Effects of pegylated G-CSF on immune cell number and function in patients with gynecological malignancies.
Bonanno Giuseppina,Procoli Annabella,Mariotti Andrea,Corallo Maria,Perillo Alessandro,Danese Silvio,De Cristofaro Raimondo,Scambia Giovanni,Rutella Sergio
Journal of translational medicine
BACKGROUND:Pegylated granulocyte colony-stimulating factor (G-CSF; pegfilgrastim) is a longer-acting form of G-CSF, whose effects on dendritic cell (DC) and regulatory T cell (Treg) mobilization, and on the in vivo and ex vivo release of immune modulating cytokines remain unexplored. METHODS:Twelve patients with gynecological cancers received carboplatin/paclitaxel chemotherapy and single-dose pegfilgrastim as prophylaxis of febrile neutropenia. Peripheral blood was collected prior to pegfilgrastim administration (day 0) and on days +7, +11 and +21, to quantify immunoregulatory cytokines and to assess type 1 DC (DC1), type 2 DC (DC2) and Treg cell mobilization. In vitro-differentiated, monocyte-derived DC were used to investigate endocytic activity, expression of DC maturation antigens and ability to activate allogeneic T-cell proliferation. RESULTS:Pegfilgrastim increased the frequency of circulating DC1 and DC2 precursors. In contrast, CD4+FoxP3+ bona fide Treg cells were unchanged compared with baseline. Serum levels of hepatocyte growth factor and interleukin (IL)-12p40, but not transforming growth factor-β1 or immune suppressive kynurenines, significantly increased after pegfilgrastim administration. Interestingly, pegfilgrastim fostered in vitro monocytic secretion of IL-12p40 and IL-12p70 when compared with unconjugated G-CSF. Finally, DC populations differentiated in vitro after clinical provision of pegfilgrastim were phenotypically mature, possessed low endocytic activity, and incited a robust T-cell proliferative response. CONCLUSIONS:Pegfilgrastim induced significant changes in immune cell number and function. The enhancement of monocytic IL-12 secretion portends favorable implications for pegfilgrastim administration to patients with cancer, a clinical context where the induction of immune deviation would be highly undesirable.
The use of rhG-CSF in chronic autoimmune neutropenia: reversal of autoimmune phenomena, a case history.
Kuijpers T W,de Haas M,de Groot C J,von dem Borne A E,Weening R S
British journal of haematology
An 8-year-old boy had been suffering from chronic autoimmune neutropenia for more than 5 years. The neutropenia proved to be resistant to high-dose steroids and intravenous (either low-or high-dose) immunoglobulin (Ig) therapy. The chronic autoimmune thrombocytopenia and recurrent phases of autoimmune haemolytic anaemia did, however, respond to high-dose prednisone. Other signs of immune dysregulation in this patient consisted of insulin-dependent diabetes mellitus type I (IDDM) and an acquired hypogammaglobulinaemia, most compatible with common variable immunodeficiency (CVI). Prior to rhG-CSF therapy the child had suffered for more than 2 years from recurrent life-threatening bacterial infections. Anti-neutrophil autoantibodies had pan-Fc gamma RIII (CD116, NA1/NA2) specificity. The neutropenia as well as the antineutrophil autoantibodies disappeared when subcutaneous rhG-CSF therapy was started. Upon tapering rhG-CSF, anti-Fc gamma RIII antibodies reappeared together with an absolute neutropenia. Renewed administration resulted again in the normalization of symptoms. Soluble Fc gamma RIII (sFc gamma RIII) antigen levels in plasma increased dramatically during rhG-CSF treatment. These high levels of sFc gamma RIII together with increased numbers as well as decreased apoptotic reactions of neutrophils apparently result in adsorption of the autoantibodies in vivo, contributing to the normalization of autoimmune-mediated neutropenia upon rhG-CSF treatment. Long-term administration of rhG-CSF represents as alternative in the treatment of autoimmune neutropenia.
Effect of recombinant human granulocyte-colony stimulation factor (rhG-CSF) on immune system in pediatric patients with aplastic anemia.
