Effect of intravenous IgM-enriched immunoglobulin (IVIgGM) on in vitro activation of T and B cell from CLL patients and its interactions with other therapeutic agents.

BORGE MERCEDES; COLADO ANA; GAMBERALE ROMINA

Edimburgo

Workshop; XVIII International Workshop on Chronic Lymphocytic Leukemia,; 2019

CLL patients have inherent immune defects affecting both cellular and humoral immunity,a condition that is often exacerbated by anti-leukemic therapies. Intravenousimmunoglobulin (IVIg) is recommended for patients with hypogammaglobulinemia, themost predominant inherent immune defect in CLL, and recurrent infections (Hallek, M. etal. 2018). Besides its use in antibody deficiencies to restore Igs levels, IVIg is used athigher doses in patients with autoimmune or inflammatory diseases due to itsimmunomodulatory capacity. Although the mechanism of action of IVIg as an immunomodulatorhas not been fully elucidated, its ability to interfere in vitro with T and B cellactivation is well-documented. Interestingly, a recent report has suggested that the use ofhigh doses of IVIg in CLL patients may have therapeutic activity, as shown by theassociation of IgG levels and disease progression and by in vitro immunomodulatoryeffects of IVIg on CLL cells including BCR-signaling inhibition (Spaner, D. E. et al, 2018).Although CLL patients with hypogammaglobulinemia have low levels of all isotypes, thestandard IVIg used in clinical practice contains more than 96% of IgG. Pentaglobin is aIVIg preparation enriched in IgM (IVIgGM) that has successfully been used mostly inpatients with sepsis (Jie, C. et al. 2019; Kakoullis L, et al 2018). Given that CLL cells overexpress the FcμR TOSO (Pallasch, C. et al., 2008) and that the immunomodulatorycapacity of IVIgGM was not explored yet, our aim was to study its in vitro effect onleukemic B cells and T lymphocytes from CLL patients.First, we determined if IVIgGM was able to modify the activation and proliferation of Tcells. To this aim peripheral blood mononuclear cells from CLL patients were stimulated invitro with immobilized anti-CD3 moAb (monoclonal antibodies) (0.5 μg/ml), in the presenceof IVIg or IVIgGM (Pentaglobin, Microsules) both at a final concentration of IgG of 10mg/ml or HSA (human serum albumin) at equimolar concentration as control. At 24 hs weevaluated the expression of the activation markers CD25 and CD69 by flow cyotmetry andfound that, as already reported for T cells from healthy donors (MacMillan, H. et al. 2009),IVIg impaired CD25 and CD69 upregulation on T cells from CLL patients (n=10, p