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Oral CD3-specific antibody suppresses autoimmune encephalomyelitis by inducing CD4+CD25LAP+ 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+CD25LAP+ regulatory T cells that contain latency-associated peptide (LAP) on their surface and that function in vitro and in vivo through a TGF-β–dependent mechanism. These findings identify a new immunologic approach that is widely applicable for the treatment of human autoimmune conditions.

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Figure 1: Effect of oral administration of CD3-specific antibody on EAE.
Figure 2: Oral versus intravenous CD3-specific antibody.
Figure 3: Immune responses after oral administration of CD3-specific antibody.
Figure 4: Oral CD3-specific antibody enhances regulatory function of CD4+CD25LAP+ T cells.
Figure 5: Kinetics of induction of CD4+CD25LAP+ regulatory cells.
Figure 6: Protection against EAE is adoptively transferred by mesenteric T cells from mice fed CD3-specific antibody and is TGF-β dependent.

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Acknowledgements

We would like to thank V. Kuchroo, S. Khoury and B. Waksman for discussions, and S. Ori for administrative support.

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Correspondence to Howard L Weiner.

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Supplementary information

Supplementary Fig. 1

Proliferative response to different antigens. (PDF 76 kb)

Supplementary Fig. 2

Proliferation after intravenous treatment with anti-CD3 Ab. (PDF 54 kb)

Supplementary Fig. 3

Cytokine profile after intravenous treatment with anti-CD3 Ab. (PDF 43 kb)

Supplementary Table 1

Percentage of CD3+, CD25+ and LAP+ cells in lymphoid organs after feeding. (PDF 30 kb)

Supplementary Table 2

Percentage of CD69+ cells among CD4+CD25LAP+ T cells in mesenteric lymph node after anti-CD3 treatment. (PDF 24 kb)

Supplementary Table 3

Percentage of LAP+ cells in popliteal lymph nodes after feeding and immunization. (PDF 24 kb)

Supplementary Methods (PDF 41 kb)

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Ochi, H., Abraham, M., Ishikawa, H. et al. Oral CD3-specific antibody suppresses autoimmune encephalomyelitis by inducing CD4+CD25LAP+ T cells. Nat Med 12, 627–635 (2006). https://doi.org/10.1038/nm1408

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