Anti-tumor necrosis factor-α antibodies induce regulatory macrophages in an Fc region-dependent manner

Gastroenterology. 2011 Jan;140(1):221-30. doi: 10.1053/j.gastro.2010.10.008. Epub 2010 Oct 16.

Abstract

Background & aims: Anti-tumor necrosis factor (TNF)α antibodies are effective in treating patients with Crohn's disease whereas soluble TNFα receptors have not shown clinical efficacy; the mechanism that underlies these different effects is not clear. We examined the immunosuppressive effects of different anti-TNFα reagents on activated T cells.

Methods: We studied the effects of anti-TNFα antibodies infliximab and adalimumab, the soluble TNFα receptor etanercept, the pegylated F(ab') fragment certolizumab, and certolizumab-immunoglobulin (Ig)G on primary activated T cells. T cells were grown in isolation or in a mixed lymphocyte reaction (MLR). Proliferation was measured by (3)H thymidine incorporation and apoptosis was examined using Annexin V labeling and a colorimetric assay for activated caspase-3. Macrophage phenotypes were assayed by flow cytometry and cytokine secretion.

Results: Infliximab and adalimumab reduced T-cell proliferation in an MLR whereas etanercept and certolizumab did not; this effect was lost after Fc receptors were blocked. The infliximab F(ab')2 fragment did not inhibit proliferation whereas certolizumab-IgG did inhibit proliferation. In the MLR, the antibodies against TNF induced formation of a new population of macrophages in an Fc region-dependent manner; these macrophages had an immunosuppressive phenotype because they inhibit proliferation of activated T cells, produce anti-inflammatory cytokines, and express the regulatory macrophage marker CD206.

Conclusions: Regulatory macrophages have immunosuppressive properties and an important role in wound healing. Antibodies against TNF induce regulatory macrophages in an Fc region-dependent manner. These functions of anti-TNFs might contribute to the resolution of inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adalimumab
  • Anti-Inflammatory Agents / immunology*
  • Anti-Inflammatory Agents / pharmacology
  • Antibodies, Monoclonal / immunology*
  • Antibodies, Monoclonal, Humanized
  • Apoptosis
  • Caspase 3 / analysis
  • Caspase 3 / immunology
  • Cell Proliferation
  • Cells, Cultured
  • Certolizumab Pegol
  • Crohn Disease / immunology*
  • Cytokines / immunology
  • Cytokines / metabolism
  • Etanercept
  • Humans
  • Immunoglobulin Fab Fragments / immunology
  • Immunoglobulin Fab Fragments / pharmacology
  • Immunoglobulin Fc Fragments / immunology*
  • Immunoglobulin G / immunology
  • Immunoglobulin G / pharmacology
  • Immunosuppressive Agents / immunology
  • Immunosuppressive Agents / pharmacology
  • Infliximab
  • Lectins, C-Type / immunology
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / immunology
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Macrophages / immunology*
  • Mannose-Binding Lectins / immunology
  • Polyethylene Glycols / pharmacology
  • Receptors, Cell Surface / immunology
  • Receptors, Fc / immunology*
  • Receptors, Tumor Necrosis Factor / immunology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / immunology*

Substances

  • Anti-Inflammatory Agents
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Cytokines
  • Immunoglobulin Fab Fragments
  • Immunoglobulin Fc Fragments
  • Immunoglobulin G
  • Immunosuppressive Agents
  • Lectins, C-Type
  • Mannose-Binding Lectins
  • Receptors, Cell Surface
  • Receptors, Fc
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha
  • mannose receptor
  • Polyethylene Glycols
  • Infliximab
  • Caspase 3
  • Adalimumab
  • Etanercept
  • Certolizumab Pegol