Animal models of skin disease for drug discovery

“1 Cutaneous wound healing Cutaneous wound healing is a complex multifaceted biological process that involves multiple tissue types influenced by local as well as systemic factors (Figure 6) [116,117].”

“Discrepancies exist in both innate and adaptive immunity, including balance of leukocyte subsets, defensins, Toll receptors, inducible NO synthase, cytokines and cytokine receptors, Th1/Th2 differentiation, Ag-presenting function of endothelial cells, and chemokine and chemokine receptor expression [12].”

“These mice also showed elevated serum levels of IgE and IgG1 and decreased IgG2a [64].”

“Later on in 1982, Ralph Brinster in collaboration with Richard Palmiter inserted the structural gene for human growth hormone into mouse embryos, and noticed that the mice with the foreign gene grew much larger in size than those without the gene and also passed this trait to its offspring (Figure 2) [27].”

“In addition, models of beta cell regeneration and the use of knockout and transgenic models in diabetic wound research are also considered by many researchers [133].”

“Stat3C mice [83], and K14/IL-6 and K14/IL-1atransgenic mice [84].”

“Excessive exposure to solar UVR causes severe acute damages to the skin, which include erythema, sunburn, immunosuppressant, and also long-term effects such as photoaging and skin cancer [150-154].”

“Pig skin is also similar to human skin in its histological and biochemical properties, such as thickness, having follicular structures that extend deeply into the dermis, well-developed rete ridges and dermal papillary bodies, epidermal turnover time, abundant subdermal adipose tissue, vascular anatomy and collagen st…”

“Drug discovery efforts in animal models for skin disease have been most notable in the psoriasis SCID mouse model where efalizumab (Raptiva ) [183] and infliximab (Remicade ) [184] were both discovered.”

“targets in the form of novel pharmaceutical molecules, which markedly improve or completely prevent scarring during adult wound healing in experimental animals [126,127].”

“These include the sheep, pig, rabbit, mouse, rat, guinea pig, chicken, opossum, and monkey [125].”

“4 Spontaneous mouse models of AD Nc/Nga mice are an inbred mouse strain, the first mouse model of AD reported [58].”

“The healing efficacy of different novel types of dressings, dermal substitutes, and local and external therapeutic agent can be investigated by this model [120].”

“Antigen-presenting cells in the skin, in particular immunoglobulin E (IgE)-bearing Langerhans cells, may be interacting with these environmental allergens, leading to the local Th2-mediated inflammatory responses that have been detected in the skin of patients with AD [45].”

“Food allergen is also a type of pathogenic factor in a subset of ADpatients [54].”

“Pig skin is also similar to human skin in its histological and biochemical properties, such as thickness, having follicular structures that extend deeply into the dermis, well-developed rete ridges and dermal papillary bodies, epidermal turnover time, abundant subdermal adipose tissue, vascular anatomy and collagen st…”

“The list of animal models that have been used in the study of acne include the rabbit ear model, rhino mouse model [138], Mexican hairless dog model [138,139], Golden Hamster model, swine, and guinea pig [140].”

“, gene gun, electroporation, laser irradiation), chemical (calcium phosphate precipitation, diethylaminoethanol (DEAE)-dextran), and biological (lipids, virus, plasmids), and currently, transgenic animals can be constructed in several ways such as microinjection [15], embryonic stem cell (ESC) injection [16], retrovir…”

“These include the transgenic and knockout models, such as human leukocyte antigen B27 (HLA-B27) transgenic rats [74], CD18 hypomorphic mice [75], K14/VEGF and Tie2 mice [76,77], K14/TGF-a, K5/TGF-b1, K14/KGF and K14/IL-20 transgenic mice [78-80], IKK2 [81] and JunB/c-Jun transgenic mice [82], K5.”

“Injection of nude mice with Notch1-deficient primary keratinocytes expressing activated Ras treated with a Notch signaling inhibitor results in the formation of poorly differentiated and invasive SCC [13].”

