Skin Xenotransplants Research Articles

Ultraviolet B irradiation increases the expression of cornulin and retepin in human skin xenotransplants.

Cornulin (CRNN) and repetin (RPTN) belong to the fused-type S100 protein family. Although these proteins have been reported to be expressed in the granular layer of the epidermis and have been suggested to be associated with barrier formation in the epidermis, their exact function remains unclear. This study examined the effects of ultraviolet B (UVB) irradiation on CRNN and RPTN expression in human skin xenotransplantation. The CRNN expression increased in the granular layer of UVB-irradiated skin 2 days after UVB irradiation compared to that in sham-irradiated skin. Interestingly, CRNN signals were observed not only in the cytoplasm, but also in the peripheral regions of granular keratinocytes. In contrast, RPTN was rarely expressed in sham-irradiated skin; however, RPTN signals were markedly increased in the granular layer of the UVB-irradiated skin. In addition, activation of ERK1/2 and STAT3 was observed in UVB-irradiated skin. Accordingly, the present study demonstrated that CRNN and RPTN are novel proteins whose expression can be increased by UVB irradiation. The activation of ERK1/2 and STAT3 may be associated with the regeneration of a UVB-damaged epidermis, and CRNN and RPTN may be induced to repair any dysfunction in the epidermal barrier during this regeneration process.

Interleukin-15 is a hair follicle immune privilege guardian

The autoimmunity-promoting cytokine, Interleukin-15 (IL-15), is often claimed to be a key pathogenic cytokine in alopecia areata (AA). Yet, rhIL-15 promotes human hair follicle (HF) growth ex vivo. We have asked whether the expression of IL-15 and its receptor (IL-15R) isoforms is altered in human AA and how IL-15 impacts on human HF immune privilege (HF-IP) in the presence/absence of interferon-γ (IFNγ), the well-documented key AA-pathogenic cytokine, as well as on hair regrowth after experimental AA induction in vivo. Quantitative immunohistomorphometry showed the number of perifollicular IL-15+ T cells in AA skin biopsies to be significantly increased compared to healthy control skin, while IL-15, IL-15Rα, and IL-15Rγ protein expression within the hair bulb were significantly down-regulated in AA HFs. In organ-cultured human scalp HFs, rhIL-15 significantly reduced hair bulb expression of MICA, the key “danger” signal in AA pathogenesis, and increased production of the HF-IP guardian, α-MSH. Crucially, ex vivo, rhIL-15 prevented IFNγ-induced HF-IP collapse, restored a collapsed HF-IP by IL-15Rα-dependent signaling (as documented by IL-15Rα−silencing), and protected AA-preventive immunoinhibitory iNKT10 cells from IFNγ-induced apoptosis. rhIL-15 even promoted hair regrowth after experimental AA induction in human scalp skin xenotransplants on SCID/beige mice in vivo. Our data introduce IL-15 as a novel, functionally important HF-IP guardian whose signaling is constitutively defective in scalp HFs of AA patients. Our data suggest that selective stimulation of intrafollicular IL-15Rα signaling could become a novel therapeutic approach in AA management, while blocking it pharmacologically may hinder both HF-IP restoration and hair re-growth and may thus make HFs more vulnerable to AA relapse.

323 A Novel, Stress-Responsive and Clinically Predictive Humanized Mouse Model of Atopic Dermatitis: Autologous Th2-Polarized Lymphocytes Suffice to Induce Characteristic Lesions in Healthy Non-Atopic Human Skin Xenotransplants In Vivo

Clinically relevant in vivo models for atopic dermatitis (AD) are needed, in which the minimal signals required for AD induction in human skin can be defined and candidate therapeutics explored. Here, we report a novel humanized AD mouse model that uses split-thickness skin from healthy, non-atopic female human donors xenotransplanted onto SCID/beige mice and injected with autologous, Th2-polarized PBMCs. After intradermal injection of PBMCs preincubated only with IL-2, IL-4 and LPS, the xenotransplants develop a phenocopy of human AD lesions, including epidermal hyperplasia, hyperproliferation, erythema, and skin barrier impairment (reduced filaggrin and claudin-1 expression, altered corneocyte nanotexture [atomic force miocroscopy]).

