similar hair shaft abnormalities also have little or no Crisp1 expression. Shotgun proteomics, used to determine strain difference in hair proteins, confirmed that there was very little CRISP1 within normal C3H/HeJ mouse hair in comparison to 11 other strains. However, mutant mice with hair medulla defects also had undetectable levels of CRISP1 in their hair. Crisp1 null mice had normal skin, hair follicles, and hair shafts indicating that the lack of the CRISP1 protein does not translate directly into defects in the hair shaft or hair follicle. These results suggest that CRISP1 may be an important structural component of mouse hair and that its strain-specific dysregulation may indicate a predisposition to hair shaft disease such as AA.
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http://dx.doi.org/10.1016/j.yexmp.2014.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4262666PMC
December 2014

Transplantable malignant melanoma in LT.B6 congenic mice resembling pigmented epithelioid melanocytoma in humans.

J Invest Dermatol 2014 Jun 29;134(6):1772-1775. Epub 2014 Jan 29.

The Jackson Laboratory, Bar Harbor, Maine, USA; Vanderbilt University, Nashville, Tennessee, USA.

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http://dx.doi.org/10.1038/jid.2014.47DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4085667PMC
June 2014

Alopecia areata: updates from the mouse perspective.

J Investig Dermatol Symp Proc 2013 Dec;16(1):S23-4

1] Department of Research, The Jackson Laboratory, Bar Harbor, Maine, USA [2] Division of Dermatology, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.

Alopecia areata (AA) is a cell-mediated autoimmune disease that targets actively growing hair follicles in mammals, including humans and mice. Development of the C3H/HeJ spontaneous mouse model AA nearly 20 years ago provided a much needed tool to test the hypotheses and ultimately serve as a preclinical model for drug testing. Discoveries in both human AA patients and the mouse model supported each other and lead to discoveries on the incredibly complex genetic basis of this disease. The discovery that A/J, MRL/MpJ, SJL/J, and SWR/J strains also develop AA now allows genome-wide association mapping studies to expand the list of genes underlying this disease. Potential new targets for unraveling the pathogenesis of AA include the role of retinoic acid metabolism in the severity of disease and hair shaft proteins that may be either the inciting antigen or ultimate target of the immune reaction leading to breakage of the shaft causing clinical alopecia. Comparing these model systems with human and mouse clinical disease, for both discovery and validation of the discoveries, continues to resolve the complex questions surrounding AA.
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http://dx.doi.org/10.1038/jidsymp.2013.6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4071566PMC
December 2013

Oral antimycobacterial therapy in chronic cutaneous sarcoidosis: a randomized, single-masked, placebo-controlled study.

JAMA Dermatol 2013 Sep;149(9):1040-9

Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee2Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee.

Importance: Sarcoidosis is a chronic granulomatous disease for which there are limited therapeutic options. This is the first randomized, placebo-controlled study to demonstrate that antimycobacterial therapy reduces lesion diameter and disease severity among patients with chronic cutaneous sarcoidosis.

Objective: To evaluate the safety and efficacy of once-daily antimycobacterial therapy on the resolution of chronic cutaneous sarcoidosis lesions.

Design And Participants: A randomized, placebo-controlled, single-masked trial on 30 patients with symptomatic chronic cutaneous sarcoidosis lesions deemed to require therapeutic intervention.

Setting: A tertiary referral dermatology center in Nashville, Tennessee.

Interventions: Participants were randomized to receive either the oral concomitant levofloxacin, ethambutol, azithromycin, and rifampin (CLEAR) regimen or a comparative placebo regimen for 8 weeks with a 180-day follow-up.

Main Outcomes And Measures: Participants were monitored for absolute change in lesion diameter and decrease in granuloma burden, if present, on completion of therapy.

Observations: In the intention-to-treat analysis, the CLEAR-treated group had a mean (SD) decrease in lesion diameter of -8.4 (14.0) mm compared with an increase of 0.07 (3.2) mm in the placebo-treated group (P = .05). The CLEAR group had a significant reduction in granuloma burden and experienced a mean (SD) decline of -2.9 (2.5) mm in lesion severity compared with a decline of -0.6 (2.1) mm in the placebo group (P = .02).

