Gayle Cocita Baldwin

Therapy for Neutropenia in Hairy Cell Leukemia with Recombinant Human Granulocyte Colony-Stimulating Factor

STUDY OBJECTIVE To determine whether recombinant human granulocyte colony-stimulating factor (G-CSF) is effective in increasing neutrophil counts in patients with hairy cell leukemia and neutropenia. DESIGN Open label, phase I/II study of G-CSF, given by daily subcutaneous injection for up to 7 weeks. SETTING Outpatient oncology clinic of a university medical center. PATIENTS A consecutive sample of four patients with hairy cell leukemia complicated by severe neutropenia. Three patients completed the study; one patient was removed after 2 weeks of therapy. INTERVENTIONS Granulocyte colony-stimulating factor was given by daily subcutaneous injection. Each patient began therapy with 1 microgram/kg body weight.d; after 1 week the dose was increased to 3 micrograms/kg.d, and 1 week later to 6 micrograms/kg.d. Therapy was continued for 5 to 6 weeks. Patients were taught self-injection, and administered treatment at home. MEASUREMENTS AND MAIN RESULTS In three patients, an increase in absolute neutrophil counts from less than 0.9 X 10(9)/L to greater than 4.0 X 10(9)/L was noted within 2 weeks of beginning G-CSF therapy. In two patients, infections resolved during therapy. One patient developed acute neutrophilic dermatosis (the Sweet syndrome) while receiving 3 micrograms/kg.d of G-CSF, and drug therapy was discontinued. CONCLUSIONS Granulocyte colony-stimulating factor may increase neutrophil counts within 2 weeks in patients with hairy cell leukemia and neutropenia. This therapy may be a useful adjunct to definitive treatment of hairy cell leukemia with interferon or pentostatin.

Respiratory and Immunologic Consequences of Marijuana Smoking

Habitual smoking of marijuana has a number of effects on the respiratory and immune systems that may be clinically relevant. These include alterations in lung function ranging from no to mild airflow obstruction without evidence of diffusion impairment, an increased prevalence of acute and chronic bronchitis, striking endoscopic findings of airway injury (erythema, edema, and increased secretions) that correlate with histopathological alterations in bronchial biopsies, and dysregulated growth of the bronchial epithelium associated with altered expression of nuclear and cytoplasmic proteins involved in the pathogenesis of bronchogenic carcinoma. Other consequences of regular marijuana use include ultrastructual abnormalities in human alveolar macrophages along with impairment of their cytokine production, antimicrobial activity, and tumoricidal function. Cannabinoid receptor expression is altered in leukocytes collected from the blood of chronic smokers, and experimental models support a role for Δ9‐tetrahydrocannabinol in suppressing T cell function and cell‐mediated immunity. The potential for marijuana smoking to predispose to the development of respiratory malignancy is suggested by several lines of evidence, including the presence of potent carcinogens in marijuana smoke and their resulting deposition in the lung, the occurrence of premalignant changes in bronchial biopsies obtained from smokers of marijuana in the absence of tobacco, impairment of antitumor immune defenses by Δ9‐tetrahydrocannabinol, and several clinical case series in which marijuana smokers were disproportionately overrepresented among young individuals who developed upper or lower respiratory tract cancer. Additional well‐designed epidemiological and immune monitoring studies are required to determine the potential causal relationship between marijuana use and the development of respiratory infection and/or cancer.

Cocaine Enhances Human Immunodeficiency Virus Replication in a Model of Severe Combined Immunodeficient Mice Implanted with Human Peripheral Blood Leukocytes

Epidemiologic studies have identified cocaine as a cofactor for development of acquired immunodeficiency syndrome (AIDS). To evaluate this interaction, human peripheral blood leukocytes (PBL) were implanted into severe combined immunodeficient mice and infected with human immunodeficiency virus (HIV) in both the presence and absence of cocaine. Concurrent administration of cocaine resulted in significantly more PBL becoming infected with HIV in vivo (38.85% vs. 18.5%). The number of CD4(+) cells recovered from HIV-infected, cocaine-treated animals was significantly lower than that from mice infected with HIV in the absence of cocaine (6.5 x 10(4) vs. 19 x 10(4)) and was associated with a lower CD4:CD8 ratio and a dramatic increase in virus load. Exposure to cocaine alone did not affect the implantation of PBL, suggesting a specific interaction between cocaine and HIV. This report describes a model for evaluating HIV cofactors and supports cocaines role in the development and progression of AIDS.

Acute and chronic effects of cocaine on the immune system and the possible link to AIDS

The pathogenesis of AIDS is a complex and prolonged process that is affected by a variety of cofactors, including the abuse of both intravenous and smoked (crack) cocaine. The exact mechanisms by which cocaine facilitates this disease are yet to be proven, but likely include a combination of increased risk due to cocaine-related social behaviours, a wide-ranging capacity for cocaine to suppress the immune system, and an effect of cocaine on the infectivity and replication of HIV. While sometimes contradictory, both human and animal studies document that cocaine alters the function of natural killer (NK) cells, T cells, neutrophils and macrophages, and alters the ability of these cells to secrete immunoregulatory cytokines. In addition to these effects on the immune system, cocaine also enhances the infectivity and/or replication of HIV when tested using human cells in vitro.

The biology of granulocyte-macrophage colony-stimulating factor: Effects on hematopoietic and nonhematopoietic cells☆

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is one of a family of glycoprotein cytokines that have potent effects in stimulating the proliferation, maturation, and function of hematopoietic cells. Deriving its name from its ability to stimulate the formation of macroscopic colonies containing neutrophils, eosinophils, macrophages, or mixtures of these cell types, GM-CSF stimulates the proliferation and maturation of myeloid progenitors, as well as functionally activating mature neutrophils, eosinophils, and macrophages. As most of the effects observed using GM-CSF in vitro have been shown to occur in vivo either in animal models or in human subjects, it is important to consider that GM-CSF may also exert some biological effects on nonhematopoietic cells. In response to immunologic stimuli, immunologic surveillance cells and cells of the microenvironment are capable of producing GM-CSF. In vitro experiments indicate that GM-CSF production is tightly regulated. In that regard, GM-CSF is not present in measurable quantities in normal serum, but little is known about the in vivo process of GM-CSF production and regulation. The biologic capabilities of GM-CSF have triggered its widespread clinical use in situations where hematopoiesis is compromised. GM-CSF can act as a potent growth factor in vivo, increasing the number and enhancing the function of hematopoietic progenitors and mature cells. However, the precise in vivo effect that GM-CSF may have on normal and neoplastic cells of nonhematopoietic origin remains undefined. The full range of GM-CSF bioactivity is mediated following binding to its receptor. The presence of specific receptors for GM-CSF has been demonstrated in all responsive cells of hematopoietic lineage, as well as in nonhematopoietic cells, both responsive and unresponsive. In conclusion, a large body of work from a number of laboratories has defined the biology of GM-CSF. Currently available reagents and technology will provide additional insights into the biology of this molecule, thereby expanding our present definition and allowing us to explore the mechanisms regulating hematopoiesis.

Cocaine and σ-1 receptors modulate HIV infection, chemokine receptors, and the HPA axis in the huPBL-SCID model

Cocaine is associated with an increased risk for, and progression of, clinical disease associated with human immunodeficiency virus (HIV) infection. A human xenograft model, in which human peripheral blood mononuclear cells were implanted into severe combined immunodeficiency mice (huPBL‐SCID) and infected with a HIV reporter virus, was used to investigate the biological interactions between cocaine and HIV infection. Systemic administration of cocaine (5 mg/kg/d) significantly increased the percentage of HIV‐infected PBL (two‐ to threefold) and viral load (100‐ to 300‐fold) in huPBL‐SCID mice. Despite the capacity for cocaine to increase corticosterone and adrenocorticotropic hormone levels in control mice, the hypothalamic‐pituitary‐adrenal axis was suppressed in HIV‐infected animals, and corticosterone levels were further decreased when animals were exposed to HIV and cocaine. Activating huPBL in vitro in the presence of 10−8 M cocaine increased expression of CC chemokine receptor 5 (CCR5) and CXC chemokine receptor 4 (CXCR4) coreceptors. Expression of CCR5 was also increased at early time‐points in the huPBL‐SCID model following systemic exposure to cocaine (54.1±9.4% increase over control, P<0.01). This effect preceded the boost in viral infection and waned as HIV infection progressed. Cocaine has been shown to mediate immunosuppressive effects by activating σ‐1 receptors in immune cells in vitro and in vivo. Consistent with these reports, a selective σ‐1 antagonist, BD1047, blocked the effects of cocaine on HIV replication in the huPBL‐SCID mouse. Our results suggest that systemic exposure to cocaine can enhance HIV infection in vivo by activating σ‐1 receptors and by modulating the expression of HIV coreceptors.

Impairment of Antimicrobial Activity and Nitric Oxide Production in Alveolar Macrophages from Smokers of Marijuana and Cocaine

Human alveolar macrophages (AMs) were recovered from the lungs of healthy nonsmokers (NS) or smokers of tobacco (TS), marijuana (MS), or crack cocaine (CS) and challenged in vitro with Staphylococcus aureus. AMs from NS and TS exhibited potent antibacterial activity that correlated with the production of nitric oxide (NO) and induction of NO synthase without the requirement for priming with exogenous cytokines. In contrast, AMs from MS and CS exhibited minimal antibacterial activity and failed to produce NO unless primed with additional cytokines. These results confirm that NO plays a significant role as an effector molecule used by normal human AMs, but this capacity is suppressed in AMs from MS and CS because of a lack of intrinsic cytokine priming.