90 Efficacy of Porcine Skin Xenotransplants Indistinguishable from Allograft in First-in-human Clinical Evaluation

IntroductionHuman cadaver allograft (HCA) is the current standard of care for temporary wound closure of large burns, but a critical need for high-quality alternatives exists. Porcine skin shares many similarities with human skin, and hyperacute rejection is prevented via a single genetic modification. Like human skin, non-terminally sterilized porcine skin contains viable dermal and epidermal cells and intact vasculature that enables restoration of barrier function. These characteristics are distinct from those of traditional, terminally sterilized “xenografts” and may offer greater therapeutic capability. We report here key efficacy outcomes specific to severe burn care from a first-in-human clinical trial to assess the capability of genetically engineered porcine skin xenotransplants to provide temporary wound closure for severe and extensive deep-partial and full-thickness burn wounds, compared to HCA.MethodsSplit-thickness skin containing epidermal and dermal layers was harvested from Designated Pathogen Free, GalT-KO, porcine donors, cGMP processed to achieve USP< 71 > sterility and cryopreserved to retain >70% cell viability. These were transplanted side by side with HCA on debrided full-thickness burn wounds in six human subjects. Temporary wound closure, incidence of complete wound closure following autografting, and quality of healing, including scarring, contour, and feel of healed skin, normalization of skin markings or pigmentation, were independently assessed.ResultsAcross all patients and assessment time points, adherence, vascularity, and overall appearance were indistinguishable between porcine skin xenotransplants and HCA control. After surgical removal, wound beds treated with each type of dressing were perfused and otherwise appeared equivalent and clinically suitable for autografting. Long-term outcomes were comparable between wound sites treated with porcine skin or HCA with no discernable differences in scarring or cosmesis.ConclusionsSkin xenotransplants effectively provided temporary wound closure and restoration of barrier function via intact native vasculature, active cells, decreased antigenicity, and high-quality tissue architecture unimpacted by cryopreservation and thawing. These results show clinical promise as an interchangeable alternative to HCA in the treatment of severe burns. Expanded clinical evaluation is ongoing.

LB709 Therapeutic effect of γδTregs cells in Alopecia Areata

Regulatory γδ T cells (γδTregs) may exert therapeutic effects under some experimental autoimmune disease (AID) conditions. This encouraged us to explore whether this this also applies to alopecia areata (AA), one of the most common human AIDs. Triple immunofluorescence (IF) staining was performed to determine the distribution of γδTregs in human skin presence of γδTregs on skin sections of AA patients. Autologous circulating human γδ Tregs were expanded and either co-cultured with organ-cultured, stressed human scalp hair follicles (HFs) ex vivo or injected into experimentally induced AA lesions on human scalp skin xenotransplants on SCID mice.

135 Vital, Porcine Skin Xenotransplants Provide Safe and Efficacious Temporary Wound Closure of Severe Burns in a First-in-Human Phase I Clinical Trial

Abstract Introduction Temporary wound closure with human allograft skin is considered the gold standard after early excision of a large burn injury. Limitations of allograft include availability, cost, and safety; thus, an alternative that provides the same quality with enhanced safety would be a valuable surgical adjunct to the clinical options currently available to treat severe and extensive full thickness burn wounds. A live cell skin xenotransplant from a clinical grade porcine donor is one candidate. Advantages of this alternative include retention of 70% or more of the innate metabolic activity following cryopreservation, vascularly favorable dermal thickness, and genetic modifications that eliminate hyperacute graft rejection. Combined, these result in pliability, strength, survivability, and function that far exceed those of conventional xenografts and mirror those of human allograft. Methods Split-thickness skin xenotransplants containing vital dermal and epidermal cells were aseptically procured from alpha-galactosyltransferase knockout porcine donors from a closed, Designated Pathogen Free, colony. They were then processed to achieve both sterility and cellular viability and cryopreserved for long term storage. In 2018, the FDA authorized a first-in-human Phase I clinical trial to evaluate the safety and tolerability of a genetically modified skin xenotransplant to treat severe and extensive burn wounds. A two cohort, open-label, dose-escalation study evaluated 6 consenting patients with severe burns requiring allograft. Each received surgical grafting with a skin xenotransplant and human allograft skin in a side-by-side, in-situ comparison. Results The skin xenotransplant was well tolerated by all patients, resulting in zero adverse events or safety issues, and without zoonotic disease transmission. In all cases, the skin xenotransplant appeared indistinguishable from the human allograft comparator and at the time of autografting, both were vascularized and fully adherent. These findings build upon the series of preclinical studies reported by these authors and presented at the ABA in 2019. Conclusions These highly promising patient outcomes demonstrate a potential treatment for complicated burns, especially when human allograft skin is unavailable. Further study of the efficacy of the porcine skin xenotransplants is warranted. As such, a multi-center, Phase II efficacy trial is planned for 2021.