Conclusions And Relevance: Antimycobacterial therapy may result in significant reductions in chronic cutaneous sarcoidosis lesion diameter compared with placebo. These observed reductions, associated with a clinically significant improvement in symptoms, were present at the 180-day follow-up period. Transcriptome analysis of sarcoidosis CD4+ T cells revealed reversal of pathways associated with disease severity and enhanced T-cell function following T-cell receptor stimulation.

Trial Registration: clinicaltrials.gov Identifier: NCT01074554.
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http://dx.doi.org/10.1001/jamadermatol.2013.4646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3927541PMC
September 2013

Mouse alopecia areata and heart disease: know your mouse!

J Invest Dermatol 2014 Jan 17;134(1):279-281. Epub 2013 Jun 17.

Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

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http://dx.doi.org/10.1038/jid.2013.273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3825791PMC
January 2014

Lack of response to laser comb in spontaneous and graft-induced alopecia areata in C3H/HeJ mice.

J Invest Dermatol 2014 Jan 10;134(1):264-266. Epub 2013 Jun 10.

Division of Dermatology, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA; The Jackson Laboratory, Department of Basic Research, Bar Harbor, Maine, USA. Electronic address:

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http://dx.doi.org/10.1038/jid.2013.252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3825825PMC
January 2014

Poorly differentiated squamous cell carcinoma arising from an intraepidermal epithelioma.

Pathol Res Pract 2013 Apr 11;209(4):260-3. Epub 2013 Mar 11.

Department of Medicine, Vanderbilt University, Nashville, TN, United States.

The intraepidermal epithelioma (of Borst-Jadasson) constitutes a much discussed and debated entity. Currently, this diagnosis is rarely made in part, as ascribing clinical features to such lesions has, to date, proven difficult. In addition, intraepidermal proliferation of atypical cells with clonal features is more likely diagnosed as squamous cell carcinomas in situ, porocarcinomas or inflamed seborrheic keratoses. However, cutaneous tumors exhibiting microscopic and immunohistochemical features of clonally profligate malignant basaloid cells solely of epidermal origin do rarely exist. Their progression to dermal invasion appears even more uncommon.
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http://dx.doi.org/10.1016/j.prp.2013.01.011DOI Listing
April 2013

Retinoid metabolism is altered in human and mouse cicatricial alopecia.

J Invest Dermatol 2013 Feb 25;133(2):325-33. Epub 2012 Oct 25.

Department of Nutrition, The Ohio State University, Columbus, Ohio, USA.

C57BL/6 mice develop dermatitis and scarring alopecia resembling human cicatricial alopecias (CAs), particularly the central centrifugal CA (CCCA) type. To evaluate the role of retinoids in CA, the expression of retinoid metabolism components were examined in these mice with mild, moderate, or severe CA compared with hair cycle-matched mice with no disease. Two feeding studies were conducted with dams fed either NIH 31 diet (study 1) or AIN93G diet (study 2). Adult mice were fed AIN93M diet with 4 (recommended), 28, or 56 IU vitamin A g(-1) diet. Feeding the AIN93M diet to adults increased CA frequency over NIH 31 fed mice. Increased follicular dystrophy was seen in study 1 and increased dermal scars in study 2 in mice fed the 28 IU diet. These results indicate that retinoid metabolism is altered in CA in C57BL/6J mice that require precise levels of dietary vitamin A. Human patients with CCCA, pseudopelade (end-stage scarring), and controls with no alopecia were also studied. Many retinoid metabolism proteins were increased in mild CCCA, but were undetectable in pseudopelade. Studies to determine whether these dietary alterations in retinoid metabolism seen in C57BL/6J mice are also involved in different types of human CA are needed.
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http://dx.doi.org/10.1038/jid.2012.393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3546159PMC
February 2013

Endogenous retinoids in the pathogenesis of alopecia areata.

J Invest Dermatol 2013 Feb 27;133(2):334-43. Epub 2012 Sep 27.

Department of Nutrition, The Ohio State University, Columbus, Ohio 43210, USA.

