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Effect of systemic exposure of JAK1 Inhibition (AZ13748709) in C3H/HeJ Mice with Alopecia Areata In Vivo

ABSTRACT: JAK inhibition by means of clinically available pan JAK inhibitors has recently demonstrated great efficacy in both restoring hair growth and resolving inflammation in the skin of patients with Alopecia Areata (AA). These effects are dose dependent and mainly efficacious at ranges close to a questionable risk profile. Given the great responses to JAK inhibition and the current lack of efficacious treatments in AA, it is exciting to explore the possibilities to separate the beneficial and adverse effects in order to provide a successful treatment option for these patients where the medical need is still vastly unmet. We have demonstrated that specific inhibition of JAK1 at relevant concentrations produces a fast resolution of inflammation and complete restoration of hair growth in the C3H/HeJ model of AA and importantly, that systemic exposure is essential for efficacy.

ORGANISM(S): Mus musculus

PROVIDER: GSE94236 | GEO | 2023/01/30

REPOSITORIES: GEO

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Project description:We have demonstrated therapeutic efficacy of MDSC in mouse Alopecia Areata (AA). In the same AA model, we now asked whether MDSC exosomes (MDSC-Exo) can replace MDSC. MDSC-Exo from bone marrow cells (BMC) cultures of healthy donors could substantially facilitate treatment. With knowledge on MDSC-Exo being limited, their suitability needs to be verified in advance. Protein marker profiles suggest comparability of BMC- to ex vivo collected inflammatory MDSC/MDSC-Exo in mice with a chronic contact dermatitis, which is a therapeutic option in AA. Proteome analyses substantiated a large overlap of function-relevant molecules in MDSC and MDSC-Exo. Furthermore, MDSC-Exo are taken up by T cells, macrophages, NK, and most avidly by Treg and MDSC-Exo uptake exceeds binding of MDSC themselves. In AA mice, MDSC-Exo preferentially target skin-draining lymph nodes and cells in the vicinity of remnant hair follicles. MDSC-Exo uptake is accompanied by a strong increase in Treg, reduced T helper proliferation, mitigated cytotoxic activity, and a slight increase in lymphocyte apoptosis. Repeated MDSC-Exo application in florid AA prevented progression and sufficed for partial hair regrowth. Deep sequencing of lymphocyte mRNA from these mice revealed a significant increase in immunoregulatory mRNA, including FoxP3 and arginase 1. Downregulated mRNA was preferentially engaged in prohibiting T cell hyperreactivity. Taken together, proteome analysis provided important insights into potential MDSC-Exo activities, these Exo preferentially homing into AA-affected organs. Most importantly, changes in leukocyte mRNA seen after treatment of AA mice with MDSC-Exo sustainably supports the strong impact on the adaptive and the non-adaptive immune system, with Treg expansion being a dominant feature. Thus, MDSC-Exo could potentially serve as therapeutic agents in treating AA and other autoimmune diseases. These shotgun data represent GeLC-MS/MS analyses of murine MDSC and CDMS+ cells and of the exosomes from both cell types. Three pulldown RPLC-MS/MS experiments are also included. Cysteines were carbamidomethylated via iodoacetamide. Tandem mass spectrometry took place in an LTQ Orbitrap XL, with scans acquired in the linear ion trap.

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Effect of systemic exposure of JAK1 Inhibition (AZ13748709) in C3H/HeJ Mice with Alopecia Areata In Vivo

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