ABSTRACT
A Euro-Lupus regimen of low-dose intravenous cyclophosphamide (CFA) is commonly used to treat severe organ manifestations of systemic lupus erythematosus (SLE), particularly lupus nephritis (LN). There are no data on the distributions and dynamics of immune cell populations in patients with various treatment outcomes. The circulating immune cells of 11 female SLE patients were assessed before and after Euro-Lupus regimen (cumulative dose of 3000 mg CFA) by flow cytometry together with those of 16 healthy women. A subanalysis was performed in LN patients who achieved complete remission (CR; n = 3), partial remission (PR; n = 4), and no response (NR; n = 2). In SLE, the Euro-Lupus regimen decreased the percentage and absolute count of B cells; increased the percentage of CD8+ T cells, T regulatory cells, neutrophils, and monocyte subsets; and activated T and NK cells compared to healthy controls (P < 0.050). Patients with LN achieving CR had significantly lower proportions of CD27+ B memory cells compared to poor responders (PR/NR, P = 0.035). The post-treatment percentages and absolute numbers of B cells, T cells, NK cells, monocytes, and neutrophils showed high inter-individual variability with no association with treatment outcome. Our pilot study revealed the dynamics of changes in immune cell populations in SLE patients during a Euro-Lupus regimen, mainly the lowering of B cells. In LN patients who achieved CR, a lower proportion of CD27+ B memory cells was evident compared to poor responders (PR/NR). Further studies on usefulness of monitoring immune cells for treatment response prediction on larger cohorts are needed.
Subject(s)
Cyclophosphamide/therapeutic use , Immunosuppressive Agents/therapeutic use , Lupus Erythematosus, Systemic/drug therapy , Lupus Nephritis/drug therapy , Lymphocytes/immunology , Administration, Intravenous , Adult , Blood Circulation , Clinical Protocols , Cohort Studies , Female , Flow Cytometry , Humans , Immunologic Memory , Immunomodulation , Lymphocytes/drug effects , Middle Aged , Remission Induction , Young AdultABSTRACT
There is the first evidence of changes in the kinetics of B cell antigen receptor (BCR) internalisation of neoplastic cells in chronic lymphocytic leukemia (CLL) after the short-term and long-term administration of ibrutinib. We aimed to assess the influence of short-term and long-term ibrutinib treatment on the HLA-DR expression on CLL cells, T cells and monocytes. The immunophenotyping of CLL and immune cells in peripheral blood was performed on 16 high-risk CLL patients treated with ibrutinib. After early ibrutinib administration, the HLA-DR expression on CLL cells reduced (P = 0.032), accompanied by an increase in CLL cell counts in peripheral blood (P = 0.001). In vitro culturing of CLL cells with ibrutinib also revealed the reduction in the HLA-DR expression at protein and mRNA levels (P < 0.01). The decrease in HLA-DR on CLL cells after the first month was followed by the gradual increase of its expression by the 12th month (P = 0.001). A one-month follow-up resulted in elevated absolute counts of CD4+ (P = 0.002) and CD8+ (P < 0.001) T cells as well as CD4+ and CD8+ cells bearing HLA-DR (P < 0.01). The long-term administration of ibrutinib was associated with the increased numbers of CD4+ bearing HLA-DR (P = 0.006) and elevation of HLA-DR expression on all monocyte subsets (P ≤ 0.004). Our results provide the first evidence of the time-dependent immunomodulatory effect of ibrutinib on CLL and T cells and monocytes. The clinical consequences of time-dependent changes in HLA-DR expression in ibrutinib treated patients deserve further investigation.
Subject(s)
Gene Expression Regulation, Leukemic/drug effects , HLA-DR Antigens/biosynthesis , Leukemia, Lymphocytic, Chronic, B-Cell , Neoplasm Proteins/biosynthesis , Pyrazoles/administration & dosage , Pyrimidines/administration & dosage , Adenine/analogs & derivatives , Aged , CD4-Positive T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/pathology , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/pathology , Female , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Male , Middle Aged , Piperidines , Time FactorsABSTRACT
A growing body of studies highlights involvement of neutrophils in cancer development and progression. Our aim was to assess the phenotypic and functional properties of circulating neutrophils from patients with chronic lymphocytic leukemia (CLL). The percentage of CD54+ and CD64+ neutrophils as well as CD54 expression on these cells were higher in CLL patients than in age-matched healthy controls. Neutrophils from CLL produced more reactive oxygen species (ROS) compared to controls in both resting and activated conditions. Lipopolysaccharide-induced production of IL-1ß and TNF-a as well as reduced TLR2 expression in neutrophils from CLL than in neutrophils from controls suggesting their tolerant state. Finally, phenotypic alterations of neutrophils, particularly elevation of CD64 and CD54 markers, correlated with disease activity and treatment, and low percentage of neutrophils. Taken together, the alterations in percentage and functional characteristics of neutrophils reflect the clinical course of CLL. Our data provide first evidence that neutrophils in CLL are permanently primed and have functional defects.
