The C3H/HeJ mouse and DEBR rat models for alopecia areata: review of preclinical drug screening approaches and results

Abstract

The C3H/HeJ inbred mouse strain and the Dundee Experimental Bald Rat (DEBR) strain spontaneously develop adult onset alopecia areata (AA), a cell-mediated disease directed against actively growing hair follicles. The low frequency of AA and the inability to predict the stage of AA as it evolves in the naturally occuring C3H/HeJ model of AA can be converted into a highly predictable system by grafting full thickness skin from AA-affected mice to normal haired mice of the same strain. The rat DEBR model develops spontaneous AA at a higher frequency than in the mouse model but they are more expensive to use in drug studies owing to their larger size. Regardless of the shortcomings of either model, these rodent models can be used succesfully to screen novel or approved drugs for efficacy to treat human AA. As the pathogenesis of AA follows the canonical lymphocytic co-stimulatory cascade in the mouse AA model, it can be used to screen compounds potentially useful to treat a variety of cell-mediated diseases. Efficacy of various agents can easily be screened by simply observing the presence, rate, and cosmetic acceptability of hair regrowth. More sophisticated assays can refine how the drugs induce hair regrowth and evaluate the underlying pathogenesis of AA. Some drugs commonly used to treat human AA patients work equally as well in both rodent models validating their usefulness as models for drug efficacy and safety for humanAA.

Figure 1

C3H/HeJ mice with full thickness skin graft-induced alopecia areata compared to the haired control that received normal skin from a normal C3H/HeJ mouse 20 weeks after skin grafts. Here are 3 views of the same mice (A-C) to illustrate the extent of the hair loss. The pale patch on the dorsal thorax is the healed full thickness skin graft from an affected C3H/HeJ mouse.

Figure 2

Histologic features of graft induced alopecia areata in C3H/HeJ mice. A late anagen hair follicle is surrounded and invaded by lymphocytes (A). Disruption of the root sheaths is seen in the higher magnification of A (B) and in cross sections of other affected follicles (C). Earlier stages of anagen and catagen can be affected (not shown).

Figure 3

Bulbs of late anagen hair follicles in normal C3H/HeJ mice form a well organized, pigmented hair fiber (A). By contrast, there are various degrees of follicular dystrophy in the bulb of mice with AA associated with lymphocyte infiltration (B, C).

Figure 4

Normal DEBR rats have a pigmented “hood” around their head and neck (A). By contrast, rats with alopecia areata have a scant hair coat. The pigmented “hood” is still visible as a consequence of melanin incontinence in the dystrophic hair follicles (B). Histologically, late anagen hair follicles in non-AA affected rats are similar to those in mice (C) while those affected with AA have lymphocytes in and around the follicles with various degrees of follicular dystrophy (D).