|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
PHAGOCYTES
From the Department of Infectious and Tropical
Diseases, La Sapienza University, Rome, Italy.
Polymorphonuclear leukocyte (PMN) dysfunction has been reported in
human immunodeficiency virus (HIV)-infected patients. Interleukin (IL)-15 is a recently discovered cytokine that potentiates
antimicrobial functions of normal PMNs. We evaluated the in vitro
effect of IL-15 on chemotaxis and fungicidal activity of PMNs from 9 patients with untreated advanced HIV infection, 8 patients with viral
suppression after 52 to 130 weeks of highly active antiretroviral
therapy (HAART), and 12 patients with treatment failure. We also
studied oxidative burst and apoptosis of PMNs in 5 patients with
untreated advanced HIV infection. Twelve healthy donors were included
as controls. Chemotaxis and fungicidal activity of unprimed PMNs was
significantly lower in patients with untreated HIV infection compared
with controls. After incubation with IL-15, a significant increase in
PMN chemotaxis and fungicidal activity was found; moreover, IL-15
induced a significant reduction in the number of apoptotic
HIV+ PMNs. IL-15 did not modulate oxidative burst of
HIV+ PMNs as measured by chemiluminescence production. The
in vitro priming of PMNs with IL-15 determined a complete reversal of
defective chemotaxis and killing in all HAART-treated patients with
long-term HIV suppression. IL-15 significantly enhanced chemotaxis and
fungicidal activity also in patients with HAART failure. In conclusion,
IL-15 is an important cytokine in the activation of the functional
properties of HIV+ PMNs, by delaying apoptosis and
enhancing chemotaxis and fungicidal activity. The potent stimulant
effect of IL-15 on PMN function was observed in antiretroviral naive
patients as well as in individuals who were receiving HAART,
including those with treatment failure.
(Blood. 2000;96:1979-1984) Polymorphonuclear leukocytes (PMNs) are the first
line of defense in the innate immune response to invading pathogens.
During the course of human immunodeficiency virus (HIV) infection, PMNs exhibit a variety of immunologic and functional defects that may contribute to increased susceptibility to bacterial and fungal infections.1 In particular, decreased chemotaxis and
killing activity, as well as altered respiratory burst response and
accelerated apoptosis,2-6 have been reported.
Interleukin (IL)-15 is a recently discovered cytokine that belongs to
the 4 In this study, we therefore evaluated the in vitro effect of IL-15 on
functional activity of PMNs from healthy donors and HIV-infected
patients by assessing chemotaxis, fungicidal activity, oxidative burst,
and apoptosis. It was the purpose of the study to determine whether
addition of IL-15 to HIV+ PMNs could induce a normalization
of these functional parameters. We observed that the in vitro treatment
with IL-15 has a profound effect on the enhancement of chemotaxis and
killing activity of PMNs from both antiretroviral naive patients and
individuals who were receiving highly active antiretroviral therapy
(HAART), including those with virologic and immunologic treatment failure.
Patients and controls
Opportunistic infections occurred in the patients during advanced
untreated disease (Pneumocystis carinii pneumonia = 3,
pulmonary tuberculosis = 2, progressive multifocal
leukoencephalopathy = 2; cytomegalovirus disseminated disease = 2;
cerebral toxoplasmosis = 1) and in those with treatment failure
(Mycobacterium avium-complex disease = 1, pulmonary
tuberculosis = 1). No infectious complications were found in the
patients during continuous suppression of viral load after HAART.
Nevertheless, all HIV-seropositive individuals included in the
study had no evidence of active opportunistic infections at the
time of blood sample handling.
Twelve healthy blood donors (9 men, 3 women; age range, 27-69 years)
were included as HIV-negative controls. Samples from healthy donors
were run on different days to determine day-to-day variations in assay.
Control and HIV-positive PMNs were tested in parallel, using identical
reagents under identical conditions. All subjects gave informed consent
for the study.