Mouse models of atopic dermatitis: a critical reappraisal.

Mouse models for atopic dermatitis (AD) are an indispensable preclinical research tool for testing new candidate AD therapeutics and for interrogating AD pathobiology in vivo. In this Viewpoint, we delineate why, unfortunately, none of the currently available so-called "AD" mouse models satisfactorily reflect the clinical complexity of human AD, but imitate more "allergic" or "irriant" contact dermatitis conditions. This limits the predictive value of AD models for clinical outcomes of new tested candidate AD therapeutics and the instructiveness of mouse models for human AD pathophysiology research. Here, we propose to initiate a rational debate on the minimal criteria that a mouse model should meet in order to be considered relevant for human AD. We suggest that valid AD models should at least meet the following criteria: (a) an AD-like epidermal barrier defect with reduced filaggrin expression along with hyperproliferation, hyperplasia; (b) increased epidermal expression of thymic stromal lymphopoietin (TSLP), periostin and/or chemokines such as TARC (CCL17); (c) a characteristic dermal immune cell infiltrate with overexpression of some key cytokines such as IL-4, IL-13, IL-31 and IL-33; (d) distinctive "neurodermatitis" features (sensory skin hyperinnervation, defective beta-adrenergic signalling, neurogenic skin inflammation and triggering or aggravation of AD-like skin lesions by perceived stress); and (e) response of experimentally induced skin lesions to standard AD therapy. Finally, we delineate why humanized AD mouse models (human skin xenotransplants on SCID mice) offer a particularly promising preclinical research alternative to the currently available "AD" mouse models.

Immunological response in cynomolgus macaques to porcine α-1,3 galactosyltransferase knockout viable skin xenotransplants-A pre-clinical study.

Allogeneic skin recovered from human deceased donors (HDD) has been a mainstay interim treatment for severe burns, but unfortunately risk of infectious disease and availability limitations exist. Genetically engineered ɑ-1,3 galactosyltransferase knockout (GalT-KO) porcine source animals for viable skin xenotransplants may provide a promising clinical alternative. Four cynomolgus macaque recipients received full-thickness surgical wounds to model the defects arising from excision of full-thickness burn injury and were treated with biologically active skin xenotransplants derived from GalT-KO, Designated Pathogen Free (DPF) miniature swine. Evaluations were conducted for safety, tolerability, and recipient immunological response. All skin xenotransplants demonstrated prolonged survival, vascularity, and persistent dermal adhesion until the study endpoint at post-operative day 30. No adverse outcomes were observed during the study. Varying levels of epidermolysis coincided with histologic detection of CD4+ and CD8+T cells, and other cellular infiltrates in the epidermis. Recipient sera IgM and IgG demonstrated significant antibody immune response to non-α-1,3-galactose porcine xenoantigens. Separately, specific wound healing mediators were quantified. Neither porcine cell migration nor PERV were detected in circulation or any visceral organs. These results provide a detailed analysis of vital skin xenotransplants utilizing a non-human primate model to predict the anticipated immunological response of human patients. The lack of adverse rejection even in the presence of elevated Ig indicates this is a prospective therapeutic option. The findings reported here directly supported regulatory clearance for a first-in-man, Phase I xenotransplantation clinical trial.

Skin xenotransplantation: technological advances and future directions.

To summarize the evolution of skin xenotransplantation and contextualize technological advances and the status of clinically applicable large animal research as well as prospects for translation of this work as a viable future treatment option. Porcine xenografts at the start of the millennium were merely biologic dressings subject to rapid rejection. Since then, numerous important advances in swine to nonhuman primate models have yielded xenotransplant products at the point of clinical translation. Critical genetic modifications in swine from a designated pathogen-free donor herd have allowed xenograft survival reaching 30 days without preconditioning or maintenance immunosuppression. Further, xenograft coverage appears not to sensitize the recipient to subsequent allograft placement and vice versa, allowing for temporary coverage times to be doubled using both xeno and allografts. Studies in large animal models have led to significant progress in the creation of living, functional skin xenotransplants with clinically relevant shelf-lives to improve the management of patients with extensive burns.

Vital, Porcine, Gal-Knockout Skin Transplants Provide Efficacious Temporary Closure of Full-Thickness Wounds: Good Laboratory Practice-Compliant Studies in Nonhuman Primates.

Vital, genetically engineered porcine skin transplants have long been regarded as a promising treatment option for severe burn wounds. The objective of this two-part, preclinical study was to evaluate the ability of vital, split-thickness skin xenotransplants derived from designated pathogen-free, alpha 1,3 galactosyltransferase knockout miniature swine to provide temporary wound closure of full-thickness wound defects intended to model severe and extensive, deep partial- and full-thickness burn wounds. In part 1 of the study, four full-thickness wound defects were introduced in four cynomolgus macaques recipients and, then engrafted with two xenografts and two allografts to achieve temporary wound closure. On POD-15, autografts were used to achieve definitive wound closure and were observed until POD-22. In part 2 of the study, four additional subjects each received two full-thickness wound defects, followed by two xenografts to achieve temporary wound closure, and were observed postoperatively for 30 days without further intervention. All grafts were assessed for signs of adherence to the wound bed, vascularity, and signs of immune rejection via gross clinical and histological methods. Xenograft and allograft comparators were equivalent in part 1, and later autografts were otherwise indistinguishable. In part 2, all xenotransplants demonstrated adherence, vascularity, and survival until POD-30. These were unexpected results that exceed previously published findings in similar models. Furthermore, the ensuing GLP-study report directly supported regulatory clearance, permitting a phase I clinical trial. This solution holds great promise as an alternative to human cadaver allograft, the current standard of care for the treatment of severe burns.

An osteopontin-derived peptide inhibits human hair growth at least in part by decreasing fibroblast growth factor-7 production in outer root sheath keratinocytes.

Given that unwanted hair growth (hirsutism, hypertrichosis) can cause major psychological distress, new pharmacological treatment strategies with safe and effective hair growth inhibitors that do not destroy the hair follicle (HF) and its stem cells need to be developed. To establish if osteopontin-derived fragments may modulate human hair growth given that human HFs express the multifunctional, immunomodulatory glycoprotein, osteopontin. Our hypothesis was tested exvivo and invivo by using a newly generated, toxicologically well-characterized, modified osteopontin-derived peptide (FOL-005), which binds to the HF. In organ-cultured human HFs and scalp skin, and in human scalp skin xenotransplants onto SCID mice, FOL-005 treatment (60 nmol L-1 to 3 μmol L-1 ) significantly promoted premature catagen development without reducing the number of keratin 15-positive HF stem cells or showing signs of drug toxicity. Genome-wide DNA microarray, quantitative reverse-transcriptase polymerase chain reaction and immunohistochemistry revealed decreased expression of the hair growth promoter, fibroblast growth factor-7 (FGF7) by FOL-005, while cotreatment of HFs with recombinant FGF7 partially abrogated FOL-005-induced catagen promotion. With caveats in mind, our study identifies this osteopontin-derived peptide as an effective, novel inhibitory principle for human hair growth exvivo and invivo, which deserves systematic clinical testing in hirsutism and hypertrichosis. What's already known about this topic? The treatment of unwanted hair growth (hypertrichosis, hirsutism) lacks pharmacological intervention, with only few and often unsatisfactory treatments available. Osteopontin is prominently expressed in human HFs and has been reported to be elevated during catagen in the murine hair cycle. What does this study add? We tested the effects on hair growth of a novel, osteopontin-derived fragment (FOL-005) exvivo and invivo. In human hair follicles, high-dose FOL-005 significantly reduces hair growth both exvivo and invivo. What is the translational message? High-dose FOL-005 may provide a new therapeutic opportunity as a treatment for unwanted hair growth.

Ultraviolet B irradiation increases the expression of trichohyalin-like 1 protein in human skin xenotransplants.

