Efalizumab down-regulates CD25 expression on FOXP3+ regulatory T cells and exacerbates the autoimmunity in primary Sjogren’s syndrome (96.4)

Rationale: FOXP3+ regulatory T cells (Tregs) are central to prevention of autoimmunity. Tregs expressed high level of CD25 and require IL-2 signaling for their function. Since CD25 is up-regulated with activation and LFA-1 is required, we hypothesize that efalizumab treatment would result in down-regulation of CD25 on Tregs and potential exacerbation of autoimmunity. Methods: Subjects with Sjogren’s syndrome were enrolled in a phase II clinical trial for weekly injection of efalizumab (1mg/kg) up to 25 weeks. Peripheral bloods were analyzed for Tregs by flow cytometry. Clinical conditions were measured by objective improvement in salivary and lacrimal flows and minor salivary gland (MSG) inflammation. Results: All three subjects had progressive down-regulation of CD11a and CD18 on Tregs (CD4+FOXP3+), which also correlated with dramatic decrease in CD25. There was no clinical improvement but instead repeat MSG biopsy showed significant increase in inflammation. Two subjects developed anti-dsDNA; one of whom developed multiple autoantibodies and lupus-like syndrome which resolved after efalizumab discontinuation. Conclusions: Efalizumab exacerbates Sjogren’s syndrome and induces significant increase in local inflammation and systemic autoimmunity. Inhibition of LFA-1 interaction on Tregs negatively affected their CD25 without altering their FOXP3 level. This study cautions the potential detrimental effect of efalizumab on Tregs and autoimmunity.