Cytokines and stimuli
Microorganisms Candida albicans was a clinical isolate obtained from the Microbiology Service of the Department of Infectious and Tropical Diseases of La Sapienza University of Rome. Cultures were maintained by serial passage on Sabouraud agar plates (Bio-Mérieux, Lyon, France). Yeast cells were cultured for 24 hours at 37°C on Sabouraud broth, harvested by suspending in RPMI 1640 medium (Sigma), and adjusted to the desired concentration. C albicans were opsonized by incubating yeasts with human type AB serum (Sigma) for 30 minutes at 37°C, followed by washing twice in phosphate-buffered saline (PBS).Specimen collection and polymorphonuclear leukocyte isolation Venous blood samples were collected into heparinized glass tubes and ethylenediamine tetracetic acid (EDTA)-containing tubes and plasma and cells were separated immediately. PMNs were prepared from heparinized blood by Ficoll-Hypaque (Pharmacia Biotech, Uppsala, Sweden) density gradient centrifugation, followed by dextran sedimentation. Contaminating erythrocytes were removed by a single hypotonic lysis in sterile distilled water for 30 seconds at room temperature. PMNs were suspended in Hanks balanced salt solution (HBSS) without Ca++ or Mg++ (Sigma) and adjusted to the desired concentration. The purity of PMNs isolated was always more than 98%, as determined by Giemsa staining. PMN preparations consistently contained fewer than 1% monocytes. The PMN viability was more than 98%, as estimated by trypan blue exclusion.HIV RNA levels and CD4+ and CD8+ lymphocyte counts HIV RNA levels were measured in 70°C stored plasma prepared
from blood obtained in EDTA-containing tubes. A quantitative polymerase
chain reaction (Amplicor HIV Monitor; Roche Diagnostics Systems,
Branchburg, NJ), was used. The limit of detection was 50 copies/mL. The
enumeration of CD4+ and CD8+ lymphocyte numbers
was assayed in blood collected in EDTA-containing tubes; 2-color flow
cytometric analysis was performed with the Becton Dickinson flow
cytometer FACScan using the whole-blood lysis procedure and SimulTEST
reagents (Becton Dickinson, San Jose, CA).
Chemotaxis assay Isolated PMNs at 2 × 106 cells/mL in DMEM (BioWhittaker, Boeringher Ingelheim, Belgium) were incubated with human recombinant IL-15 (10 to 1000 ng/mL) at 37°C under 5% CO2 atmosphere. In preliminary experiments, a time-course study was performed at 3, 6, and 18 hours to select the optimal incubation time. We found that maximal priming effect of IL-15 was seen at 6 hours (data not shown). Control cells were incubated in medium alone. After cytokine treatment, the cells were resuspended in DMEM and used at a final concentration of 1 × 106. PMN migration toward fMLPB (10 7M) or IL-8 (100 ng/mL) was carried out
as previously reported.17,18 Briefly, 200 µL aliquots of
chemoattractant was placed in the lower well of a blind-well chamber
(Neuroprobe, Cabin John, MD), separated by polyvinylpyrrolidone-free
micropore polycarbonate filter (Neuroprobe, Corp, Pleasanton, CA) from
300 µL of cell suspensions placed in the upper well. The filter pore
sizes were 5 µm. After 90 minutes incubation at 37°C in 5%
CO2 in a humidified atmosphere, the filters were removed.
After cleaning the upper side, they were fixed and stained by adding
DiffQuik (Baxter Diagnostics AG, Dudingen, Switzerland). All assays
were carried out in triplicate. Migrated cells were then counted
microscopically in 10 randomly selected, oil-immersion fields. Cell
migration was expressed as the mean number of neutrophils that migrated
per field. Spontaneous migration in the absence of chemoattractant was
also calculated (8-10 cells per field) and was subtracted from
migration in response to fMLPB or IL-8. In some experiments, direct PMN
migration in response to IL-15 (10 ng/mL) as chemoattractant
was analyzed.