“in AD might be related to epidermal barrier dysfunction and the introduction of environmental antigens, rather than intrinsic immune hypersensitivity [46,47].”

“Krueger’s group tested an antibody directed against IL-15 that was known to inhibit the production of T lymphocytes as well as the liberation of TNF-a in vitro [70].”

“Human and animal skins vary in many aspects; for example, percutaneous absorption of certain topical drugs is different among rabbits, rats, and pigs [3].”

“The first transgenic animal was a mice generated through the microinjection of viral gene transfer (simian virus 40 leukemia genes) to explanted mouse blastocysts [25] and early embryonic exposure to retroviruses [26].”

“These include the transgenic and knockout models, such as human leukocyte antigen B27 (HLA-B27) transgenic rats [74], CD18 hypomorphic mice [75], K14/VEGF and Tie2 mice [76,77], K14/TGF-a, K5/TGF-b1, K14/KGF and K14/IL-20 transgenic mice [78-80], IKK2 [81] and JunB/c-Jun transgenic mice [82], K5.”

“The first transgenic animal was a mice generated through the microinjection of viral gene transfer (simian virus 40 leukemia genes) to explanted mouse blastocysts [25] and early embryonic exposure to retroviruses [26].”

“Controlled gene expression in mouse models is studied based on the tamoxifen-inducible Cre recombinase system [33,34], Cre-loxP and the tetracycline (Tet)-inducible systems [35], and tet-operon/repressor bi-transgenic system, the estrogen receptor (ER) ligand-binding domain, the cell-specific activation and inactivati…”

“Overt skin lesions were not noted in these mice, except for areas exposed to significant mechanical stress such as the skin around the snout, the nipples of nursing females, and the mucocutaneous junctions in the eyes [86,87].”

“These include the transgenic and knockout models, such as human leukocyte antigen B27 (HLA-B27) transgenic rats [74], CD18 hypomorphic mice [75], K14/VEGF and Tie2 mice [76,77], K14/TGF-a, K5/TGF-b1, K14/KGF and K14/IL-20 transgenic mice [78-80], IKK2 [81] and JunB/c-Jun transgenic mice [82], K5.”

“In addition, IL-4 and Th2specific chemokines are overproduced [59], indicating that Th2-type immune responses are upregulated as well as in human subjects with AD in the initial phase.”

“Excessive exposure to solar UVR causes severe acute damages to the skin, which include erythema, sunburn, immunosuppressant, and also long-term effects such as photoaging and skin cancer [150-154].”

“Tape-stripped skin imitates skin barrier dysfunction and it can respond to allergen more easily [49].”

“Themain examples of SLE-pronemice areNewZealand Black (NZB), F1 hybrids of NZB New Zealand White (NZW) (B/W F1), MRL/Mp-lpr/lpr, and BXSB mice (Table 1) [100-102].”

“These include the transgenic and knockout models, such as human leukocyte antigen B27 (HLA-B27) transgenic rats [74], CD18 hypomorphic mice [75], K14/VEGF and Tie2 mice [76,77], K14/TGF-a, K5/TGF-b1, K14/KGF and K14/IL-20 transgenic mice [78-80], IKK2 [81] and JunB/c-Jun transgenic mice [82], K5.”

“These include the transgenic and knockout models, such as human leukocyte antigen B27 (HLA-B27) transgenic rats [74], CD18 hypomorphic mice [75], K14/VEGF and Tie2 mice [76,77], K14/TGF-a, K5/TGF-b1, K14/KGF and K14/IL-20 transgenic mice [78-80], IKK2 [81] and JunB/c-Jun transgenic mice [82], K5.”

“4 IL-4 transgenic mice Transgenic mice overexpressing IL-4 in the skin develop spontaneous pruritus and chronic dermatitis at the age of 4 months [61].”

