SummaryInfliximab is a chimeric anti-tumour necrosis factor (TNF)-a 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-a antibodies play any role in the response to infliximab. Blood was drawn prior to the initial dose of infliximab. Serum anti-TNF-a antibodies were quantitated by enzyme-linked immunosorbent assay (ELISA). Affinity-purified anti-TNF-a antibodies were isolated from serum immunoglobulin G using TNF-a-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-a-neutralization was assessed by the reversal of the lytic actions of TNF-a on WEHI cells. The amounts of innate anti-TNF-a 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-a antibodies, but these findings did not vary with the patients' responses to infliximab. Effects of the anti-TNF-a 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 Ϯ 4% of the TNF-a activity while those from non-responders reduced 70 Ϯ 5% of the TNF-a activity (P < 0·01). Non-responders have innate anti-TNF-a antibodies with greater neutralizing activity than antibodies from responders. Any TNF-a-mediated disease process would be neutralized by intrinsic antibodies, so that the disease is likely to be driven by non-TNF-a-mediated events.
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