Fungicidal assay The 2 × 106 PMNs suspended in DMEM were incubated for 6 hours at 37°C under 5% CO2 atmosphere with human recombinant IL-15 (10 to 1000 ng/mL) or IFN- (500 U/mL) as positive
control. After treatment, the fungicidal activity of PMNs was assessed
by the methylene blue staining technique.19 Untreated PMNs
were subjected to the same experimental conditions. Briefly,
2 × 106 PMNs were mixed with opsonized C
albicans in a 1:5 ratio in MEM (BioWhittaker) containing 10%
human type AB serum (Sigma) and incubated at 37°C on a shaker for 60 minutes. Deoxycholic acid (250 µL of a 2.5% solution in distilled
water) was added to immediately lyse the cells. No alteration of
viability of C albicans was detectable. Methylene blue (2 mL
of 0.01% solution in PBS) was then added and the suspension was kept
on ice for 10 minutes. After centrifugation, the pellet was resuspended
in PBS and observed under light microscopy (×40) to determine the
number of blue-stained (dead) versus the number of unstained (alive)
C albicans yeasts (a total of 300 yeasts were counted for
each slide). The killing activity against C albicans was
calculated by the following formula: % killing activity = [stained
yeasts/(stained + unstained yeasts)] × 100.
Measurement of oxidative burst by chemiluminescence assay Isolated PMNs at 2.5 × 106 cells/mL in DMEM were incubated with human recombinant IL-15 (10 ng/mL) for 3 hours at 37°C under 5% CO2 atmosphere.16 Control cells were incubated in medium alone. After cytokine treatment, luminol-enhanced chemiluminescence (CL) production was recorded on a luminometer (Luminometer DCR-1; Digene Diagnostic, Inc), as previously reported.17 In each assay, the reaction mixture was made by adding 100 µL of cell suspension (2.5 × 106/mL PMN), 10 µL of 0.2 mmol/L luminol (5-amino-2,3deydro-1,4-phthalazinedione) (Sigma), an aliquot of stimulus, and DMEM to bring the final volume of 1 mL. Two different stimuli were used: fMLPB (109 mol/L); opsonized C
albicans (40 µL of 5 × 107 yeasts/mL). CL
production was measured after 30 minutes of incubation at 37°C in
agitation. The results of each assay were expressed as relative light
units (RLU)/103 cells. In some experiments, we studied the
direct effect of IL-15 (10 ng/mL) on CL production.
Apoptosis Isolated PMNs (1 × 106) in RPMI 1640 supplemented with 10% human type AB serum (Sigma) were incubated for 18 hours at 37°C under 5% CO2 atmosphere in 24-well tissue culture plates in the absence or presence of human recombinant IL-15 (10 ng/mL). After incubation, 200 µL of cell preparation were cytocentrifuged and fixed with 4% paraformaldehyde. Apoptosis was evaluated by in situ cell death detection kit, POD (Boerhinger Mannheim, Germany), according to the manufacturer's instructions. This assay measured DNA fragmentation by immunocytochemistry using TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling) method. Cell death was confirmed by immunofluorescence analysis of phosphatidylserine on the outer leaflet of apoptotic cell-membranes (Annexin-V-FLUOS, Boerhinger Mannheim). One hundred cells were counted per sample and results are expressed as percentage of apoptotic cells.Statistical analysis The difference between PMNs treated or untreated with cytokines and PMNs from HIV-infected patients or healthy donors was evaluated using analysis of variance, followed by Dunnett's test. Linear regression analysis was used to determine whether correlation existed between numbers of CD4+ and PMN chemotaxis or fungicidal activity.