“in AD might be related to epidermal barrier dysfunction and the introduction of environmental antigens, rather than intrinsic immune hypersensitivity [46,47].”

“Animal models of SSc can be divided into three groups (Table 2) [105,106].”

“Controlled gene expression in mouse models is studied based on the tamoxifen-inducible Cre recombinase system [33,34], Cre-loxP and the tetracycline (Tet)-inducible systems [35], and tet-operon/repressor bi-transgenic system, the estrogen receptor (ER) ligand-binding domain, the cell-specific activation and inactivati…”

“IL-1b-deficient CASP1 and IL-18 transgenic mice exhibited similar dermatitis [66].”

“These include the transgenic and knockout models, such as human leukocyte antigen B27 (HLA-B27) transgenic rats [74], CD18 hypomorphic mice [75], K14/VEGF and Tie2 mice [76,77], K14/TGF-a, K5/TGF-b1, K14/KGF and K14/IL-20 transgenic mice [78-80], IKK2 [81] and JunB/c-Jun transgenic mice [82], K5.”

“These workers transplanted samples of involved scalp tissue from AA patients into subcutaneous tissue of SCID mice and the graft tissue was then injected with autologous T lymphocytes which had been isolated from affected scalp [175].”

“These findings indicated that flaky tail mice demonstrate Th17-dominated skin inflammation and eczematous dermatitis with advancing age change [56].”

“infection and dehydration (Figure 5) [69].”

“Although both photoaging and chronological aging are associated with wrinkles, photoaging-induced wrinkles are regarded as deeper and more coarse, whereas those associated with chronological aging are generally more superficial and delicate [156].”

“It has been used as a mouse model for generalized non-Herlitz junctional epidermolysis bullosa (JEB) [23] and generalized non-Herlitz JEB to find out the response to fibroblast therapy [24].”

“These include the transgenic and knockout models, such as human leukocyte antigen B27 (HLA-B27) transgenic rats [74], CD18 hypomorphic mice [75], K14/VEGF and Tie2 mice [76,77], K14/TGF-a, K5/TGF-b1, K14/KGF and K14/IL-20 transgenic mice [78-80], IKK2 [81] and JunB/c-Jun transgenic mice [82], K5.”

“Stat3C mice [83], and K14/IL-6 and K14/IL-1atransgenic mice [84].”

“Unlike the common belief that was widely accepted for a very long time, there is now little support for the view that AD is the result of allergies [43,44].”

“aureus infection in a partial-thickness skin abrasion [130] and Acinetobacter baumanii infection in a third-degree burn [131].”

“Solar-induced damage to mitochondria in skin fibroblasts is proposed to be one of the key factors in premature photoaging of human skin, and the defective powerhouse model (mtDNA mutator mice) has been used in order to demonstrate this phenomenon [161].”

“Recently, efficacy of different novel pharmacotherapeutic agents and tissue-engineered wound dressings have been evaluated for augmenting nonhealing diabetic and burn wounds [118].”

“An example of the former is the diphtheria toxin receptor [39], and an example of the later is viral TK that can produce a lethal toxin from gancyclovir [40].”

“In this approach, a tissue-specific promoter is used to direct expression of one of the site-specific recombinases to limit gene inactivation to only those cells expressing the recombinase [31].”

“targets in the form of novel pharmaceutical molecules, which markedly improve or completely prevent scarring during adult wound healing in experimental animals [126,127].”

“6 SC chymotryptic enzyme transgenic mice Overexpression of a human SC chymotryptic enzyme transgene in suprabasal epidermal keratinocytes of mice led to the development of AD-like skin starting at the age of 7 -- 8 weeks or older [63].”

“6 External traumatic wound infection models The external traumatic wound has been studied with experimental infections in animal models of surgical site wounds, burns, skin abrasions, lacerations, excisional wounds, and open fractures [128].”

