Subcutaneous recombinant granulocyte-macrophage colony-stimulating factor used as a single agent and in an alternating regimen with azidothymidine in leukopenic patients with severe human immunodeficiency virus infection [see comments] (original) (raw)
Related papers
The Journal of Infectious Diseases, 2000
Preliminary preclinical and clinical data suggest that granulocyte-macrophage colony-stimulating factor (GM-CSF) may decrease viral replication. Therefore, 105 individuals with AIDS who were receiving nucleoside analogue therapy were enrolled in a placebo-controlled, doubleblind study and were randomized to receive either 125 mg/m 2 of yeast-derived, GM-CSF (sargramostim) or placebo subcutaneously twice weekly for 6 months. Subjects were evaluated for toxicity and disease progression. A significant decrease in mean virus load (VL) was observed for the GM-CSF treatment group at 6 months (Ϫ0.07 log 10 vs. Ϫ0.60 log 10 ; P p). More subjects achieved human immunodeficiency virus (HIV)-RNA levels !500 copies/ .02 mL at у2 evaluations (2% on placebo vs. 11% on GM-CSF;). Genotypic analysis of P p .04 46 subjects demonstrated a lower frequency of zidovudine-resistant mutations among those receiving GM-CSF (80% vs. 50%;). No difference was observed in the incidence of P p .04 opportunistic infections (OIs) through 6 months or survival, despite a higher risk for OI among GM-CSF recipients. GM-CSF reduced VL and limited the evolution of zidovudineresistant genotypes, potentially providing adjunctive therapy in HIV disease.
British Journal of Haematology, 1991
Acute myeloblastic leukaemia (AML) is a malignant disease (HTB9-CM) was chosen; HTB9-CM contains an active with the progressive accumulation of leukaemic cells. The stimulator of blast cell growth (Hoang & McCulloch, 1985). leukaemic cell population is maintained by blast progenitors After 7 days incubation at 37°C in a humidified atmosphere which are characterized as stem cells; they may renew of 5% Co2 in air, colonies of more than 20 cells were themselves and/or undergo terminal divisions (McCulloch, scored. Secondly, 3 x 106 cells were cultured in 3 ml of a-1986). Self-renewal has been considered the biological nature MEM with 20% FCS with or without recombinant G-CSF of blast progenitors and is closely correlated with the in Lux petri dishes (Miles Lab., Naperville, Ill) as described prognosis of the leukaemia patients. In patients with blast (Nara & McCulloch, 1985a). After 7 days suspension progenitors of high self-renewal capacity it is difficult to culture, cells were harvested, counted and used for blast achieve complete remission or long term survival assay (Buick et al., 1977). The recovery of clonogenic cells in (McCulloch et al., 1982). From this point of view, it is suspension was obtained by multiplying the plating efficiency
The Journal of Infectious Diseases, 1999
An obstacle to stem cell gene therapy for AIDS is the limited numbers of hematopoietic progenitors available. Granulocyte colony-stimulating factor (G-CSF) is used for mobilization of progenitors, but little is known about the functional characteristics of mobilized progenitors, and immature and T cell progenitors may not be mobilized. This study examined the effect of G-CSF on the function of progenitors. Ten human immunodeficiency virus-infected patients received G-CSF (filgrastim, 300 mg/day) for 5 days. Absolute numbers of immature and T cell progenitors did not increase. The ability of CD34 + progenitor cells to generate lymphocytes was examined by use of thymic organ cultures. The mean number of lymphocytes generated per CD34 + cell on day 0 was 0.72 and on day 4 was 0.09 ( ). The number P ! .003 of CD4 + cells generated per CD34 + cell was significantly reduced after G-CSF treatment. Thus, G-CSF increased the number of mature progenitor cells but did not increase T cell progenitors.
Experimental Cell Research, 1999
Apoptosis plays a major role during HIV infection, including the primary, acute HIV syndrome (AHS), during which such phenomenon is massive. We asked whether apoptosis involved not only peripheral blood lymphocytes, but also monocytes (PBM) and granulocytes (PBG). Thus, we studied cells from different patients during the acute phase of the viral syndrome. The CD95 molecule was expressed at high density on the PBM and PBG surface during AHS. Culturing PBG for a few hours resulted in a significant membrane expression of phosphatidylserine, consistent with apoptosis. However, cells maintained for hours plasma membrane integrity and showed no relevant changes in mitochondrial membrane potential. The overexpression of CD95 was not associated with high plasmatic levels of sCD95 and, together with apoptosis and its related markers decreased after a few weeks of highly active antiretroviral therapy. During AHS, a deregulation of the CD95 system occurs in monocytes and granulocytes, is related to a high propensity of PBG to undergo apoptosis, and may contribute to the pathogenesis of the disease. Antiretroviral treatment resulted not only in a decrease of virus production, but also in a reduced PBG tendency to undergo spontaneous apoptosis. Even if the mechanism(s) responsible for this phenomenon remains to be elucidated, our data suggest a possible (indirect?) action of antiretroviral therapies on PBG and PBM which could explain, at least partially, the rescue of natural immunity and the reduced use of granulocyte-colony stimulating factor during such treatments.