Effect of IL-15 on chemotaxis, fungicidal activity, oxidative burst, and apoptosis of PMNs from normal subjects and patients with untreated advanced HIV infection The PMNs from 7 healthy donors and from 9 untreated HIV-seropositive individuals were studied for their chemotactic responsiveness toward fMLPB as chemoattractant, as well as killing activity against C albicans. Results showed that the baseline chemotactic activity of unstimulated PMNs from HIV-infected patients was significantly decreased compared with seronegative controls (mean ± SEM, 15.44 ± 1 versus 61.43 ± 1.1) (P < .001) (Figure 1A). The percentage killing of C albicans by PMNs from HIV-infected subjects was also significantly lower compared with healthy controls (mean ± SEM, 17.22 ± 0.6 versus 60.14 ± 1.4) (P < .001) (Figure 1B). To evaluate the effect of IL-15 on the PMN chemotaxis and fungicidal activity, PMNs from the same subjects were cultured with the cytokine for 6 hours. As shown in Figure 1A, in vitro priming of PMNs with IL-15 significantly enhanced the chemotactic activity in response to fMLPB of normal PMNs (101 ± 1.92) as well as that of PMNs from HIV-infected patients with defective chemotaxis (44.4 ± 2.21) (P < .05). To investigate whether IL-15 was equally effective in enhancing chemotactic response to other chemoattractants, we evaluated PMN chemotaxis toward IL-8 in 5 untreated HIV+ patients and 5 healthy controls. The results showed that IL-15-primed PMNs from HIV+ subjects and controls exhibited a significant increase in chemotactic activity toward IL-8 compared with unprimed PMNs (mean ± SEM, 44.4 ± 0.74 and 102 ± 2.7 versus 17.6 ± 0.7 and 65.5 ± 1.65, respectively; P < .05). When chemotaxis was directly assessed in response to IL-15 as chemoattractant (10 ng/mL), we found that IL-15 did not have any direct chemoattractant effect on PMNs (data not shown). Figure 1B illustrates the enhanced fungicidal activity of PMNs preincubated with IL-15 from both healthy donors and patients with untreated advanced HIV infection. IL-15 significantly augmented PMN-mediated killing activity against C albicans to 88.14% ± 1.96% in healthy controls and to 55.22% ± 1.43% in HIV-seropositive individuals (P < .05 for both). The effect of IL-15 on the candidacidal activity of PMNs was comparable with the effect of IFN (500 U/mL), which was used as positive control.16
In some experiments, chemotaxis and killing activity were assessed
after stimulation of PMNs with increased concentrations of IL-15. As
reported in Figure 2, IL-15 enhanced the
chemotactic and antifungal activity of PMNs from HIV+
subjects and healthy controls in a dose-dependent manner.
We next studied the priming effect of IL-15 on PMN oxidative respiratory burst from 5 untreated HIV-infected patients. Results showed that there was no significant difference in CL production (mean ± SEM) after stimulation with fMLPB and opsonized C albicans when PMNs were preincubated in the presence or absence of IL-15 (1.05 ± 0.18 RLU and 1.21 ± 0.21 RLU for primed PMNs versus 1.35 ± 0.26 RLU and 1.53 ± 0.12 RLU for unprimed PMNs, respectively; P > .05). In addition, when CL production of PMNs was assessed after stimulation with IL-15, we found that this cytokine did not directly modulate oxidative burst response (data not shown). Because abnormalities in PMN function during HIV infection were associated with accelerated apoptosis of these cells, we also analyzed the effect of IL-15 on PMN apoptosis of 5 patients with untreated advanced HIV infection. IL-15 in vitro treatment significantly decreased the percentage of apoptotic cells (27.6% ± 1.4%) when compared with that of unprimed PMN (59.6% ± 8.0%) (P < .05). Chemotaxis and fungicidal activity of PMN from patients with continuous HIV suppression after HAART and effect of IL-15 We next studied a cohort of 8 HIV-infected patients who received HAART for 52 to 130 weeks and showed continuous viral suppression and sustained increase in CD4+ T-cell count over the treatment period. PMNs were isolated from blood samples collected before and after HAART and assessed for chemotaxis and fungicidal activity. As reported in Table 1, HAART regimen was associated with a significant increase in both chemotactic response and anticandidal activity of PMNs (P < .05), which positively correlated with elevation in CD4+ T-cell counts (r = 0.70 and r = 0.71, respectively). Despite the improvement in the chemotactic and antifungal function after HAART, the values of these parameters remained below the range found for healthy controls. To investigate whether IL-15 could induce a complete restoration of the PMN chemotactic and fungicidal activity of these patients in vitro, we incubated PMNs from HAART-treated subjects with IL-15 (10 ng/mL) for 6 hours before functional studies. In all experiments, IL-15 significantly enhanced the chemotactic responsiveness and candidal activity of PMNs (Figure 3). The defect that was present before the in vitro IL-15 treatment was completely reversed and the chemotaxis and killing rate reached the ranges of normal PMNs.
