Hypothesis Testing: CTLA4 Co-stimulatory Pathways Critical in the Pathogenesis of Human and Mouse Alopecia Areata

Rodent models with autoimmune diseases provide many insights to unravel the complexities of human diseases as tools for hypothesis testing and preclinical drug efficacy screening (Sun et al., 2008). Nearly ten years ago, we performed a comparative mouse and human gene array study to identify potentially dysregulated genes in alopecia areata (AA). One such gene was CLTA4, a co-stimulatory T cell ligand that binds B7.1 (CD80) and B7.2 (CD86) on antigen presenting cells (Carroll et al., 2002). Since AA is an autoimmune disease in humans and mice, we hypothesized that CTLA4, through its co-stimulatory T cell and antigen presenting cell (APC) pathways, is a critical regulator of AA onset and maintenance based on studies in the mouse model of AA (Sundberg et al., 1994). We performed pre-clinical studies by intraperitoneally injecting monoclonal antibodies against APC surface markers B7.1 (CD80) and B7.2 (CD86) and a monoclonal anti-CTLA4 antibody into C3H/HeJ mice with and without AA to disrupt T cell and APC interactions involving CTLA4. The studies conclusively showed that these monoclonal antibodies effectively prevented onset of AA in the mouse model (Carroll et al., 2002; Sun et al., 2008). Subsequently, we confirmed increased numbers of skin infiltrating cells and skin draining lymph node cells in AA mice expressed CD80/86 while CTLA4 was increased in both populations; primarily on CD4+/CD25− cells (Zoller et al., 2002). CTLA4 (CD152) was similarly found with significantly elevated expression in peripheral blood CD4+/CD25− cells of AA patients (Zoller et al., 2004a) and a significantly larger percentage of peripheral blood mononuclear cells expressed CD80 (Zoller et al., 2004b).