“Each female is capable of laying 200 -- 300 eggs per week, external fertilization allows manipulation of embryos ex utero, and rapid development of optically clear embryos allows the direct observation of developing internal organs and tissues in vivo [113].”

“The collagen VII knockout mouse has been used for pilot studies of protein replacement- and cell-based treatments [93], but the short life span of the mouse has prevented long-term follow-up and limited the interpretation of results [94-96].”

“Targeted inactivation of the Shh, Ptch, Smo, and Gli genes, which are all involved in sonic hedgehog signaling (SHH) pathway, has enabled important insights into BCC development, proliferation, and oncogenesis [115].”

“Excessive exposure to solar UVR causes severe acute damages to the skin, which include erythema, sunburn, immunosuppressant, and also long-term effects such as photoaging and skin cancer [150-154].”

“The collagen VII knockout mouse has been used for pilot studies of protein replacement- and cell-based treatments [93], but the short life span of the mouse has prevented long-term follow-up and limited the interpretation of results [94-96].”

“aureus infection in a partial-thickness skin abrasion [130] and Acinetobacter baumanii infection in a third-degree burn [131].”

“, the leptin receptor defect, the streptozotocin, or the immunologic defect of the NOD mouse [134].”

“Application of SEB instead of OVA by repeated EC sensitization to tapestripped skin was able to elicit Th2-dominated allergic skin inflammation accompanied by a systemic Th2 response to the superantigen [53].”

“In wave pattern, the entry of hair follicles begins from the head and moves toward the tail, which is a pattern seen in neonatal rats and hair loss in CIA [182].”

“Unlike the common belief that was widely accepted for a very long time, there is now little support for the view that AD is the result of allergies [43,44].”

“lesions in up to 35% mice, accompanied by elevated serum levels of specific IgE and blood eosinophilia [55].”

“The content of ceramide in the skin is remarkably decreased in NC/Tnd mice before dermatitis, and it became clear that transepidermal water loss was promoted in the affected skin as a result [60].”

“These events are initiated by UVR of certain wavelengths, and include formation of DNA damage products, DNA repair, and mutation of proto-oncogenes and tumor suppressor genes [162].”

“5 Embryonic wound models Unlike in adult skin, wound healing in early gestational stage mammalian embryos involves repair processes that result in the essentially perfect regeneration of damaged tissue [124].”

“Vismodegib [187] is a potent and selective inhibitor of the Hedgehog (Hh) pathway that showed antitumor activity in patient-derived colorectal cancer xenograft tumor models and medulloblastoma allograft tumors driven by mutational or ligand-dependent activation of the Hh pathway.”

“For example, the host’s vascular and immune systems, as well as the external environment, influence animal models like humans [119].”

“An innovative technique has been developed employing bioluminescent (glow-in-the-dark) bacteria and low-light imaging cameras to noninvasively monitor the progress of the infection in real time in the same animal [129].”

“Microinjection (Figure 2) exposes the fertilized egg to the transgene before the embryo forms, thus allowing the gene to be present in the embryo before development [28].”

“Rhesus monkey was found to be similar to human in terms of percutaneous absorption studies of hydrocortisone, testosterone, and benzoic acid [5].”

“Controlled gene expression in mouse models is studied based on the tamoxifen-inducible Cre recombinase system [33,34], Cre-loxP and the tetracycline (Tet)-inducible systems [35], and tet-operon/repressor bi-transgenic system, the estrogen receptor (ER) ligand-binding domain, the cell-specific activation and inactivati…”

“, during embryogenesis or postnatal) [11].”

“Spontaneous mutation mouse models, such as homozygous asebia (Scd1ab/Scd1ab) mutant mice [71], Flaky skin mice (Ttcfsn/Ttcfsn) [72], spontaneous chronic proliferative dermatitis mutation mice [73] and so on, do not closely mimic the disease enough to be considered as good models of psoriasis.”

“aureus was identified [67].”

