Anti-CD81 antibodies reduce migration of activated T lymphocytes and attenuate mouse experimental colitis.

Inflammatory bowel disease (IBD) is an immunological disease associated with CD4+ T cell activation in the intestines. CD81 is a regulator of the immune system with multiple biological functions. Therefore, in this study, we assessed the contribution of CD81 to IBD pathophysiology and the therapeutic efficacy of anti-CD81 antibodies. Expression of CD81 was increased on activated T cells in vitro and in colitic mice in vivo. Therapeutic effects of anti-CD81 antibodies on colitic symptoms and inflammation were evaluated in mice with colitis, including long-term effects of the antibodies. Treatment with anti-CD81 antibodies improved colitis scores, reduced colon shortening, decreased loss of body weight, and resulted in fewer pathological changes of the colon in colitic mice. Moreover, the increased inflammatory markers in the blood of colitic mice were decreased by anti-CD81 antibodies. The anti-CD81 antibody treatment had long-lasting therapeutic effects on colitic mice, even after cessation of treatment. Two different clones of the anti-mouse CD81 antibody were also effective in mice with colitis. Furthermore, anti-CD81 antibodies reduced migration of CD4+ T cells both in colitic mice and in vitro. Thus, CD81 contributes to IBD pathology and treatment with anti-CD81 antibodies may be a potential novel therapy for IBD patients.

A monoclonal antibody recognizing a new epitope on CD81 inhibits T-cell migration without inducing cytokine production.

CD81 is involved in leukocyte migration and cytokine induction. Previous work found that anti-CD81 monoclonal antibodies (mAbs) showed therapeutic potential for several immune diseases via inhibiting leukocyte migration. Although the suppression of cell migration is a promising approach for treating immune diseases, some anti-CD81 mAbs can induce cytokine production, which may exacerbate disease. To obtain new anti-human CD81 mAbs that inhibited migration in the absence of cytokine production enhancement activity, we screened a human single chain variable fragment by phage library. One of the new anti-CD81 mAbs isolated, DSP-8250, had equivalent inhibitory cell migration activity with the established anti-CD81 mAb 5A6, but it lacked cytokine induction activity. These mAbs recognized different epitopes on CD81. mAb 5A6, which had inhibitory activity on T-cell migration and increased cytokine production, bound to three residues, Ser179, Asn180 and Phe186 of CD81. In contrast, DSP-8250, which had inhibitory activity on T-cell migration but no cytokine enhancement activity, bound to four residues, His151, Ala164, Ser168 and Asn172 of CD81 as a unique epitope. These results indicate that the set of His151, Ala164, Ser168 and Asn172 forms a novel epitope that might make the application of anti-CD81 mAb therapeutically useful.