Trichohyalin-like (TCHHL)1 is a member of the fused-type S100 protein family. Its function remains unknown, although it has been reported to be expressed in the basal layer of the normal epidermis. The aim of this study was to investigate the effects of ultraviolet B (UVB) irradiation on the expression of TCHHL1 in human skin xenotransplants. Expression of TCHHL1 mRNA was increased in the UVB-exposed skin 2 days after UVB irradiation. TCHHL1 was immunohistochemically detected in the basal layers after sham irradiation. However, on Day 2 after irradiation, the TCHHL1 signals were spread throughout the basal and spinous layers of the irradiated skin, with increased expression of cytokeratin 14 and a dramatic increase in the number of Ki67-positive cells observed. These results show that TCHHL1 is a novel protein whose expression can be increased by UVB irradiation. In addition, this study experimentally shows that TCHHL1 is expressed in proliferative keratinocytes.

1429 VEGF mediates rejuvenation of aged human skin xenografts in young mice

Previously we have shown that transplantation of aged human skin onto young SCID mice results in a rejuvenated human epidermal phenotype. Here, we demonstrate that the rejuvenation of old human skin xenotransplants onto young SCID/beige mouse skin well extends beyond the epidermis and leads to statistically significant improvements in multiple skin aging-associated read-outs assessed by quantitative histomorphometry, which showed e.g. thickening of the epidermis, along with basal layer keratinocyte proliferation, increased vascularization, significantly more collagen type I and III and elastic fibers, and number of epidermal melanocytes in aged human skin xenotransplants.Gene expression RNA-Seq analyses of DEGs showed in 1week versus pre-transplant numerous transcripts related to hypoxia, VEGF and angiogenesis, inflammation, the Notch, TGF-β and IGF pathways, genes related to reinnervation, as well as keratins and epidermal regulators. qRT-PCR confirmed an upregulation of VEGFA and HIF1A, as well as angiogenesis-related genes. Proinflammatory infiltrates expressing CXCL1 and CXCL5 were also confirmed by these data. Skin rejuvenation was primarily mediated by the angiogenesis-promoting growth factor, VEGF, since injection of anti-VEGF blocking antibodies alone, but not of TGF-ß, IGF-1- or HGF-neutralizing antibodies, sufficed to prevent the rejuvenation of old human skin in vivo. Conversely, intradermal injection of VEGF-loaded nanoparticles reversed the aged human skin phenotype when aged human skin was grafted onto old mice. Our study shows that a remarkable degree of rejuvenation of aged human skin is possible in vivo and that VEGF-mediated signaling i a key pathway in this process.

INKT cells ameliorate human autoimmunity: Lessons from alopecia areata

Alopecia areata (AA) is understood to be a CD8+/NKG2D+ T cell-dependent autoimmune disease. Here, we demonstrate that human AA pathogenesis of is also affected by iNKT10 cells, an unconventional T cell subtype whose number is significantly increased in AA compared to healthy human skin. AA lesions can be rapidly induced in healthy human scalp skin xenotransplants on Beige-SCID mice by intradermal injections of autologous healthy-donor PBMCs pre-activated with IL-2. We show that in this in vivo model, the development of AA lesions is prevented by recognized the iNKT cell activator, α-galactosylceramide (α-GalCer), which stimulates iNKT cells to expand and produce IL-10. Moreover, in pre-established humanized mouse AA lesions, hair regrowth is promoted by α-GalCer treatment through a process requiring both effector-memory iNKT cells, which can interact directly with CD8+/NKG2D+ T cells, and IL-10. This provides the first in vivo evidence in a humanized model of autoimmune disease that iNKT10 cells are key disease-protective lymphocytes. Since these regulatory NKT cells can both prevent the development of AA lesions and promote hair re-growth in established AA lesions, targeting iNKT10 cells may have preventive and therapeutic potential also in other autoimmune disorders related to AA.