Hibi S,Yoshihara T,Nakajima F,Misu H,Mabuchi O,Imashuku S
Pediatric hematology and oncology
To determine the effect of recombinant human granulocyte-colony stimulation factor (rhG-CSF) on the immune system, serum immunoglobulins, lymphocyte subsets, and serum cytokines were analyzed in eight pediatric patients with aplastic anemia (AA) during 8-week rhG-CSF therapy. The rhG-CSF was administered either subcutaneously (200 micrograms/m2 x 4 weeks, followed by 400 micrograms/m2 x 4 weeks) or intravenously (400 micrograms/m2 x 4 weeks, followed by 800 micrograms/m2 x 4 weeks). In response to rhG-CSF therapy, neutrophil counts exceeded the pretreatment counts by twofold during the first week except for one case that did not attain twofold increase until day 41. While serum IgG and IgA were not affected, serum IgM was elevated during treatment in six of the eight cases to more than 1.2-fold basal levels (P < 0.04); however, there was no increase in serum interleukin (IL)-6 and interferon-gamma levels. On the other hand, CD56 positive NK cells significantly dropped from 7.7% to 4.5% (P < 0.02). These results indicate that systemic administration of rhG-CSF affects not only the neutrophil count, but also serum IgM levels and the natural killer cell population in patients with AA.
Effect of rhg-csf (filgrastim) on leukocyte kinetics and immune function in cytotoxic chemotherapy for gynecologic malignancies.
Takeshima N,Umezawa S,Shimizu Y,Fukuda M,Kimura M,Hasumi K
International journal of oncology
The effects of human recombinant granulocyte colony-stimulating factor (rhG-CSF) on leukocyte kinetics and immune function were assessed in patients with gynecologic malignancies receiving cytotoxic chemotherapy. Five day-rhG-CSF administration (50 mu g/m(2)/day) increased leukocyte counts in most of the chemotherapy courses. There was a significant difference in the leukocyte increase between the previously irradiated group and the nonirradiated group. An appreciable increase in LAK activity owing to an increased IL-2 production was noted after rhG-CSF administration. Despite a remarkable increase in the neutrophils observed, the CD57(+) cell count and NK activity in peripheral blood mononuclear cells were unexpectedly reduced.
Immune recovery after autologous or rhG-CSF primed PBSC transplantation.
Rosillo M C,Ortuño F,Moraleda J M,Lozano M L,Heras I,De Arriba F,Vicente V
European journal of haematology
We performed a prospective study in 17 consecutive patients following Autologous bone marrow (BM) or rhG-CSF primed peripheral blood item cell (PBSC) transplantation, with the objective of comparing immune recovery between both procedures and to evaluate results in rhG-CSF mobilized peripheral blood stem cell transplantation (PBSCT). Kinetics of immune reconstitution showed differences, with a faster recovery of CD3+ and CD8+ T cells, and a more rapid and sustained recovery of CD8+/-/CD56+ natural killer (NK) cells in the PBCSCT group. Autologous bone marrow transplantation (ABMT) was associated with a improved reconstitution of the CD19+/CD5+/-subpopulation. Moreover, rhG-CSF mobilized PBSCT generated a greater recovery of CD8+/-/CD56+ cells than previous data concerning transplantation with peripheral blood (PB) progenitors collected after myelosuppressive chemotherapy or myelosuppressive therapy plus rhG-CSF. Our results show differences in the rate and pattern of B and T lymphocytes reconstitution after ABMT and PBSCT. Additionally, we state an enhancement of CD56+ cells in patients undergoing PBSCT mobilized solely using rhG-CSF.
[Peripheral blood T cell immuno-tolerance in PBSCT donors induced by rhG-CSF in vivo].
Chang Ying-Jun,Zhao Xiang-Yu,Huang Xiao-Jun
Zhongguo shi yan xue ye xue za zhi
The study was aimed to investigate the mechanism of T cell tolerance in human peripheral blood induced by rhG-CSF in vivo. Dendritic cell (DC) subsets, CD8(+)CD28(-) T suppressor cells and the expression of CD28 on T cells of peripheral blood before and after mobilization were analyzed by multicolor flow cytometry. The results showed that after mobilization by rhG-CSF in vivo, the relative counts of CD3(+)CD28(+) cells increased significantly (P < 0.01), and so did the CD8(+)CD28(+) cells (P < 0.01). The mean fluorescence intensity of CD28 expression on CD3(+) cells decreased greatly (P < 0.05), but there were no significant changes of the relative fluorescence intensity of CD28 overall expression on T cells (P > 0.05). The percentages of DC2 before mobilization were significantly lower as compared with normal bone marrow (P < 0.01). After using rhG-CSF, the DC2 count was significantly higher in the apheresis graft than in peripheral blood and bone marrow before mobilization (P < 0.01), while the DC1:DC2 ratios were lower (P < 0.01) and there was no significant difference of DC1 before and after mobilization (P > 0.05). The percentages of CD8(+)CD28(-) T suppressor cells increased significantly also after mobilization (P < 0.05). It is concluded that the higher numbers of DC2 and CD8(+)CD28(-) T suppressor cells in peripheral blood grafts may contribute to the ability of tolerance in peripheral blood T cells induced by rhG-CSF in vivo.