Enhancement of chemotactic and fungicidal activity of PMNs by IL-15 in patients with HAART-treatment failure In another set of experiments, we also studied a selected group of 12 HIV-infected individuals with virologic and immunologic treatment failure after 48 to 96 weeks of HAART regimen. In these subjects, baseline chemotactic activity and percentage killing of C albicans by unprimed PMNs were significantly reduced when compared with those of HIV-positive subjects with long-term viral suppression after HAART (P < .001). When PMNs from patients with HAART-treatment failure were incubated with IL-15, a significant increase in both chemotactic response to bacterial peptide fMLPB and killing activity against C albicans were found (P < .05) (Table 2). Interestingly, in these subjects the enhancement of PMN chemotaxis and antifungal function by IL-15 reached values that were significantly higher than those of unprimed PMNs from HAART-responder individuals.
Patients with HIV infection display a variety of immunologic defects that almost invariably lead to the development of a diverse array of opportunistic infections.20 In particular, the emergence of bacterial and fungal infections could in part be ascribed to functional defects of neutrophils that represent a crucial component of the innate antimicrobial immunity. Several studies have shown dysfunctional activity of PMNs from AIDS patients in their chemotactic, phagocytic, bactericidal, and fungicidal activity and oxidative metabolism processes.1,21 It has been suggested that the dysregulated production of cytokines modulating neutrophil function may be the underlying cause of decreased PMN function during HIV infection. In this respect, cytokines, such as granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), have been reported to up-regulate functional properties of HIV+ PMNs, whereas IL-4 and IL-10 have been shown to induce a down-regulation of functional status of PMNs from HIV-infected patients.4,22,23 In this study, we evaluated the biologic role on HIV-associated
neutrophil dysfunctions of IL-15, a recently discovered cytokine that
is an important regulator of the innate immune response to invading
microrganisms. IL-15 is produced by activated monocytes early in the
course of the innate immune response and may contribute to host defense
against intracellular pathogens. In addition to its biologic effects on
the development, survival, and activation of NK cells, IL-15 plays an
important role in the activation of immune response of phagocytic
cells. Previous studies have shown that IL-15 augmented superoxide
production and candidal activity of human monocytes and induced the
production of IL-8 and monocyte chemotactic protein-1 (MCP-1) in the
same cells.24,25 Also, PMN has been shown to be a cellular
target for IL-15, which was able to induce morphologic changes and
delay apoptosis in these cells.26 Recently, Musso et
al16 demonstrated that IL-15 was a potent stimulant of
proinflammatory and antimicrobial functions of normal PMNs by
activating several functional properties of PMNs involved in the innate
immune response to C albicans. In agreement with these
findings, we found that IL-15 enhanced in vitro the functional activity
of PMNs from healthy blood donors, as demonstrated by increased
chemotactic responsiveness as well as killing activity against C
albicans. PMN activation by IL-15 was dose-dependent and, with
regard to the antifungal activity, was comparable with the priming
effect of IFN- Previous studies have suggested a immunoregulatory role of IL-15 during
HIV infection.27-33 To our knowledge, this study
represents the first data to report that the depressed chemotactic and
fungicidal activity observed in PMNs from patients with advanced HIV
infection could be improved by in vitro treatment with IL-15 and was
associated with decreased apoptosis. IL-15 has been shown to be a
chemoattractant for T-lymphocytes and NK cells, promoting
transendothelial migration of T cells into perivascular