Alopecia areata (AA) is an autoimmune disease that attacks anagen hair follicles. Gene array in graft-induced C3H/HeJ mice revealed that genes involved in retinoic acid (RA) synthesis were increased, whereas RA degradation genes were decreased in AA compared with sham controls. This was confirmed by immunohistochemistry in biopsies from patients with AA and both mouse and rat AA models. RA levels were also increased in C3H/HeJ mice with AA. C3H/HeJ mice were fed a purified diet containing one of the four levels of dietary vitamin A or an unpurified diet 2 weeks before grafting and disease progression followed. High vitamin A accelerated AA, whereas mice that were not fed vitamin A had more severe disease by the end of the study. More hair follicles were in anagen in mice fed high vitamin A. Both the number and localization of granzyme B-positive cells were altered by vitamin A. IFNγ was also the lowest and IL13 highest in mice fed high vitamin A. Other cytokines were reduced and chemokines increased as the disease progressed, but no additional effects of vitamin A were seen. Combined, these results suggest that vitamin A regulates both the hair cycle and immune response to alter the progression of AA.
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http://dx.doi.org/10.1038/jid.2012.344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3546144PMC
February 2013

Identification of an mtDNA mutation hot spot in UV-induced mouse skin tumors producing altered cellular biochemistry.

J Invest Dermatol 2012 Feb 20;132(2):421-8. Epub 2011 Oct 20.

Department of Medicine, Dermatology Division, Arizona Cancer Center, University of Arizona, Tucson, Arizona 85724, USA.

There is increasing awareness of the role of mtDNA alterations in the development of cancer, as mtDNA point mutations are found at high frequency in a variety of human tumors. To determine the biological effects of mtDNA mutations in UV-induced skin tumors, hairless mice were irradiated to produce tumors, and the tumor mtDNAs were screened for single-nucleotide changes using temperature gradient capillary electrophoresis (TGCE), followed by direct sequencing. A mutation hot spot (9821insA) in the mitochondrially encoded tRNA arginine (mt-Tr) locus (tRNA(Arg)) was discovered in approximately one-third of premalignant and malignant skin tumors. To determine the functional relevance of this particular mutation in vitro, cybrid cell lines containing different mt-Tr (tRNA(Arg)) alleles were generated. The resulting cybrid cell lines contained the same nuclear genotype and differed only in their mtDNAs. The biochemical analysis of the cybrids revealed that the mutant haplotype is associated with diminished levels of complex I protein (CI), resulting in lower levels of baseline oxygen consumption and lower cellular adenosine triphosphate (ATP) production. We hypothesize that this specific mtDNA mutation alters cellular biochemistry, supporting the development of keratinocyte neoplasia.
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http://dx.doi.org/10.1038/jid.2011.320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3258376PMC
February 2012

Skin diseases in laboratory mice: approaches to drug target identification and efficacy screening.

Methods Mol Biol 2010 ;602:193-213

The Jackson Laboratory, Bar Harbor, ME, USA.

A large variety of mouse models for human skin and adnexa diseases are readily available from investigators and vendors worldwide. While the skin is an obvious organ to observe lesions and their response to therapy, actually treating and monitoring progress in mice can be challenging. This chapter provides an overview on how to use the laboratory mouse as a preclinical tool to evaluate efficacy of a new compound or test potential new uses for a compound approved for use for treating an unrelated disease. Basic approaches to handling mice, applying compounds, and quantifying effects of the treatment are presented.
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http://dx.doi.org/10.1007/978-1-60761-058-8_12DOI Listing
February 2010

Recombinant human hepatitis B vaccine initiating alopecia areata: testing the hypothesis using the C3H/HeJ mouse model.

Vet Dermatol 2009 Apr 17;20(2):99-104. Epub 2009 Jan 17.

The Jackson Laboratory, Bar Harbor, ME 04609-1500, USA.

Untoward effects of human vaccines suggest that recombinant hepatitis B vaccine may induce alopecia areata (AA) in some patients. Similar untoward immunological effects may also account for AA-like diseases in domestic species. In this study, the C3H/HeJ spontaneous adult onset AA mouse model was used to test the role, if any, of recombinant hepatitis B vaccine on the initiation or activation of AA. Initial experiments demonstrated no effect on induction of AA in young adult female C3H/HeJ mice (P = 0.5689). By contrast, older females, those at the age when AA first begins to appear in this strain, had a significant increase (P = 0.0264) in the time of onset of AA, suggesting that the vaccine may initiate disease in mice predisposed to AA. However, larger vaccine trials, which included diphtheria and tetanus toxoids as additional controls, did not support these initial result findings and suggest that AA associated with vaccination may be within the normal background levels of the given population.
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http://dx.doi.org/10.1111/j.1365-3164.2008.00692.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2956183PMC
April 2009

The C3H/HeJ mouse and DEBR rat models for alopecia areata: review of preclinical drug screening approaches and results.

