Apremilast and tofacitinib exert differential effects in the humanized mouse model of alopecia areata

Abstract

skin diseases reflected in the Cochrane Database of Systematic Reviews, 5 where psoriasis and decubitus ulcer were overrepresented diseases in terms of research, whereas urticaria and bacterial skin infections were underrepresented. A strength of this study is the interrelationship made between two large national datasets, from studies designed to be representative both of outpatient consultations and research activity in Spain, 3,4 and data from the GBDS. Among the limitations are that this study is restricted to 14 groups of diseases and only outpatient consultations, which may not be representative of all skin conditions, and that the unweighted number of publications might not be a good measure of research activity. Another limitation is that the periods of the three studies did not match exactly, which could affect the comparability of the data. However, burden of skin diseases and frequency of consultations are unlikely to differ from those in the period of the MaIND study. Our data suggest that melanoma might be overrepresented in research, whereas acne and viral infections could be underrepresented according to the demand for consultations and the disease burden. Research in psoriasis and dermatitis is proportional to the disease burden and demand for consultations whereas research in NMSC is scarce according to demand for consultations but disproportionate according to disease burden. Research priorities, should be conscious decisions that take into account quantitative data, such as the burden of skin conditions and the demand for clinical assistance in order to sort the need for resources, and qualitative research, such as James Lind Alliance Prioritization exercises, could be useful to select the main research questions within each topic.

Mouse models of atopic dermatitis: a critical reappraisal

“…Based on our long‐standing experience with humanized mouse models for psoriasis 128 and alopecia areata, 131 we expect that the systematic exploration of split thickness human skin xenotransplants on SCID mice likewise offers a particularly promising strategy for meeting the majority of the criteria identified above. If lesional AD skin is transplanted ideally to fully humanized SCID mice, the in vivo response of human AD to topical or systemic candidate therapeutics can likely be studied with much greater predictive value for clinical outcomes than any of the currently available mouse models.…”

“…We have shown that the intradermal injection of autologous PBMCs that have been pretreated in vitro with appropriate cytokine stimuli can robustly induce skin lesions in previously healthy human skin that are macroscopically and histologically indistinguishable from psoriasis 128 or alopecia areata lesions 131 . Therefore, it is reasonable to assume that the same can be achieved for AD lesions if one identifies and employs the right combination of AD‐promoting stimuli.…”

Frontiers in alopecia areata pathobiology research

“…[134][135][136] The question of whether IL-23 antagonism, such as through ustekinumab therapy, can reproducibly promote hair regrowth in patients with AA awaits systemic analysis. 137 Only a mild therapeutic effect was observed after treatment with IL-17, 138 whereas the phosphodiesterase 4 antagonist apremilast had insufficient therapeutic effects in patients with AA 139 and in the humanized AA mouse model, 140 in which apremilast nevertheless inhibited experimental induction of AA lesions in vivo. Collectively, in addition to targeting IFN-g-and JAK/ STAT-mediated signaling in patients with AA, several additional pathways that also deserve therapeutic targeting, at least in selected AA subpopulations/subtypes, deserve systematic exploration.…”

Involvement of ILC1-like innate lymphocytes in human autoimmunity, lessons from alopecia areata

“…This immune phenotype suggests that the immune cells used in our study are best classified as ILC1-like cells (Nabekura et al, 2021a), and documents that all experiments reported below were indeed performed with autologous ILC1-like cells rather than with NK cell subpopulations. Note that we had previously shown that NKG2D+/CD56+ NK cells suffice to induce AA lesions in human skin in vivo (Gilhar et al, 2013a;Laufer Britva et al, 2020) while iNKT cells are AA-protective in the humanized AA mouse model (Ghraieb et al, 2018). Subsequently, these ILC1-like cells were either used for HF co-culture assays or injected into healthy human scalp skin xenotransplants on SCID/beige mice (Gilhar et al, 2013a;Ito et al, 2005a).…”

“…Hematoxylin and eosin (H&E) staining was performed on cryo-or paraffin sections as previously described (Keren et al, 2018). For the ex vivo experiments, HFs cryosections were dehydrated for 40 minutes and fixed with acetone for 10 minutes at -20 o C (Ghraieb et al, 2018;Laufer Britva et al, 2020;Keren et al, 2015). The following primary antibodies were used for immunohistochemistry (IHC) or immunofluorescence microscopy (IF) of key HF immune privilege markers (Bertolini et al, 2020;Paus et al, 2005) The immunoreactivity patterns were assessed in standardized, well-defined reference areas by quantitative immunohistomorphoemtry (qIHM) by experienced, blinded observers, following our standard protocols for evaluating human HF immunology read-outs (Bertolini et al, 2014;Bertolini et al, 2016;Christoph et al, 2000;Harries et al, 2013b;Hardman-Smart et al, 2020), counting at least three reference areas each on three non-consecutive sections, presented randomly to the blinded observer(s).…”