“These include the transgenic and knockout models, such as human leukocyte antigen B27 (HLA-B27) transgenic rats [74], CD18 hypomorphic mice [75], K14/VEGF and Tie2 mice [76,77], K14/TGF-a, K5/TGF-b1, K14/KGF and K14/IL-20 transgenic mice [78-80], IKK2 [81] and JunB/c-Jun transgenic mice [82], K5.”

“However, it has been reported that multiple challenges with haptens of the skin over an extended period cause the skin inflammation to shift from Th1-dominated responses to chronic Th2-dominated inflammatory responses that are similar to those in human AD patients [52].”

“, gene gun, electroporation, laser irradiation), chemical (calcium phosphate precipitation, diethylaminoethanol (DEAE)-dextran), and biological (lipids, virus, plasmids), and currently, transgenic animals can be constructed in several ways such as microinjection [15], embryonic stem cell (ESC) injection [16], retrovir…”

“Table 3 shows a brief summary of commonly used mouse strains with histologically confirmed AA-like diseases [172].”

“Swine (Duroc-Jersey swine, Sinclair miniature swine, Munich Troll miniature swine) [110] and Camargue horses develop melanoma; however, neither of these develop melanoma with a sunlightbased etiology [10].”

“This short synchronized hair cycle allows hair follicles to be harvested and examined at specific time points in the cycle very easily [14].”

“The DEBR model develops spontaneous AA at a higher frequency than in the mouse model; however, the disadvantage of this model is that they are more expensive to use in drug studies owing to their larger size [173].”

“On the other hand, mice-sensitized features by the recombinant house dust mite allergen were similar to those observed with EC sensitization models with OVA, and manifested epidermal hyperplasia and spongiosis (intracellular swelling within the epidermis), infiltration of CD4 and CD8 cells, and a skewed Th2 response l…”

“Excessive exposure to solar UVR causes severe acute damages to the skin, which include erythema, sunburn, immunosuppressant, and also long-term effects such as photoaging and skin cancer [150-154].”

“An alternative way to induce cutaneous lesions is through TCR alpha -/- mice that are treated with fluorouracil and UVB light irradiation [104].”

“Recent discoveries have shown that genetic susceptibility to autoimmune diseases involves a large number of genes with small individual contributions, but in spite of this great complexity, significant advances have been made and a small but growing number of susceptibility genes have been identified [99].”

“C57BL/6J, SKH1, and BALB/c mice are the three main strains used for photoaging and photocarcinogenesis studies [157-159].”

“Thus, the Tet-regulated and Cre-ER systems are complementary in animal models, through utility in the cell-specific activation and inactivation of gene expression [37].”

“1 Alopecia areata Alopecia areata (AA) like hair loss has been observed in several species, including monkeys, dogs, cats, horses, cattle, poultry, and non-human primates [171,172].”

“The list of animal models that have been used in the study of acne include the rabbit ear model, rhino mouse model [138], Mexican hairless dog model [138,139], Golden Hamster model, swine, and guinea pig [140].”

“Controlled gene expression in mouse models is studied based on the tamoxifen-inducible Cre recombinase system [33,34], Cre-loxP and the tetracycline (Tet)-inducible systems [35], and tet-operon/repressor bi-transgenic system, the estrogen receptor (ER) ligand-binding domain, the cell-specific activation and inactivati…”

“, gene gun, electroporation, laser irradiation), chemical (calcium phosphate precipitation, diethylaminoethanol (DEAE)-dextran), and biological (lipids, virus, plasmids), and currently, transgenic animals can be constructed in several ways such as microinjection [15], embryonic stem cell (ESC) injection [16], retrovir…”

“Spontaneous mutation mouse models, such as homozygous asebia (Scd1ab/Scd1ab) mutant mice [71], Flaky skin mice (Ttcfsn/Ttcfsn) [72], spontaneous chronic proliferative dermatitis mutation mice [73] and so on, do not closely mimic the disease enough to be considered as good models of psoriasis.”

