title: Non-response to infliximab may be due to innate neutralizing anti-tumour necrosis factor-alpha antibodies.
abstract: Infliximab is a chimeric anti-tumour necrosis factor (TNF)-alpha antibody that is therapeutic in many patients with inflammatory bowel disease. What causes certain patients not to respond is unknown. The question posed is whether innate anti-TNF-alpha antibodies play any role in the response to infliximab. Blood was drawn prior to the initial dose of infliximab. Serum anti-TNF-alpha antibodies were quantitated by enzyme-linked immunosorbent assay (ELISA). Affinity-purified anti-TNF-alpha antibodies were isolated from serum immunoglobulin G using TNF-alpha-coated beads. The ability of these antibodies to induce apoptosis of macrophages was measured by annexin and propidium iodide staining. Changes in TNF receptor type 2 (TNFR2) expression and release were determined by immunofluorescence and ELISA respectively. TNF-alpha-neutralization was assessed by the reversal of the lytic actions of TNF-alpha on WEHI cells. The amounts of innate anti-TNF-alpha antibodies in the serum from infliximab responders versus non-responders were the same. Apoptosis of monocytes increased with infliximab and by several of the purified anti-TNF-alpha antibodies, but these findings did not vary with the patients' responses to infliximab. Effects of the anti-TNF-alpha antibodies on the expression of TNFR2 on monocytes and their release of soluble TNFR2 did not vary with the patients' responses to infliximab. However, the neutralizing capacity of these antibodies differed, with responders having antibodies that reduced only 47 +/- 4% of the TNF-alpha activity while those from non-responders reduced 70 +/- 5% of the TNF-alpha activity (P < 0.01). Non-responders have innate anti-TNF-alpha antibodies with greater neutralizing activity than antibodies from responders. Any TNF-alpha-mediated disease process would be neutralized by intrinsic antibodies, so that the disease is likely to be driven by non-TNF-alpha-mediated events.
authors.affiliation: Department of Medicine, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ 08903, USA. ebertec@umdnj.edu
authors.forename: E C
authors.initials: EC
authors.lastname: Ebert
authors.forename: K M
authors.initials: KM
authors.lastname: Das
authors.forename: V
authors.initials: V
authors.lastname: Mehta
authors.forename: C
authors.initials: C
authors.lastname: Rezac
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001323:Autoantibodies / Q000097:blood*; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005765:Gastrointestinal Agents / Q000627:therapeutic use*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000276:immunology; D000069285:Infliximab; D007376:Interleukin-2 / Q000276:immunology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D011446:Prospective Studies; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism; D017211:Treatment Failure; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D005765:Gastrointestinal Agents; D007074:Immunoglobulin G; D007376:Interleukin-2; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab