Reactive oxygen product formation after Fcγ receptor‐mediated neutrophil activation by monomeric mouse IgG2a: implications for the generation of first dose effects after OKT3 treatment

Abstract

In the present study, we provide evidence that IgG2a monoclonal antibody (mAb) OKT3 is able to induce reactive oxygen intermediate (ROI) formation in polymorphonuclear leukocytes (PMN) when Fc gamma RIIIB as well as Fc gamma RII are bound concomitantly. Inhibition of binding to either Fc gamma R by specific mAb (3G8 or IV.3, respectively) resulted in complete abrogation of the OKT3-induced respiratory burst. The effect of OKT3 was independent from its specificity and thus also from its T cell-activating property, since nonbinding IgG2a isotype controls induced similar amounts of ROI. The IgG2b mAb BMA031 as well as the respective nonbinding isotype control were only minimally effective. With regard to the potential role of PMN activation in inflammation and tissue damage, our findings offer an extended explanation for the generation of initial adverse reactions to OKT3. Thus, one might speculate that the concerted action of cytokines liberated after its administration, what may lead to margination of leukocytes, and activation of PMN via Fc gamma R might produce first-dose reactions to OKT3 by directing radical-mediated damage against the endothelium.

Serum Proteins Modified by Neutrophil-Derived Oxidants as Mediators of Neutrophil Stimulation

“…As previously demonstrated (19), the neutrophil oxidative burst is strongly activated by murine monomeric IgG2a in a Fc␥R-dependent way. Similarly, IgG2a immobilized to microtiter plates to mimic immune complexes markedly induced ROI formation by purified PMN (Fig.…”

“…In recent years data have accumulated on the contribution of ROI to the development of various disease states, such as ARDS (16,21), atherosclerosis (17), chronic obstructive pulmonary disease (18), sepsis (24), or side effects of hemodialysis (20,29) and mAb treatment (19). The therapeutically used anti-CD3 mAb OKT3 strongly induces the neutrophil oxidative burst in a strictly IgG2a-dependent Fc␥R-mediated fashion (19).…”

“…The therapeutically used anti-CD3 mAb OKT3 strongly induces the neutrophil oxidative burst in a strictly IgG2a-dependent Fc␥R-mediated fashion (19). It was speculated that this massive ROI release could be involved in the frequently occurring first dose effects of OKT3, characterized by adhesive activation of PMN and sequestration in the pulmonary microvasculature, pulmonary compromise, and neutropenia (32,33,57).…”

“…In addition, ROI are able to activate complement factor C5 in a nonenzymatic way, generating either C5b-like activity without C5 cleavage (14) or anaphylatoxins (15) depending on the ROI species studied. Moreover, ROI are implicated in the pathogenesis of a variety of conditions, such as adult respiratory distress syndrome (ARDS) (16), atherosclerosis (17), chronic obstructive pulmonary disease (18), and Ab therapy-and hemodialysis-associated side effects (19,20). Reduced plasma antioxidant status (21) and protein oxidation correlating with either PMN infiltration or tissue MPO content (22)(23)(24)(25)(26) was observed in patients suffering from inflammatory disorders.…”

Herbal medicinal products target defined biochemical and molecular mediators of inflammatory autoimmune arthritis

“…In regard to RA pathogenesis, the effects of free radicals on connective tissue macromolecules (collagen, hyaluronic acid (HA), proteoglcans), intact tissues and immunoglobulins are of high relevance 80. The free radicals generated by polymorphonuclear cells (PMNs) alter IgG, which could in turn activate PMNs to generate additional superoxides 81. Free radicals themselves also activate PMNs 82.…”