“Transgenic mice have been developed as models for different forms of EB [89].”

“Examples include the transforming growth factor-b-induced, myofibroblastmediated contractile fibrosis in severe DEB [90] and the Langerhans cell-mediated inflammatory processes described in keratin 5-deficient mice [91].”

“Furthermore, the development of melanocytes from the embryonic neural crest is well characterized [114].”

“Transgenic models are also in use both in mouse [112] [e.”

“The Smyth line chicken model is not yet widely used; however, it also shows promising results for future use, both in alopecia areata and alopecia universalis [176].”

“It is classified according to the site of blister formation, and the main three groups are epidermolytic or EB simplex (EBS), JEB, and dermolytic or dystrophic EB (DEB) [85].”

“aureus-associated AD [68].”

“Footpad was the preferred site of inoculation since it is a cooler site (30 C), which mirrors the preferred cooler sites in human leprosy, permits serial sampling of the tissue as the infection progresses, and there is a minimum of inflammatory response in the footpad tissues [135,136].”

“Varicella-zoster virus (VZV) infection is commonly seen as a benign disease of children causing fever and vesicular skin lesions [143].”

“braziliensis, although other types of hamsters have been used as well [148].”

“These events are initiated by UVR of certain wavelengths, and include formation of DNA damage products, DNA repair, and mutation of proto-oncogenes and tumor suppressor genes [162].”

“The model can be used both in animals and in humans for evaluation of epidermal regeneration and the influence of different compounds and drugs [121].”

“Drug discovery for dermatitis has been less well developed, although there is a skin xenotransplantation model “Trans in vivo delayed hypersensitivity model” using an antigen-specific immune response that is relevant for both psoriasis and AD [185].”

“APOC1Tg mice spontaneously develop age-severe dermatitis with moderate epidermal hyperplasia, hyperkeratosis and parakeratosis, scaling, lichenification, dermal infiltration of inflammatory cells, and pruritus [57].”

“This transgenic mouse can be used to measure the response to single exposures of UV emitted from a fluorescent source, and since promoter induction is one of the primary events causing elastin production in skin, this model provides a precise measurement of one of the earliest events leading to photoaging [160].”

“Laser photobiomodulation that stimulated healing in splinted wounds in diabetic mice has been reported [123].”

“Mice, rats, and rabbits are the animal models that have been studied so far (Table 5) [178-182].”

“Human scalp explants on SCID mice is another experimental model reported by Kyoizumi and colleagues [174] and later adapted by Gilhar and colleagues [175].”

“, gene gun, electroporation, laser irradiation), chemical (calcium phosphate precipitation, diethylaminoethanol (DEAE)-dextran), and biological (lipids, virus, plasmids), and currently, transgenic animals can be constructed in several ways such as microinjection [15], embryonic stem cell (ESC) injection [16], retrovir…”

“Of particular interest was the suitability of EB mouse models for preclinical testing of gene-, protein-, and cell-based therapies [92,93].”

“Characteristics of well-studied SLE-prone mouse strains [100-102].”

“Themain examples of SLE-pronemice areNewZealand Black (NZB), F1 hybrids of NZB New Zealand White (NZW) (B/W F1), MRL/Mp-lpr/lpr, and BXSB mice (Table 1) [100-102].”

“The xeroderma pigmentosum (XPA) mice model, on the other hand, is XPA gene deficient and therefore is defective in NER and consequently shows high incidence of skin tumors and severe acute inflammation in response to UVB irradiation [168].”

“A second method is by using retroviruses which are more efficient in integrating foreign DNA, even though the integration site for retroviruses is most often random [29].”

“C57BL/6J, SKH1, and BALB/c mice are the three main strains used for photoaging and photocarcinogenesis studies [157-159].”

“Mice, rats, and rabbits are the animal models that have been studied so far (Table 5) [178-182].”