Clinical Immunology and Immunopathology
We investigated monocyte-derived macrophage function in 25 HIV-positive patients, 19 in the CDC class III and 6 class IV; 17 were intravenous drug abusers (IVDA) and 8 were homosexual men. Macrophages from HIV-positive patients behaved normally in assays of superoxide anion (O2-) production and candidacidal activity. After 3 days' treatment with 200 U/ml recombinant interferon-gamma (rIFN-gamma) or 250 U/ml recombinant granulocyte/macrophage-colony stimulating factor (rGM-CSF), both control and HIV-positive patients' phagocytes expressed the activated state, as indicated by the increased O2- production in response to phagocytable or soluble stimuli; however, these cytokines did not enhance candidacidal activity. Compared to appropriate HIV-negative controls (18 healthy heterosexuals, 4 homosexuals and 4 IVDA), macrophages from 19 of the 25 HIV-positive patients presented a significant defect in their Fc receptor (FcR)-dependent phagocytosis, independently from the CDC stage,...
AIDS Research and Human Retroviruses, 1997
Patients infected with human immunodeficiency virus (HIV) frequently have increased production of interleukin 6 (IL-6) and tumor necrosis factor a (TNF-a), and these cytokines may in turn contribute to the disease pathogenesis. It has been hypothesized that secretion of these cytokines by HI V-exposed mononuclear cells or HIV-infected monocyte/macrophages (M/Ms) is the principal source of their overproduction in HIY infected patients, and the present study was undertaken to explore this issue. We observed that in the absence of endotoxin or cytokines, M/Ms productively infected by HIV do not produce detectable IL-6 or TNF-a. However, granulocyte-macrophage colony-stimulating factor (GM-CSF), a cytokine that enhances HIV replication in M/Ms and is frequently used to propagate monocytotropic strains of HIV, can induce the relatively long-term production of IL-6 (up to 47 U/ml) and TNF-a (up to 47 pg/ml) by M/Ms, even in the absence of HIV. Also, HIV induced production of a relatively small (<9 U/ml) quantity of IL-6 in M/Ms stimulated with macrophage-colony stimulating factor (M-CSF). Finally, while highly concentrated HIV induced production of both cytokines by either M/Ms or peripheral blood mononuclear cells (PBMCs), this production was almost completely eliminated when care was taken to avoid contamination of HIV by endotoxin. These data suggest that the excess IL-6 and TNF-a in HIV-infected patients does not simply result from their production by HIV-infected M/Ms and that alternative mechanisms are involved in this process.
The Journal of Infectious Diseases, 1999
Sargramostim is a yeast-derived, recombinant human granulocyte-macrophage colony-stimulating factor with therapeutic potential in human immunodeficiency virus (HIV) infection. Its safety and activity when used in combination with protease inhibitors were evaluated in a randomized, double-blind trial in which 20 HIV-infected subjects on stable antiretroviral regimens, including indinavir or ritonavir, received sargramostim or placebo 3 times a week for 8 weeks. Analysis of HIV virus load excluded any 0.5 log 10 increase due to sargramostim (95% confidence interval, Ϫ0.68 to 0.44). Sargramostim was well tolerated, and inflammatory cytokines and surrogate markers of disease progression, such as serum levels of interleukin-10 and soluble tumor necrosis factor receptors types I and II, remained stable in subjects receiving sargramostim. Sargramostim treatment was associated with a trend toward decreased HIV RNA (10.5 log 10) and increased CD4 + cell count (130%). These results became statistically significant only when subjects with baseline virus loads within the limits of detection or baseline CD4 cell count 150 were analyzed. No difference in indinavir pharmacokinetics was observed before or after sargramostim therapy. Sargramostim, a yeast-derived recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF), is an immunomodulatory agent that may be useful in the treatment of human immunodeficiency virus (HIV) infection. Sargramostim enhances the number and function of a wide range of immune cells, including lymphocytes, macrophages, neutrophils, and dendritic cells [1-11] through activities such as augmentation of cytokine secretion and up-regulation of class II major histocompatibility complexes and accessory receptors (B 7.1 , B 7.2) involved in the immune response. Sargramostim has additional effects that may provide clinical benefit in HIV infection. First, it enhances the antiretroviral activity of zidovudine and stavudine in macrophages and ameliorates the hematologic side effects of these agents [12-19].