Exp Dermatol 2008 Oct;17(10):793-805

The Jackson Laboratory, Bar Harbor, ME 04609-1500, USA.

The C3H/HeJ inbred mouse strain and the Dundee Experimental Bald Rat (DEBR) strain spontaneously develop adult onset alopecia areata (AA), a cell-mediated disease directed against actively growing hair follicles. The low frequency of AA and the inability to predict the stage of AA as it evolves in the naturally occuring C3H/HeJ model of AA can be converted into a highly predictable system by grafting full thickness skin from AA-affected mice to normal haired mice of the same strain. The rat DEBR model develops spontaneous AA at a higher frequency than in the mouse model but they are more expensive to use in drug studies owing to their larger size. Regardless of the shortcomings of either model, these rodent models can be used succesfully to screen novel or approved drugs for efficacy to treat human AA. As the pathogenesis of AA follows the canonical lymphocytic co-stimulatory cascade in the mouse AA model, it can be used to screen compounds potentially useful to treat a variety of cell-mediated diseases. Efficacy of various agents can easily be screened by simply observing the presence, rate, and cosmetic acceptability of hair regrowth. More sophisticated assays can refine how the drugs induce hair regrowth and evaluate the underlying pathogenesis of AA. Some drugs commonly used to treat human AA patients work equally as well in both rodent models validating their usefulness as models for drug efficacy and safety for humanAA.
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http://dx.doi.org/10.1111/j.1600-0625.2008.00773.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778023PMC
October 2008

Alopecia areata.

Curr Dir Autoimmun 2008 ;10:280-312

Division of Dermatology, Vanderbilt University Medical Center, Nashville, TN 37203, USA.

The pathogenesis of organ specific, cell mediated autoimmune alopecia areata (AA) has substantially progressed in the last decade. These advances are partly based upon advances in immunology and genetics, improved technological methodology in RNA, DNA, proteomics, and computer analyses, as well as the development of the C3H/HeJ mouse model of AA. The discovery that full thickness skin grafts transfer AA from C3H/HeJ mice that spontaneously develop AA to multiple non-affected C3H/HeJ mice greatly shortened the time of AA onset and provided many more affected mice in this highly reproducible model of AA. These methodological and genetic advances combine to form practical bases for identifying subtypes of human and mouse AA, characterizing disease mechanisms, improving currently available treatments, and developing new, more effective therapies. In the next decade even more exciting new insights into the pathogenesis of subtypes of human AA, their genetic bases, and therapy development will become available based on in-depth data on specific gene mutations and signaling pathways involved. Other organ specific autoimmune diseases will surely benefit from the rapid progress in understanding AA.
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http://dx.doi.org/10.1159/000131749DOI Listing
August 2008

Common ground?: Tetracyclines, matrix metalloproteinases, pustular dermatoses, and loxoscelism.

Authors:
Lloyd E King

J Invest Dermatol 2007 Jun;127(6):1284-6

Vanderbilt University Medical Center, Nashville, Tennessee 37203, USA.

The fear of spiders is ancient and common throughout much of the world. Skin ulceration and necrosis due to Loxosceles spider envenomation ("bites") is among the best known sequelae of a usually accidental encounter. Therapies for Loxosceles envenomations either are not well documented or have adverse side effects that limit their use by generalists. Based on in vitro and in vivo studies in rabbits injected with purified or recombinant sphingomyelinase D2, Paixão-Cavalcante et al. (2007) propose in this issue that topical tetracyclines could become safe, efficacious therapy for cutaneous loxoscelism.
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http://dx.doi.org/10.1038/sj.jid.5700724DOI Listing
June 2007

Immunolocalization of enzymes, binding proteins, and receptors sufficient for retinoic acid synthesis and signaling during the hair cycle.

J Invest Dermatol 2007 Jul 15;127(7):1593-604. Epub 2007 Mar 15.

Department of Biochemistry, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.

