Oral CD3-specific antibody suppresses autoimmune encephalomyelitis by inducing CD4+CD25−LAP+ T cells

Abstract

A major goal of immunotherapy for autoimmune diseases and transplantation is induction of regulatory T cells that mediate immunologic tolerance. The mucosal immune system is unique, as tolerance is preferentially induced after exposure to antigen, and induction of regulatory T cells is a primary mechanism of oral tolerance. Parenteral administration of CD3-specific monoclonal antibody is an approved therapy for transplantation in humans and is effective in autoimmune diabetes. We found that orally administered CD3-specific antibody is biologically active in the gut and suppresses autoimmune encephalomyelitis both before induction of disease and at the height of disease. Orally administered CD3-specific antibody induces CD4+ CD25- LAP+ regulatory T cells that contain latency-associated peptide (LAP) on their surface and that function in vitro and in vivo through a TGF-beta-dependent mechanism. These findings identify a new immunologic approach that is widely applicable for the treatment of human autoimmune conditions.

Inhibition of Autoimmune Diabetes by Oral Administration of Anti-CD3 Monoclonal Antibody

“…The frequency returned to control levels by day 21. No significant changes in frequency of either CD45RB low CD4 ϩ or CD62L ϩ CD4 ϩ were observed in MLN, spleen, and PLN after oral anti-CD3 mAb (not shown), and, as in our studies of oral anti-CD3 mAb in the EAE model, we did not find that CD3 expression was decreased and/or downregulated after oral anti-CD3 mAb treatment (16).…”

“…Recovery of biologically active anti-CD3 mAb from the intestines of mice fed anti-CD3 mAb. We previously found that oral anti-CD3 mAb accumulates in the gut villi of mice after feeding as measured by immunohistochemistry (16). To determine whether we could recover biologically active anti-CD3 mAb after feeding, mice were fed 50 g anti-CD3 mAb or isotype control antibody, and 6 h after feeding, anti-CD3 mAb or isotype control antibody was extracted from the upper intestine using a protein-G column.…”

“…We have been interested in immune therapy of autoimmune diseases by mucosal administration of autoantigens designed to induce regulatory T-cells (14,15). We have recently found that oral anti-CD3 mAb is biologically active in the gut and induces a CD4 ϩ CD25 Ϫ latency-associated peptide (LAP) ϩ regulatory T-cell that suppresses EAE in a transforming growth factor (TGF)-␤-dependent fashion (16). LAP is the NH 2 -terminal domain of the TGF-␤ precursor peptide; it remains noncovalently associated with TGF-␤ peptide after cleavage and forms the latent TGF-␤ complex.…”

Regulatory T cells and immune computation

“…Indeed, regulatory T cells can be induced by intravenous [27] or oral [28] administration of antibodies to CD3. Thus, we can conclude that the conversion, numbers and functions of T reg are responsive to the state of the immune system itself.…”

Transcription Factor Early Growth Response 3 Is Associated with the TGF-β1 Expression and the Regulatory Activity of CD4-Positive T Cells In Vivo

“…Th3 cells (12) and CD4 + CD25 2 latency-associated peptide (LAP) + T cells (13) are reported to secrete TGF-b1; however, the regulation of TGF-b1 secretion is not fully understood. It was reported that STAT3 positively regulates TGF-b1 promoter activity and enhances TGF-b1 production (14,15).…”