Controlled Delivery of T-box21 Small Interfering RNA Ameliorates Autoimmune Alopecia (Alopecia Areata) in a C3H/HeJ Mouse Model

Abstract

Autoimmune alopecia (alopecia areata) is considered to be triggered by a collapse of immune privilege in hair follicles. Here we confirmed that infiltrating CD4 T lymphocytes around hair follicles of patients with alopecia areata were primarily CCR5-positive with few CCR4-positive cells, suggesting a dominant role of Th1 cells in the alopecic lesion. Given this finding, we sought to elucidate the effect of cytokine therapy in C3H/HeJ mice, a mouse model of alopecia areata, by applying recombinant interleukin-4 and neutralizing anti-interferon-␥ antibody. We found that local injections of both interleukin-4 and neutralizing anti-interferon-␥ antibody effectively treated alopecia in C3H/ HeJ mice. Results from immunohistochemistry and semiquantitative reverse transcription-polymerase chain reaction demonstrated that intralesional injection of interleukin-4 suppressed CD8 T cell infiltrates around the hair follicles and repressed enhanced interferon-␥ mRNA expression in the affected alopecic skin. Furthermore, Th1 transcription factor T-box21 small interfering RNAs conjugated to cationized gelatin showed mitigating effects on alopecia in C3H/HeJ mice, resulting in the restoration of hair shaft elongation. Taken together, the use of gelatin-small interfering RNA conjugates promises to be a novel, efficient, and safe tool as an alternative gene therapy for the treatment of various human diseases. To our knowledge, this is the first report of effective controlled delivery of small interfering RNA using biodegradable cationized gelatin microspheres in an animal model of disease.

An update on alopecia areata

“…Possibly, the recent reports of the use of T-box21 small interfering RNA ameliorating alopecia areata in mouse models [50 ] will lead in that direction. Regardless, more controlled studies need to be performed in adults and children with alopecia areata, with particular focus on the patients' measures of quality of life.…”

Study of Th1/Th2 balance in peripheral blood mononuclear cells of patients with alopecia areata

“…For example, Nakamura et al indicated the Th1-predominant lymphocytic infi ltration around hair follicles of patients with alopecia areata [18]. In another study, Ito et al demonstrated that patients with acute AA have a higher frequency of circulating CXCR3+ CD4+ Th1 cells [19].…”

“…Their results indicate that 90% of wild-type mice [IFN-γ(+/+)] developed AA, after grafting alopecia areata-affected skin, while none of the IFN-γ(-/-) mice exhibited hair loss [26]. Moreover, it has been reported that local injections of both IL-4 and neutralizing anti-IFN-γ antibody effectively treated alopecia in C3H/ HeJ mice [27].…”

Biology of Human Hair: Know Your Hair to Control It

“…Interestingly, topical application of cationic nanoliposomes loaded with specific siRNA has been tested as an effective approach for control of cutaneous melanomas [146], and siRNAs conjugated to cationized gelatin showed a positive effect on symptoms of alopecia in C3H/HeJ mice [147]. A promising line of research has been developed by Kerner and colleagues that proposes modulating androgen receptor expression with RNAi for hair and skin therapy [148,149].…”