Chimaeric Lym-1 monoclonal antibody-mediated cytolysis by neutrophils from G-CSF-treated patients: stimulation by GM-CSF and role of Fcγ -receptors

Abstract

Chimaeric Lym-1 (chLym-1) is a monoclonal antibody generated by fusing the variable region genes of murine Lym-1 to human γ1 and κ constant regions. Owing to its selectivity and avidity for human malignant B cells, it is an attractive candidate for developing immune-interventions in B-lymphomas. In the attempt to identify rational bases for optimizing potential chLym-1 related therapeutic approaches, we studied the ability of this ch-mAb to trigger neutrophil-mediated Raji cell cytolysis in cooperation with two neutrophil-related cytokines, G-CSF and GM-CSF. ChLym-1 triggered low levels of cytolysis by normal neutrophils but induced consistent cytolysis in neutrophils from individuals treated with G-CSF. When exposed to GM-CSF, neutrophils from subjects treated with G-CSF became potent effectors, also leading to 75% lysis. By using mAbs specific for distinct FcγRs, normal neutrophils were inhibited by mAb IV.3, suggesting the intervention of FcγRII, constitutively expressed on the cells. On the other hand, neutrophils from patients treated with G-CSF were inhibited by mAb IV.3 plus mAb 197, a finding consistent with a cooperative intervention of FCγRII and G-CSF-induced FcγRI. The anti-FcγRIII mAb 3G8 promoted significant enhancement of the neutrophil cytolytic efficiency. Therefore, neutrophil FcγRIII behaves as a down-regulator of the cytolytic potential. The present findings suggest new attempts to develop mAb-based and G-CSF/GM-CSF combined immune-interventions in B lymphomas. © 2001 Cancer Research Campaign http://www.bjcancer.com

Intimate Cell Conjugate Formation and Exchange of Membrane Lipids Precede Apoptosis Induction in Target Cells during Antibody-Dependent, Granulocyte-Mediated Cytotoxicity

“…Thus, the specificity, concentration, and format of Ab, as well as E:T ratio, density, and domains of target Ag, contribute substantially to effective Ab-mediated tumor cell killing by PMN (3,7,11,12,19,21,30). As previously shown, HER-2/neu and HLA class II proved to be appropriate target Ag of PMN-mediated lysis of Raji H cells.…”

EGF-Induced Bronchial Epithelial Cells Drive Neutrophil Chemotactic and Anti-Apoptotic Activity in Asthma

“…Although the observed anti-apoptotic activity of the bronchial epithelial cells may prolong neutrophil survival, it is possible that alternative cell death programmes exist that are independent of apoptosis. Recent work has demonstrated non-apoptotic cell death pathways, such as oncosis/necrosis [64], [65], pyroptosis [65], cytolysis [66], NETosis [67] and autophagic-like neutrophil death mechanisms [68] that play important physiological roles in regulating neutrophil lifespan. In addition, the use of unprimed, blood-derived neutrophils from healthy donors raises the question of whether chemotactic and survival responses of neutrophils from asthmatic subjects might be different.…”

Impact of LL-37 on anti-infective immunity

“…GM-CSF promotes the survival, proliferation, differentiation, and activation of hematopoietic cells, predominantly in the macrophage and neutrophil lineages [54]. GM-CSF has a number of other immunomodulatory properties, including enhancement of antigen presentation, promotion of phagocytosis and antibody-dependent killing, induction of chemotaxis, and induction of the release of reactive oxygen intermediates and histamines [57][58][59][60]. It is interesting that GM-CSF is known to work synergistically with other cytokines.…”