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CD3-specific antibody-induced active tolerance: from bench to bedside

Nature Reviews Immunology volume 3, pages 123–132 (2003)Cite this article

Key Points

  • Monoclonal CD3-specific antibodies that recognize the ε-chain of the CD3 complex are potent immunosuppressants. They were introduced in clinical transplantation in the early 1980s to prevent and treat episodes of allograft rejection.

  • Experimental studies (particularly in autoimmune mice) have shown that CD3-specific antibodies are remarkably potent at promoting operational immune tolerance.

  • The immune mechanisms that mediate the tolerogenic capacity of CD3-specific antibodies seem to develop in two consecutive phases. The first phase is short lasting and associated with transient T helper 2 polarization, clearance of pathogenic cells and blockade of deleterious immune responses. The second phase is long lasting and marked by the presence of regulatory T cells that can mediate transferable or active tolerance.

  • In mice with autoimmune diabetes, CD3-specific antibodies induce stable disease remission by restoring tolerance to pancreatic β-cells. Recently, this concept was extended to the clinic — preservation of β-cell function in recently diagnosed patients with diabetes was achieved after short-term administration of a CD3-specific antibody.

Abstract

Although they were used initially as non-specific immunosuppressants in transplantation, CD3-specific monoclonal antibodies have elicited renewed interest owing to their capacity to induce immune tolerance. In mouse models of autoimmune diabetes, CD3-specific antibodies induce stable disease remission by restoring tolerance to pancreatic β-cells. This phenomenon was extended recently to the clinic — preservation of β-cell function in recently diagnosed patients with diabetes was achieved by short-term administration of a CD3-specific antibody. CD3-specific antibodies arrest ongoing disease by rapidly clearing pathogenic T cells from the target. Subsequently, they promote long-term T-cell-mediated active tolerance. Recent data indicate that transforming growth factor-β-dependent CD4+CD25+ regulatory T cells might have a central role in this effect.

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Figure 1: Mode of action of therapeutic monoclonal antibodies.
Figure 2: Humanized and engineered CD3-specific antibodies.
Figure 3: CD3-specific antibody treatment reverses established diabetes in NOD mice.

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Acknowledgements

I am indebted to M. Netter for the iconography.

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Authors and Affiliations

  1. Centre de l'Association Claude Bernard sur les Maladies Autoimmunes and Hôpital Necker Enfants Malades IRNEM, 161 Rue de Sèvres, Paris, 75015, France

    Lucienne Chatenoud

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  1. Lucienne Chatenoud
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DATABASES

LocusLink

CD3

CD4

CD8

CD28

CD62L

CD80

CD86

IFN-γ

IL-1β

IL-4

IL-5

IL-6

TGF-β

TNF

Glossary

HUMANIZED ANTIBODIES

Recombinant antibodies that contain the parental rodent antibody hypervariable regions (which determine antigen specificity) grafted to a human heavy- and light-chain immunoglobulin.

OPERATIONAL TOLERANCE

An antigen-specific unresponsiveness that is sustained in the absence of chronic immunosuppression.

IDIOTYPE

The portion of an immunoglobulin, defined by the hypervariable regions and involved in antigen recognition, that is completely unique.

T HELPER 1/2

(TH1/TH2). At least two distinct subsets of activated CD4+ T cells have been described. TH1 cells produce IL-2, IFN-γ, lymphotoxin and TNF, and support cell-mediated immunity. TH2 cells produce IL-4, IL-5, IL-6, IL-10 and IL-13, support humoral immunity and downregulate TH1 responses.

IMMUNOLOGICAL IGNORANCE

The absence of a pathogenic autoimmune response in spite of the concomitant presence in the host of the autoantigen and T cells bearing the specific autoreactive T-cell receptor.

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Chatenoud, L. CD3-specific antibody-induced active tolerance: from bench to bedside. Nat Rev Immunol 3, 123–132 (2003). https://doi.org/10.1038/nri1000

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