Monoclonal antibodies (mAbs) have become a powerful tool in the treatment of a range of diseases. However, as their therapeutic potential is generally destroyed in the gut, mAbs are usually administered intravenously. Now, researchers in the laboratory of Howard Weiner have taken advantage of the unique properties of the mucosal immune system, and show that oral delivery of mAbs directed against CD3, a component of the T-cell antigen–receptor complex, might in fact constitute a novel and powerful therapeutic approach that could be widely applicable for the treatment of human autoimmune conditions.

Tweaking the immune system to revert autoimmune disease and to prevent graft rejection after transplantation remains one of the major challenges in immunology. Over the past decade, considerable attention has been focussed on naturally occurring T-regulatory cells (Tregs) for the modulation of undesired immune responses. As these cells have an important role in ensuring oral tolerance and are preferentially induced at mucosal surfaces, Ochi et al. were first to investigate whether Tregs could be activated by oral administration of immunomodulatory antibodies.

The antibodies used in this study were based on intravenous anti-CD3 mAbs approved for transplant rejection more than 20 years ago. Recently, it became apparent that these antibodies can do more than simply depress all antibody responses — they can also induce tolerance to specific antigens by activating Tregs.

As intravenous administration of anti-CD3 mAbs can have severe side effects due to the induction of cytokine release, the authors examined whether this problem could be circumvented by orally delivering anti-CD3 mAbs.

In two different types of experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, the authors showed that a low dose of antibody could suppress and/or delay the onset of disease. Interestingly, unlike intravenous anti-CD3, oral CD3 could also prevent disease, and the fact that the same antibody was effective in both models points to a potential universal mechanism that is not antigen specific and which could be useful in a wide range of autoimmune conditions.

The authors found a fundamental immunological difference between intravenous and oral CD3-specific mAb: oral mAb did not modulate the T-cell receptor–CD3 complex on T cells, deplete T cells or induce cell division, even at high doses. Instead, the results suggest that the antibody exerts a weak signal to T cells in the gut that enhances the regulatory function of a unique subset of Tregs. These are CD4+CD25− T cells that express surface latency-associated peptide (LAP+), and their function depends on the anti-inflammatory cytokine transforming growth factor-β. How exactly they are related to other Tregs remains to be determined, and the authors speculate that they take part in the natural recovery mechanism in EAE.

The authors report that ongoing studies also demonstrate the effectiveness of oral anti-CD3 in models of diabetes, arthritis and transplantation, and are also effective when administered nasally. The simplicity of the method and presumed good tolerance, even for chronic use, make this a particularly exciting approach for the management of inflammatory T-cell-mediated diseases.