The IgM- and IgA-enriched immunoglobulin preparation trimodulin suppresses neutrophil extracellular trap formation more effectively in vitro than standard intravenous immunoglobulin

Neutrophil extracellular traps (NETs) represent an important mechanism of defense against pathogens. However, in cases of severe lung infection or sepsis, excessive NET formation has been observed to cause vascular occlusion, inflammation, and tissue damage. Treatment with intravenous immunoglobulins (IVIg), especially those enriched for IgA and IgM, has been shown to improve outcomes in patients with these conditions. We compared trimodulin, a novel polyvalent antibody preparation containing elevated levels of IgM (∼23%) and IgA (∼21%), with standard IVIg to determine their ability to reduce NET formation in vitro . Trimodulin strongly reduced NET formation by neutrophils stimulated with phorbol 12-myristate 13-acetate (PMA), complexed IgA, or complexed IgG. This effect was accompanied by reduced IL-8 secretion. Standard IVIg showed no significant effect. Dissecting trimodulin into its individual immunoglobulin components revealed that IgM has the strongest capacity to reduce NET formation, followed by IgG. Nevertheless, the combined additive effects of the individual immunoglobulins were less effective than trimodulin, potentially caused by synergistic effects between the three immunoglobulin classes within trimodulin. Together, our data show that trimodulin is a more potent regulator of NET formation than the tested standard IVIg, mainly due to its IgM component. Therefore, trimodulin may be beneficial in conditions involving excessive NET formation.