Immunomodulatory effects of different intravenous immunoglobulin preparations in chronic lymphocytic leukemia

Ana Colado,Valeria Judith Sarapura Martínez,Fernando Bezares,Mirta Giordano,Gregorio Cordini,Romina Gamberale,Pablo Morande,Esteban Enrique Elías,Mercedes Borge

doi:10.1038/s41598-021-92412-8

Abstract

Hypogammaglobulinemia is the most frequently observed immune defect in chronic lymphocytic leukemia (CLL). Although CLL patients usually have low serum levels of all isotypes (IgG, IgM and IgA), standard immunoglobulin (Ig) preparations for replacement therapy administrated to these patients contain more than 95% of IgG. Pentaglobin is an Ig preparation of intravenous application (IVIg) enriched with IgM and IgA (IVIgGMA), with the potential benefit to restore the Ig levels of all isotypes. Because IVIg preparations at high doses have well-documented anti-inflammatory and immunomodulatory effects, we aimed to evaluate the capacity of Pentaglobin and a standard IVIg preparation to affect leukemic and T cells from CLL patients. In contrast to standard IVIg, we found that IVIgGMA did not modify T cell activation and had a lower inhibitory effect on T cell proliferation. Regarding the activation of leukemic B cells through BCR, it was similarly reduced by both IVIgGMA and IVIgG. None of these IVIg preparations modified spontaneous apoptosis of T or leukemic B cells. However, the addition of IVIgGMA on in vitro cultures decreased the apoptosis of T cells induced by the BCL-2 inhibitor, venetoclax. Importantly, IVIgGMA did not impair venetoclax-induced apoptosis of leukemic B cells. Overall, our results add new data on the effects of different preparations of IVIg in CLL, and show that the IgM/IgA enriched preparation not only affects relevant mechanisms involved in CLL pathogenesis but also has a particular profile of immunomodulatory effects on T cells that deserves further investigation.

Highlights

Hypogammaglobulinemia is the most frequently observed immune defect in chronic lymphocytic leukemia (CLL)
In order to evaluate whether IVIgGMA and IVIgG differentially regulate the activation of T cells from CLL patients, peripheral blood mononuclear cells (PBMC) were stimulated in vitro with immobilized anti-CD3 mAb for 24 h, in the presence of IVIgGMA, IVIgG or human serum albumin (HSA) at equimolar concentration as control
As already reported for T cells from healthy donors, IVIgG impaired the up-regulation of the activation markers CD25, CD69 and PD-1, while IVIgGMA did not modify their expression (Fig. 1a–c)

Summary

Introduction

Hypogammaglobulinemia is the most frequently observed immune defect in chronic lymphocytic leukemia (CLL). CLL patients usually have low serum levels of all isotypes (IgG, IgM and IgA), standard immunoglobulin (Ig) preparations for replacement therapy administrated to these patients contain more than 95% of IgG. Because IVIg preparations at high doses have well-documented anti-inflammatory and immunomodulatory effects, we aimed to evaluate the capacity of Pentaglobin and a standard IVIg preparation to affect leukemic and T cells from CLL patients. Regarding the activation of leukemic B cells through BCR, it was reduced by both IVIgGMA and IVIgG None of these IVIg preparations modified spontaneous apoptosis of T or leukemic B cells. In that report they found that patients receiving IgRT that increases IgG levels over 9 g/L showed evidence of disease control, suggesting that high doses of Ig may have anti-leukemic activity in CLL patients

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