“Some of the resulting progeny will harbor both the floxed region and express the Cre recombinase in specific cell types [20,32].”

“Commonly used animal models for herpes simplex are the albino guinea pig and the hairless guinea pig [141,142].”

“Drug discovery efforts in animal models for skin disease have been most notable in the psoriasis SCID mouse model where efalizumab (Raptiva ) [183] and infliximab (Remicade ) [184] were both discovered.”

“1 Passive sensitization model This model shows IgE-mediated cutaneous inflammation reaction which is carried out by intravenous injection of murine monoclonal IgE anti-hapten antibodies [48].”

“These include the transgenic and knockout models, such as human leukocyte antigen B27 (HLA-B27) transgenic rats [74], CD18 hypomorphic mice [75], K14/VEGF and Tie2 mice [76,77], K14/TGF-a, K5/TGF-b1, K14/KGF and K14/IL-20 transgenic mice [78-80], IKK2 [81] and JunB/c-Jun transgenic mice [82], K5.”

“In this model, lpr mutation causes an alteration in the Fas gene and a defect of apoptosis, which in turn result in abnormal lymphocyte proliferation with abnormal function and autoantibody production [103].”

“Animal models of androgenetic alopecia are summarized in Table 4 [177,178].”

“The list of animal models that have been used in the study of acne include the rabbit ear model, rhino mouse model [138], Mexican hairless dog model [138,139], Golden Hamster model, swine, and guinea pig [140].”

“Recently, in SKH-1 hairless mice the effects of NO-exisulind on the growth of UVBinduced skin tumor development have been investigated [163].”

“The guinea pig (Hartley strain) is a reliable test model for protection against UVA-induced erythema with a solar-simulated source and is convenient and relatively inexpensive for testing photoprotection agents [169,170].”

“Note that the forestomach is a characteristic feature of the mouse which is not present in humans [88].”

“The rhino mouse comedolytic model and the hairless mouse photoaging model are established animal models for screening the in vivo activity of retinoids [186].”

“Footpad was the preferred site of inoculation since it is a cooler site (30 C), which mirrors the preferred cooler sites in human leprosy, permits serial sampling of the tissue as the infection progresses, and there is a minimum of inflammatory response in the footpad tissues [135,136].”

“Animal models of SSc can be divided into three groups (Table 2) [105,106].”

“Commonly used animal models for herpes simplex are the albino guinea pig and the hairless guinea pig [141,142].”

“It also enables the analysis of the function of a protein produced from a specific gene in vivo [21].”

“5 days later, sun screen agents were applied to the earlobes and subsequently challenged with TCSA/UVA [167].”

“The guinea pig (Hartley strain) is a reliable test model for protection against UVA-induced erythema with a solar-simulated source and is convenient and relatively inexpensive for testing photoprotection agents [169,170].”

“This approach facilitates the selection genetic function of interest to be expressed without compromising cell viability [22].”

“To overcome this challenge, a novel molecular method has been established which is through ‘humanization of autoantigen’ by genetic manipulation [98].”

“106 An overview of animal models for a wide range of skin conditions, with an emphasis on their application to drug discovery, has been published by Avci et al. 107 Of particular interest are the chimeric models, in which living human skin is grafted on to the skin of severe combined immunodeficient (SCID) mice.”

“Currently, the primary means of identifying therapeutics for these diseases require the use of animal models (Avci et al., 2013), increasing not only the cost of drug development, but also the cost for consumers.”

“…primates, pigs, dogs, cats, rodents, rabbits and fish, for use in medical research including studies on skin xenotransplan‐ tation, has been a major focus over the past decade (Abdullahi et al., 2014; Avci et al., 2013; Badyal & Desai, 2014; Boneva, Folks, & Chapman, 2001; Ge, Zheng, & Wei, 2009).”

“Nevertheless, mouse in vivo models have been used to greatly expand our current knowledge of the causes, pathogenesis, and treatment of Ps [21,60].”