Mechanisms for impaired effector function in alveolar macrophages from marijuana and cocaine smokers

Lung macrophages provide a first line of host defense against inhaled pathogens and their function is impaired in the lungs of inhaled substance abusers. In order to investigate the mechanism for this impairment, alveolar macrophages (AM) were recovered from nonsmokers (NS), regular tobacco smokers (TS), marijuana smokers (MS), or crack cocaine smokers (CS), and evaluated for their production of nitric oxide (NO) and the role of NO as an antimicrobial effector molecule. AM from NS and TS efficiently killed Staphylococcus aureus and their antibacterial activity correlated closely with the production of nitrite and the expression of mRNA encoding for inducible nitric oxide synthase (iNOS). In contrast, AM collected from MS and CS exhibited limited antimicrobial activity that was not affected by an inhibitor of iNOS, or associated with expression of iNOS. Treatment with either granulocyte/macrophage colony-stimulating factor (GM-CSF) or interferon-gamma restored the ability of these cells to produce NO and to kill bacteria. These findings confirm a significant role for NO as an antibacterial effector molecule used by normal human AM and suggest that this host defense mechanism is suppressed by habitual exposure to inhaled marijuana or crack cocaine in vivo.

A short-term diet and exercise intervention ameliorates inflammation and markers of metabolic health in overweight/obese children

The present study was designed to examine the effects of short-term diet and exercise on markers of metabolic health, serum-stimulated production of inflammatory biomarkers from cultured monocytes and adipocytes, and serum lipomics. Twenty-one overweight/obese children (9 boys and 12 girls, age 13.0 ± 0.5 yr, BMI 33.0 ± 1.8 kg/m(2)) were placed on a 2-wk ad libitum, high-fiber, low-fat diet and daily exercise regimen. Fasting serum samples were taken pre- and postintervention for determination of cytokines, metabolic risk markers, and lipomics. Monocytes and adipocytes were incubated with pre- and postintervention serum to investigate changes in cytokine secretion. Correlative associations were calculated, followed by hierarchical clustering to determine relationships between fatty acid (FA) species and clinical biomarkers. Despite remaining overweight/obese, interleukin (IL)-6, IL-8, TNFα, PAI-1, resistin, amylin, leptin, insulin, and IL-1ra decreased and adiponectin increased. Culture studies indicated decreases in monocyte secretion of IL-6, TNFα, and IL-1β and adipocyte secretion of IL-6. Lipomic analysis revealed a decrease in total lipids and decreases in saturated FAs and an increase in 18:1/18:0. In general, Pearsons correlations revealed that inflammatory markers are negatively associated with a cluster of polyunsaturated FAs and positively correlated with several saturated FAs. These results indicate significant modification of multiple indices of metabolic health with short-term rigorous lifestyle modification in overweight/obese children prior to obesity reversal.

Colony-stimulating factor enhancement of myeloid effector cell cytotoxicity towards neuroectodermal tumour cells.

Summary. We conducted experiments to determine the optimal conditions for colony‐stimulating factor‐enhanced neutrophil‐ and mononuclear phagocyte‐mediated antibody‐dependent cell‐mediated cytotoxicity (ADCC) using monoclonal antibodies to disialogangliosides expressed on neuroectodermal tumour target cells. Neutrophil ADCC was most effective at effector: target ratios of 100:1, with maximal cytotoxic responses to melanoma target cells generated by 3 h. Granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) and granulocyte colony‐stimulating factor (G‐CSF) were the most potent stimulators of neutrophil ADCC, and enhanced ADCC activity was inhibited in the presence of antibody to Fc receptor type II (FcRII). GM‐CSF and macrophage colony‐stimulating factor (M‐CSF) treatment of freshly isolated monocytes inhibited antibody‐independent cytotoxicity but enhanced antibody‐dependent responses. After 3 d in culture with CSF, 3–10‐fold enhancement of ADCC against melanoma target cells was observed at effector: target cell ratios of 10:1. Greatest stimulation of macrophage ADCC was obtained when GM‐CSF, M‐CSF or interleukin 3 (IL‐3) were used in conjunction with a secondary stimulus. Although gamma interferon (γ‐IFN) did not augment the cytotoxic capability of GM‐CSF‐ and IL‐3‐stimulated macrophages, prominent cytotoxic enhancement was seen when M‐CSF‐stimulated macrophages were exposed to γ‐IFN. A chimaeric mouse/human monoclonal antibody was found to be equivalent in activity to the murine antibody in neutrophil ADCC; however, in macrophage ADCC assays with submaximal effector cell stimulation, the chimaeric antibody was associated with a two‐fold greater response. These studies indicate that under specific conditions, CSFs capable of increasing the number and functional activity of mature myeloid effector cells enhance antibody‐dependent cytotoxicity to neuroectodermal tumour target cells.