Topical FK506: a potent immunotherapy for alopecia areata? Studies using the Dundee experimental bald rat model

Abstract

We elected to examine the efficacy of the topically applied immunosuppressive agent FK506 (Prograf) in the treatment of alopecia areata (AA) using the Dundee experimental bald rat (DEBR) model. Thirty lesional DEBR rats were allocated to five groups of six. Group 1 rats received 0.1 mL of a 0.25% solution of FK506 within a 2 x 2 cm marked area on one bald flank twice a week (125 micrograms FK506/cm2 per week) for 8 weeks, while the contralateral flank was left untreated. In group II, 0.05 mL of a 0.1% solution of FK 506 was applied 5 days per week on one flank (62.5 micrograms FK506/ cm2 per week) and control vehicle to the opposite flank for 8 weeks. Group III rats were treated as in group II except that drug and vehicle were applied twice a week (25 micrograms FK506/cm2 per week) for 4 weeks. A positive control group received orally administered cyclosporin A (CsA) (10 mg/kg daily) for 8 weeks and a further group was left untreated. Rats were regularly examined and photographed with skin biopsies taken from groups II and III. All FK 506-treated rats regrew hair at the site of drug application within 14-21 days. Growth continued for 3 weeks beyond termination of treatment after which gradual hair loss was observed. No hair growth was seen as a result of vehicle application and hair loss continued on untreated areas and in the untreated control group. Immunohistology revealed a drastic reduction in the follicular inflammatory infiltrate at the site of the FK506 application. The oral CsA group responded by simultaneous regrowth of hair over the whole body. Our findings suggest that FK506 may have considerable potential as a topical treatment for AA.

Collapse and Restoration of MHC Class-I-Dependent Immune Privilege

“…81,82 That the potently immunosuppressive immunophilin ligand, FK506, markedly down-modulates epithelial MHC class I expression in organ-cultured human hair follicles ( Figure 1, X and Y, and Figure 2E) is a clinically most encouraging finding: on the one hand, FK506 is already widely used in clinical medicine, eg, for the suppression of liver transplant rejection, 85 on the other, FK506 has already been shown to reverse hair loss in murine and rat models of alopecia areata. 86 Therefore, the current study identifies with FK506 a widely available, registered drug that could, in principle, be tested immediately for its MHC class I down-regulating capacity in a wide range of clinical conditions where this is therapeutically desirable (eg, multiple sclerosis, 9 autoimmune uveitis, 10 mumps orchitis, 11 autoimmune chronic active hepatitis, 13,14 and alopecia areata 7,12 ). In addition, the natural, locally generated MHC class I suppressors IGF-1, TGF-␤1, and ␣-MSH, also are promising candidates for immune privilege restoration and for MHC class I suppression whenever this is clinically desired.…”

Comparison of Alopecia areata in Human and Nonhuman Mammalian Species

“…In addition, it was not necessary to have extensive hair loss for nail deformities to occur. Unlike human AA, extreme nail involvement resulting in near absence of McElwee/Boggess/Olivry/Oliver/Whiting/ Tobin/Bystryn/King/Sundberg [130,[153][154][155][156][157][158] DEBR rat [9,11,13,110,111] C3H/HeJ mouse [9,16,17] A C3H/HeJBir mouse substrain, developed from C3H/HeJ mice, was created for use in inflammatory bowel disease/inheritable colitis studies. This strain also develops AA in similar fashion to the C3H/HeJ strain from which it was derived with a frequency of 4.7% [95].…”

“…Studies on topical application of FK506 to mice have shown its ability to induce anagen in catagen/telogen pelage hair follicles and prolongation of the hair follicles in the anagen growth phase [108,109]. Experimentally, DEBR rats generate excellent hair regrowth with topical application of FK506, an immunomodulatory drug that may have potential as a more effective clinical treatment [110,111].…”

Study of therapeutic comparison of tacrolimus 0.1% and minoxidil 2% in alopecia areata

“…Initial trials revealed tacrolimus as a potential tool for treatment of AA [9,10]. The peculiarity of tacrolimus was the induction of anagen and hence hair growth promotion was observed with topical but not systemic route of administration.…”