Ibrutinib-based therapy impaired neutrophils microbicidal activity in patients with chronic lymphocytic leukemia during the early phases of treatment.

Ibrutinib is a tyrosine kinase inhibitor used in the treatment of a variety of lymphoid malignancies, including chronic lymphocytic leukemia (CLL). Drugs inhibiting B-cell-receptor (BCR)-associated kinases, including BTK inhibitors, act on B cells and on a wide spectrum of tissues and cells, including innate immunity cells. Thus, alterations in the Bruton's tyrosine kinase (BTK) kinase function could lead to an impairment of innate immune cells functions and to an increased infectious risk in patients receiving BTK inhibitors. We analyzed in vivo neutrophils oxidative burst, neutrophils granules release and cytokine production in relapsed/refractory CLL patients treated over time with ibrutinib as single-agent. We observed a dramatic reduction of neutrophils oxidative burst, Fc gamma receptors (FcγRs)-mediated degranulation and IL-8 plasma levels already after the first forty-eight hours of therapy with ibrutinib. However, ibrutinib treatment did not alter the surface expression of CD11b nor cytokine and proteinases release not mediated by FcγRs engagement. After three weeks, oxidative burst was still impaired, while degranulation and IL-8 levels were restored. In a group of CLL patients who survived for more than three years, all processes triggered by FcγRs completely recovered except the release of neutrophil elastase (NE) and IL-8. In conclusion, during the initial phases of ibrutinib therapy, the reduction of IL-8, NE, myeloperoxidase (MPO) levels and oxidative burst negatively impacted on mechanisms involved in neutrophils microbicidal activity.

Intravenous immunoglobulin replacement treatment reduces in vivo elastase secretion in patients with common variable immune disorders.

BACKGROUND: Intravenous immunoglobulin (IVIg) treatment partially replaces antibody defects and modulates innate and adaptive immune cells in patients with primary antibody deficiencies. MATERIALS AND METHODS: This study was focused on the evaluation of the effects of in vivo IVIg administration on neutrophils from patients with common variable immune disorders (CVID). We examined polymorphonuclear neutrophil (PMN) phagocytosis, PMN oxidative burst, release of neutrophil elastase, serum level of interleukin-8 and PMN expression of CXCR1, CD11c and CD66b. RESULTS: CVID patients on chronic IVIg treatment had reduced elastase release, but normal expression of CXCR1, CD66b and CD11c receptors on PMN, normal phagocytic ability and normal secretion of interleukin-8. We found that IVIg infusions rapidly reduced the serum level of interleukin-8, the expression of its receptor, CXCR1, and the release of neutrophil elastase, suggesting that IVIg exert a dampening effect on neutrophil activity. In contrast, IVIg infusions did not alter neutrophil phagocytosis or the expression of the other receptors analysed. DISCUSSION: These findings add further information regarding the anti-inflammatory role of immunoglobulins and suggest additional benefits in keeping with recent attempts to use new therapies targeting neutrophil inflammation.

The lack of BTK does not impair monocytes and polymorphonuclear cells functions in X-linked agammaglobulinemia under treatment with intravenous immunoglobulin replacement.

The lack of BTK in X-linked agammaglobulinemia (XLA) patients does not affect monocytes and polymorphonuclear cells (PMN) phenotype and functions. In this study, we show that XLA patients had an increased frequency of the intermediate monocytes subset and that BTK-deficient monocytes and PMN had a normal expression of receptors involved in the activation and cellular responses. We demonstrate that BTK is not required for migration, phagocytosis and the production of reactive oxygen species (ROS) following engagement of FC gamma receptors (FcγR). XLA monocytes and PMN showed an efficient calcium (Ca2+)-independent activation of oxidative burst, suggesting that oxidative burst is less dependent by Ca2+ mobilization. The phagocytosis was functional and it remained unaltered also after Ca2+ chelation, confirming the independence of phagocytosis on Ca2+ mobilization. Intravenous immunoglobulin (IVIg) infusion exerted an anti-inflammatory effect by reducing the frequency of pro-inflammatory monocytes. In monocytes, the IVIg reduce the oxidative burst and phagocytosis even if these functions remained efficient.

Intravenous immunoglobulin replacement treatment does not alter polymorphonuclear leukocytes function and surface receptors expression in patients with common variable immunodeficiency.

The study of the expression of CD16, CD11b and Siglec 9 receptors and the oxidative burst provides insights on polymorphonuclear leukocytes (PMN) functionality in common variable immunodeficiency (CVID) and on the possible effects of intravenous immunoglobulin (IVIg) infusion. We evaluated in vivo before and soon after IVIg administration the CD16, CD11b and Siglec 9 expression on unstimulated and Escherichia coli-stimulated PMN and the oxidative burst induced by Escherichia coli and PMA. The E. coli stimulation up-regulated CD16 and Siglec 9 expression and it induced a strong CD11b up-regulation at baseline and soon after IVIg. The oxidative burst overlapped that observed in healthy donors when induced by Escherichia coli while it increased when induced by PMA. Soon after IVIg infusion, the oxidative burst decreased only when induced by PMA. Our results showed that the IVIg infusion in vivo had a minimal effect on CVID's PMN.

Intravenous immunoglobulin replacement induces an in vivo reduction of inflammatory monocytes and retains the monocyte ability to respond to bacterial stimulation in patients with common variable immunodeficiencies.

Intravenous IgG administration induces significant modifications in the innate and adaptive compartment of the immune system including the monocyte/macrophage system. We analyzed the in vivo effect of IgG administered at replacement dosages on the frequency of monocytes subsets, on the modulation of CD11b and sialic acid-binding immunoglobulin-like lectin receptor (Siglec 9) expression and on monocytes production of reactive oxygen species. We showed that patients with Common Variable Immune Deficiency have an increased frequency pro-inflammatory intermediate CD14(++)CD16(+) monocytes and an increased expression of CD11b and Siglec 9 on monocytes. IgG administered at replacement dosages exerted an in vivo anti-inflammatory effect as shown by a reduction of circulating monocytes, of intermediate pro-inflammatory monocytes, of CD11b and Siglec 9 expression and of ex vivo monocytes oxidative burst. Nevertheless, intravenous IgG administration did not affect the monocyte functional ability to respond to a bacterial stimulation in terms of CD11b and Siglec 9 expression and reactive oxygen species production.