Anti-tumor necrosis factor-α antibodies induce regulatory macrophages in an Fc region-dependent manner.
OBJECTIVE
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.
Vos
Anne Christine W
AC
Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands. A.C.W.Vos@lumc.nl
Wildenberg
Manon E
ME
Duijvestein
Marjolijn
M
Verhaar
Auke P
AP
van den Brink
Gijs R
GR
Hommes
Daniel W
DW
D000068879:Adalimumab; D000893:Anti-Inflammatory Agents / Q000276:immunology* / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000276:immunology*; D061067:Antibodies, Monoclonal, Humanized; D017209:Apoptosis; D053148:Caspase 3 / Q000032:analysis / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D000068582:Certolizumab Pegol; D003424:Crohn Disease / Q000276:immunology*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D000068800:Etanercept; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology / Q000494:pharmacology; D007141:Immunoglobulin Fc Fragments / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000276:immunology / Q000494:pharmacology; D000069285:Infliximab; D037181:Lectins, C-Type / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000276:immunology; D011092:Polyethylene Glycols / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000276:immunology; D011961:Receptors, Fc / Q000276:immunology*; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology*
D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D016207:Cytokines; D007140:Immunoglobulin Fab Fragments; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D011961:Receptors, Fc; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D011092:Polyethylene Glycols; D000069285:Infliximab; D053148:Caspase 3; D000068879:Adalimumab; D000068800:Etanercept; D000068582:Certolizumab Pegol