tissues.34-37 In this study, we found that IL-15 exhibited
no direct chemoattractant effect on PMNs by itself; on the other hand,
it acts as priming agent in inducing PMN migration in response to the
chemotactic bacterial peptide fMPLB and IL-8. It is known that IL-15
has the ability to stimulate neutrophils to produce IL-8, a chemokine
that induces both recruitment and activation of PMNs.38
Therefore, it is conceivable that IL-15 could indirectly exert its
biologic effect on chemotaxis by modulating the PMN expression of
chemokines or their receptors that are essential for migration of
additional neutrophils to sites of inflammation. On the other hand,
IL-15 has the capacity to activate PMNs, by delaying apoptosis and
enhancing their fungicidal and phagocytic activity. The ability of
IL-15 to elicit functional responses of PMNs correlates with the
finding that these cells express on their surface all 3 components of
high-affinity IL-15 receptor, such as IL-15R In another set of experiments, we evaluated PMN functional activity of HIV-infected patients undergoing potent antiretroviral treatments, including 2 reverse-transcriptase inhibitors and one protease inhibitor. We found that there was a significant enhancement in PMN chemotaxis and fungicidal activity in patients who had continuous viral suppression, sustained increase in CD4+ T-cell count, and lack of infectious complications during HAART treatment. These findings are in agreement with our recent investigation assessing the phagocyte function in patients with moderate-advanced HIV-infection.17 In such patients, the administration of HAART led to a considerable improvement in the neutrophil and monocyte function that had not been observed in earlier studies among patients receiving only reverse transcriptase inhibitors. Such functional improvement was associated with suppression of HIV replication, but an immunomodulating effect of HIV reverse transcriptase or protease inhibitors on PMN function has been suggested.39,40 Although PMNs exhibited increasing chemotactic and killing activity after HAART, a complete recovery of these functional parameters was never achieved. In this study, we showed that the in vitro addition of IL-15 to PMNs fully corrected and normalized the chemotactic responsiveness and candidal activity of these cells. The positive effect of IL-15 on HIV+ PMN function was also documented in HIV-infected patients who developed virologic and immunologic treatment failure during HAART. In these patients, the persistence of high levels of plasma HIV-RNA and the inadequate CD4+ T-cell response was associated with the impairment in PMN functional activity. The in vitro priming of PMNs with IL-15 induced in patients with HAART-treatment failure considerable improvements in PMN chemotaxis and antifungal function that was comparable to those obtained in patients who successfully responded to HAART. Taken together, our results show that IL-15 is an important cytokine in activating the functional properties of PMNs from both HIV-negative and HIV-positive individuals. The potent stimulant effect of IL-15 on PMN function was observed in antiretroviral naive patients as well as in individuals who were receiving HAART, including those with treatment failure. Additional studies are needed to investigate the usefulness of IL-15 alone or in combination with antiretroviral drugs for enhancing the innate immune response during HIV infection.
Submitted November 19, 1999; accepted May 11, 2000.
Supported by a grant from the Ministero della Sanità-Istituto Superiore della Sanità-Progetto AIDS 1997 (30A.0.74) and 1998 (30B.88) (Rome, Italy).
Parts of this paper were presented at the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, September 26-29, 1999, San Francisco, CA.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Claudio M. Mastroianni, Department of Infectious and Tropical Diseases, La Sapienza University, Policlinico Umberto I, Viale Regina Elena 331, 00161 Rome, Italy; e-mail: cm.mastroianni{at}tiscalinet.it.