Retinoic acid (RA) is essential for maintenance of most epithelial tissues. One RA biosynthesis pathway consists of cellular retinol-binding protein (Crbp), retinol dehydrogenase (Dhrs9/eRoldh), retinal dehydrogenase 1-3 (Aldh1a1-3), and cellular RA-binding protein 2 (Crabp2). Previously, we localized Aldh1a2 and Aldh1a3 to both epithelial and mesenchymal cells within the hair follicle throughout the hair cycle. This study expands that observation by examining the complete pathway of RA biosynthesis and signaling via RA receptors alpha, beta, and gamma by immunohistochemistry in C57BL/6J mice wax-stripped to initiate and synchronize the cycle. This pathway of RA biosynthesis and signaling localized to the majority of layers of the hair follicle, sebaceous gland, and interfollicular epidermis in a hair cycle-dependent manner, suggesting that RA biosynthesis within the hair follicle is regulated in both a spatial and temporal manner. This localization pattern also revealed insights into epithelial-mesenchymal interactions and differentiation state differences within the RA biosynthesis and signaling pathway, as well as novel observations on nuclear versus cytoplasmic localization of Crabp2 and RA receptors. This complex pattern of RA biosynthesis and signaling identified by immunolocalization suggests that endogenous RA regulates specific aspects of hair follicle growth, differentiation, and cycling.
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http://dx.doi.org/10.1038/sj.jid.5700753DOI Listing
July 2007

Oestrogen receptor-beta expression in melanocytic lesions.

Exp Dermatol 2006 Dec;15(12):971-80

Division of Dermatology, Department of Medicine, Vanderbilt University Medical School, Nashville, TN 37232, USA.

Melanomas rarely occur before puberty, have a higher death rate for males, and tend to be more invasive during pregnancy. Prior to the discovery of a second oestrogen receptor (ERbeta), studies with the initial oestrogen receptor, ERalpha, showed no obvious role for oestrogen in the pathophysiology of benign or malignant melanocytic lesions. To investigate the specific immunostaining patterns of ERalpha and ERbeta, benign nevocytic nevi, dysplastic nevi with mild, moderate and severe cytological atypia, lentigo malignas and melanomas of varying depth (Clark) and thickness (Breslow) were studied. ERbeta but not ERalpha was the predominant oestrogen receptor we found in all types of benign and malignant melanocytic lesions. The most intense ERbeta immunostaining was seen in melanocytes in dysplastic nevi with severe cytological atypia and in lentigo malignas. ERbeta expression levels also correlated with the malignant tumor microenvironment; i.e., melanocytes in proximity with keratinocytes>deeper dermal melanocytes in contact with stroma>minimally invasive melanomas>Clark Level III/IV or thick melanomas (Breslow). Discovery that ERbeta expression varies in relation to the tumor microenvironment and increasing depth of invasion suggests its possible usefulness as a surrogate marker for neoplasia and prognosis in malignant melanoma.
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http://dx.doi.org/10.1111/j.1600-0625.2006.00502.xDOI Listing
December 2006

A protective role for matrix metalloproteinase-3 in squamous cell carcinoma.

Cancer Res 2004 Oct;64(19):6965-72

Department of Cancer Biology, Division of Dermatology, Vanderbilt University, Nashville, Tennessee 37232-6840, USA.

Elevated expression of matrix metalloproteinase-3 (MMP-3/stromelysin-1) is associated with a variety of tumor types, although its in vivo functional role remains unclear. In human and murine squamous cell carcinoma (SCC), MMP-3 is expressed in the stromal compartment at all of the stages of tumor progression and is expressed by the malignant epithelial cells in late-stage, highly invasive tumors. To elucidate whether MMP-3 plays a causal role during SCC, wild-type and MMP-3 null mice were subjected to chemical carcinogenesis procedures by topical application of either the complete carcinogen 1-methyl-3-nitro-1-nitroso-guanidine or two-stage initiation and promotion with 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate. Contrasting with our expectations, tumors originating on MMP-3 null mice had enhanced initial tumor growth rates as compared with control animals, although there was no difference in tumor onset or incidence. This elevated rate in growth was coupled with an elevated proliferative index and a reduced vasculature density but with no significant effect on apoptosis. Tumors from MMP-3 null mice had a prevalence of undifferentiated spindle tumors as compared with controls, which was concomitant with a higher percentage of MMP-3 null mice evidencing surface lung metastases. Tumor progression in MMP-3 null mice was inversely associated with leukocyte infiltration, in which an overall reduction in tumor-associated macrophages and neutrophils was evident. We propose that MMP-3 is expressed as a protective response and plays an important role in host defense during SCC tumorigenesis.
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http://dx.doi.org/10.1158/0008-5472.CAN-04-0910DOI Listing
October 2004