Pegylated recombinant human granulocyte colony-stimulating factor regulates the immune status of patients with small cell lung cancer.
Sun Jing,Bai Hua,Wang Zhijie,Duan Jianchun,Li Jin,Guo Ruimin,Wang Jie
BACKGROUND:Small cell lung cancer (SCLC) is an aggressive disease involving immunodeficiency for which chemotherapy is the standard treatment. Pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) is widely used for primary or secondary prophylaxis of febrile neutropenia (FN) in chemotherapy. However, whether PEG-rhG-CSF influences immune cells, such as lymphocytes, remains unclear. METHODS:A total of 17 treatment-naïve SCLC patients were prospectively enrolled and divided into the PEG-rhG-CSF and control groups according to their FN risk. Longitudinal sampling of peripheral blood was performed before, after and 4-6 days after the first cycle of chemotherapy. Flow cytometry was used to assess lymphocyte subsets, including CD3 T, CD4 T, CD8 T, NK, and B cells. The diversity and clonality of the T-cell receptor (TCR) repertoire was analyzed by next-generation sequencing. RESULTS:In the PEG-rhG-CSF group, the proportions of CD3 T and CD4 T cells had increased significantly (P = 0.002, P = 0.020, respectively), whereas there was no increase in CD8 T cells. Further, TCR diversity increased (P = 0.009) and clonality decreased (P = 0.004) significantly after PEG-rhG-CSF treatment. However, these factors showed opposite trends before and after chemotherapy. Vβ and Jβ gene fragment types, which determine TCR diversity, were significantly amplified in the PEG-rhG-CSF group. The change in TCR diversity was significantly correlated with changes in the CD3 T or CD4 T cell proportions, but not the CD8 T cell proportion. CONCLUSIONS:PEG-rhG-CSF regulates the immune status of SCLC patients; CD4 T cells may be the main effector cells involved in this process. These findings may optimize the treatment of SCLC. KEY POINTS:PEG-rhG-CSF regulates SCLC immunity. PEG-rhG-CSF increased CD3 T and CD4 T cell proportions. PEG-rhG-CSF increased TCR diversity and decreased clonality in peripheral blood. Change in TCR diversity were correlated with CD3 T or CD4 T changes.
[Comparative study on the treatment effects with rhIL-11 and rhG-CSF in combination or alone on immune function].
Zhao Jie,Zhao Xiang-Yu,Huang Xiao-Jun
Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi
OBJECTIVE:To investigate the effect of in vivo administration of rhG-CSF and/or rhIL-11 on mice immune system function. METHODS:T cell subgroups, suppressor T cells (CD8+ CD28-, CD4+ CD25+, CD3+ CD4- CD8- T cells), expression of CD28 on T cells, and spleen T cells intracellular IL4/IFN-gamma secretion were determined by multicolor flow cytometry. MTT was used to determine the T cell proliferation capacity and mixed lymphocyte reactions. RESULTS:In vivo administration of cytokines decreased the percentage of lymphocytes (P < 0.05), rhIL-11 and rhG-CSF in combination significantly decreased the CD4+/CD8+ ratio and increased the percentage of CD8+ CD28- suppressor T cells compared to either cytokine alone (P < 0.01). There was no difference in the percentage of CD3+ CD4- CD8- and CD4+ CD25+ suppressor T cells between either of the cytokines. Furthermore, cytokines treatments significantly decreased the capacities of splenic T cells proliferation and the response to alloantigens compared with the PBS treatment (P < 0.05), the combination group being more significantly decreased (P < 0.01). And cytokines treatment significantly decreased the production of IFN-gamma and increased the production of IL-4 compared with the PBS treatment(P < 0.05). The ratio of IFN-gamma/IL-4 were significantly decreased after the combination compared with either of them alone. CONCLUSION:The combination of rhIL-11 and rhG-CSF is potentially synergistic in the induction of immune tolerance by their effects on the proliferation capacity and function of T lymphocytes.