311 Group 3 innate lymphoid cells (ILC3) induce psoriasiform lesions in human skin xenotransplants in vivo

311 Group 3 innate lymphoid cells (ILC3) induce psoriasiform lesions in human skin xenotransplants in vivo

136 The expression of trichohyalin-like 1 protein in human skin xenotransplants is enhanced by ultraviolet B irradiation

136 The expression of trichohyalin-like 1 protein in human skin xenotransplants is enhanced by ultraviolet B irradiation

Targeting miR-21 to Treat Psoriasis

Psoriasis is a common inflammatory skin disease with limited treatment options that is characterized by a complex interplay between keratinocytes, immune cells, and inflammatory mediators. MicroRNAs (miRNAs) are regulators of gene expression and play critical roles in many human diseases. A number of miRNAs have been described to be up-regulated in psoriasis, but their causal contribution to disease development has not been demonstrated. We confirm that miR-21 expression is increased in epidermal lesions of patients with psoriasis and that this leads to reduced epidermal TIMP-3 (tissue inhibitor of matrix metalloproteinase 3) expression and activation of TACE (tumor necrosis factor-α-converting enzyme)/ADAM17 (a disintegrin and metalloproteinase 17). Using patient-derived skin samples and mouse models of psoriasis, we demonstrate that increased miR-21 may be a consequence of impaired transcriptional activity of Jun/activating protein 1 (AP-1), leading to activation of the interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (Stat3) pathway. Inhibition of miR-21 by locked nucleic acid (LNA)-modified anti-miR-21 compounds ameliorated disease pathology in patient-derived psoriatic skin xenotransplants in mice and in a psoriasis-like mouse model. Targeting miR-21 may represent a potential therapeutic option for the treatment of psoriasis.

α5 and α2 Integrin Gene Transfers Mimic the PDGF-B–Induced Transformed Phenotype of Fibroblasts in Human Skin

Platelet-derived growth factor (PDGF)-B is a proto-oncogene capable of transforming fibroblasts. Using adenoviral vectors, we tested whether endogenous PDGF-B expression in human skin xenotransplants leads to changes in the expression of α5 and α2 integrin subunits and whether integrin overexpression leads to PDGF-related changes in the skin. In vitro, transduction of fibroblasts with PDGF-B or the integrin α5 subunit stimulated multilayered growth and spindle-type morphology, both markers of mesenchymal cell transformation. In vivo, PDGF-B transduction of the human dermis was associated with up-regulation of collagen and fibronectin synthesis, increases in α5 and α2 integrin subunit expression, vessel formation, and proliferation of fibroblasts, keratinocytes, and pericytes. A similar stromal response was induced when α5 and α2 integrin subunits were overexpressed in the human dermis, suggesting that integrins play a major role in the induction of a transformed phenotype of fibroblasts by PDGF-B.

1α,25-Dihydroxycholecalciferol and Cyclosporine Suppress Induction and Promote Resolution of Psoriasis in Human Skin Grafts Transplanted on to SCID Mice

Accumulating evidence has emphasized the importance of immunocompetent cells in determining the psoriatic phenotype. We have investigated the effect of 1alpha,25-dihydroxycholecalciferol, the naturally occurring active form of vitamin D3, cyclosporine A, and interleukin-10 on the phenotype of human psoriatic skin xenotransplants. First, psoriatic skin transplants were injected with either 1alpha,25-dihydroxy- cholecalciferol, cyclosporine A, or interleukin-10. Second, we determined the ability of autologous lymphocytes, activated in vitro using staphylococcal enterotoxin B and interleukin-2 and then exposed to either 1alpha, 25-dihydroxycholecalciferol or cyclosporine A, to induce psoriatic lesions if they were injected into the dermis of uninvolved skin grafts. We found that injections into transplanted psoriatic plaques of either 1alpha,25-dihydroxycholecalciferol or cyclosporine A, but not interleukin-10, resulted in a consistent reduction in the clinical and histologic score of psoriasis with remission towards uninvolved psoriatic skin. Injection of activated immunocytes into symptomless psoriatic skin grafts, changed the grafts towards plaque-type psoriasis with silvery scale, parakeratosis, elongated rete pegs, acanthosis, and dermal angiogenic reaction. In contrast, if activated immunocytes were exposed to 1alpha, 25-dihydroxycholecalciferol or cyclosporine A prior to injection, only minimal changes occurred. It was determined that neither staphylococcal enterotoxin B and interleukin-2 activation by itself, nor the drugs investigated, changed the CD4/CD8 ratio of activated (CD25 + ) cells. Our results are consistent with the hypothesis that psoriasis may be induced by activated T lymphocytes, and indicate that novel immunomodulatory drugs can serve to inhibit the pathogenetic ability of immunocytes in psoriasis.

Migration of langerhans cells and maturation of their peripheral blood precursors are stimulated by vitamin D3 in normal and psoriatic skin xenotransplants

Migration of langerhans cells and maturation of their peripheral blood precursors are stimulated by vitamin D3 in normal and psoriatic skin xenotransplants