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

ANA COLADO; ELÍAS ESTEBAN ENRIQUE; DENISE RESNIK; CORDINI, GREGORIO; MARICEF VERGARA RUBIO; ALEXIA VEREERTBRUGGHEN; ALICIA DIAZ; MORANDE PABLO; BEZARES FERNANDO; GIORDANO MIRTA; GAMBERALE ROMINA; BORGE MERCEDES

Edimburgo

Workshop; XVIII International Workshop on Chronic Lymphocytic Leukaemia; 2019

iwCLL Consortium

CLL patients have inherent immune defects affecting both cellular and humoral immunity, a condition that is often exacerbated by anti-leukemic therapies. Intravenous immunoglobulin (IVIg) is recommended for patients with hypogammaglobulinemia, the most predominant inherent immune defect in CLL, and recurrent infections (Hallek, M. et al. 2018). Besides its use in antibody deficiencies to restore Igs levels, IVIg is used at higher doses in patients with autoimmune or inflammatory diseases due to its immunomodulatory capacity. Although the mechanism of action of IVIg as an immuno-modulator has not been fully elucidated, its ability to interfere in vitro with T and B cell activation is well-documented. Interestingly, a recent report has suggested that the use of high doses of IVIg in CLL patients may have therapeutic activity, as shown by the association of IgG levels and disease progression and by in vitro immunomodulatory effects 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, the standard IVIg used in clinical practice contains more than 96% of IgG. Pentaglobin is a IVIg preparation enriched in IgM (IVIgGM) that has successfully been used mostly in patients with sepsis (Jie, C. et al. 2019; Kakoullis L, et al 2018). Given that CLL cells over express the FcμR TOSO (Pallasch, C. et al., 2008) and that the immunomodulatory capacity of IVIgGM was not explored yet, our aim was to study its in vitro effect on leukemic B cells and T lymphocytes from CLL patients. First, we determined if IVIgGM was able to modify the activation and proliferation of T cells. To this aim peripheral blood mononuclear cells from CLL patients were stimulated in vitro with immobilized anti-CD3 moAb (monoclonal antibodies) (0.5 μg/ml), in the presence of IVIg or IVIgGM (Pentaglobin, Microsules) both at a final concentration of IgG of 10 mg/ml or HSA (human serum albumin) at equimolar concentration as control. At 24 hs we evaluated the expression of the activation markers CD25 and CD69 by flow cyotmetry and found 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