The novel polyclonal Ab preparation trimodulin attenuates ex vivo endotoxin-induced immune reactions in early hyperinflammation

Abstract

Sepsis is a syndrome associated with excessive inflammation. Since mortality from sepsis remains high, more laboratory research is needed to provide insight into more effective ways to use novel, potentially more beneficial agents in sepsis. We investigated the ex vivo immunomodulatory effect of a novel polyclonal Ab preparation, trimodulin, containing IgM (∼23%), IgA (∼21%) and IgG (∼56%). Using whole blood and purified PBMCs from healthy volunteers and patients with sepsis, various ex vivo investigations upon endotoxin challenge and pre- and post-trimodulin treatment were performed. Endotoxin-induced TNF-α secretion was noticeably lower with than without trimodulin, implying attenuation of the hyper-responsive state. Trimodulin also lowered TLR2, TLR4, CD11b and CD64 detection on LPS/lipoteichoic acid-stimulated monocytes. These responses were observed in cells from healthy volunteers only shortly after ex vivo endotoxin stimulation and in whole blood from patients with early-stage sepsis. Furthermore, trimodulin markedly reduced lymphocyte proliferation and release of pro- and anti-inflammatory cytokines, but did not affect phagocytosis or oxidative-burst activities of endoxin-stimulated cells. Thus, trimodulin mitigated monocyte and lymphocyte hyperinflammatory responses early after endotoxin exposure. Determining whether early in vivo administration of trimodulin will elicit similar positive immunomodulatory effects and offer a clinical benefit warrants investigation.

Best-practice IgM- and IgA-enriched immunoglobulin use in patients with sepsis

“…Furthermore, a recent clinical study in patients treated with either IgM and IgA enriched immunoglobulin or placebo (NaCl) showed a significant decrease of IL-6 and IL-10 levels at 72 h in the IgM and IgA enriched immunoglobulin group only [74]. Ex vivo data also showed that the investigational preparation, trimodulin, lowered monocyte expression of recognition receptors (TLR2 and TLR4) and coagulation receptors (CD11b and CD64) and also reduced lymphocyte proliferation and release of pro-and anti-inflammatory cytokines including TNF-α and IL-10 [83]. Recently, a beneficial effect of IgM administration on microvascular perfusion parameters could be demonstrated in humans [74], which corroborated earlier research in an animal model of endotoxemia [84].…”

Approaches for Controlling Antibody-Mediated Allograft Rejection Through Targeting B Cells

“…A polyclonal antibody preparation designated trimodulin, which contains IgM (~23%), IgA (~21%), and IgG (~56%), decreases the levels of TLR2, 4 as well as those of coagulation receptors (CD11b and CD64) in monocytes and inhibits lymphocyte proliferation and regulate of the production of pro-and antiinflammatory cytokines, including TNF-a and IL-10. Therefore, these antibodies achieve a protective effect to alleviate the inflammatory reaction to target organs through these extents of involvement in immune system (243,246,247,(250)(251)(252).…”

“…Significantly, in addition to the potential induction of immune tolerance of humoral immunity-associated components to transplanted grafts (35,243,247,248,(250)(251)(252), AIM and IgMenriched IVig have a tissue repair and regeneration effect through the clearance of injured tissue (42,224,(233)(234)(235). Therefore, humoral immunity associated injury after the onset of AMR, which was considered irreversible, could be recovered by clinical application of these humoral immunity-associated components.…”

The Functional Role of IgA in the IgM/IgA-Enriched Immunoglobulin Preparation Trimodulin

“…Previous investigations address desirable effects on the well-known effector functions of IgG and IgM [ 23 , 25 , 26 , 27 , 28 , 36 ]. In contrast, some other work—focused on plasma-derived IgA—demonstrate promising anti-pathogenic and immunomodulatory effects of IgA by the interaction with FcαRI [ 37 , 38 , 39 , 40 , 41 , 42 ].…”