1. Shyur S-D, Hill HR. Polymorphonuclear leukocyte function in HIV. In: Gupta S, ed. Immunology of HIV Infection. New York, NY: Plenum Press; 1996:377-386. 2. Murphy PM, Lane C, Fauci AS, Gallin JI. Impairment of neutrophil bactericidal capacity in patients with AIDS. J Infect Dis. 1998;158:627-630. 3. Ellis M, Gupta S, Galant S, et al. Impaired neutrophil function in patients with AIDS or AIDS-related complex: a comprehensive evaluation. J Infect Dis. 1988;158:1268-1276[Medline] [Order article via Infotrieve]. 4. Roilides E, Mertins S, Eddy J, Walsh TJ, Pizzo PA, Rubin M. Impairment of neutrophil chemotactic and bactericidal function in children infected with human immunodeficiency virus type 1 and partial reversal after in vitro exposure to granulocyte-macrophage colony-stimulating factor. J Pediatr. 1990;117:531-540[Medline] [Order article via Infotrieve]. 5. Gabrilovich D, Ivanova L, Serebrovskaya L, Shepeleva G, Pokrovsky. Clinical significance of neutrophil functional activity in HIV infection. Scand J Infect Dis. 1994;26:41-47[Medline] [Order article via Infotrieve]. 6. Pitrak DL, Tasi HC, Mullane KM, Sutton SH, Stevens P. Accelerated neutrophil apoptosis in the acquired immunodeficiency syndrome. J Clin Invest. 1996;98:2714-2719[Medline] [Order article via Infotrieve]. 7. Carson W, Caligiuri MA. Interleukin-15 as potential regulator of the innate immune response. Brazil J Med Biol Res. 1998;31:1-9[Medline] [Order article via Infotrieve]. 8. Waldmann TA, Tagaya Y. The multifaceted regulation of interleukin-15 and the role of this cytokine in NK cell differentiation and host response to intracellular pathogens. Annu Rev Immunol. 1999;17:19-49[Medline] [Order article via Infotrieve].
9.
Giri JG, Kumaki S, Ahdieh M, et al.
Utilization of the
10.
Giri JG, Ahdieh M, Eisenman J, et al.
Identification and cloning of a novel IL-15 binding protein that is structurally related to the 11. Armitage RJ, MacDuff BM, Eisenman J, Paxton R, Grabstein KH. IL-15 has stimulatory activity for the induction of B cell proliferation and differentiation. J Immunol. 1995;154:483-490[Abstract]. 12. Lewko WM, Smith TL, Bowman DJ, Good RW, Oldgham RK. Interleukin-15 and the growth of tumor-derived activated T-cells. Cancer Biother. 1995;10:13-20[Medline] [Order article via Infotrieve].
13.
Wilkinson PC, Liew FY.
Chemoattraction of human blood T lymphocytes by interleukin-15.
J Exp Med.
1995;181:1255-1259
14.
Bamford RN, Grant AJ, Burton JD, et al.
The interleukin (IL) 2 receptor beta chain is shared by IL-2 and a cytokine, provisionally designated IL-T, that stimulates T-cell proliferation and the induction of lymphokine-activated killer cells.
Proc Natl Acad Sci U S A.
1994;91:4940-4944
15.
Carson WE, Giri JG, Lindemann MJ, et al.
Interleukin (IL) 15 is a novel cytokine that activates human natural killer cells via components of the IL-2 receptor.
J Exp Med.
1994;180:1395-1403
16.
Musso T, Calosso L, Zucca M, et al.
Interleukin-15 activates proinflammatory and antimicrobial functions in polymorphonuclear cells.
Infect Immun.
1998;66:2640-2647 17. Mastroianni CM, Lichtner M, Mengoni F, et al. Improvement in neutrophil and monocyte function during highly active antiretroviral treatment of HIV-1-infected patients. AIDS. 1999;13:883-890[Medline] [Order article via Infotrieve]. 18. Meddows-Taylor S, Martin DJ, Tiemessen CT. Reduced expression of interleukin-8 receptors A and B on polymorphonuclear neutrophils from persons with human immunodeficiency virus type 1 diseases and pulmonary tuberculosis. J Infect Dis. 1998;177:921-930[Medline] [Order article via Infotrieve]. 19. Lehrer RI, Cline MJ. Interaction of C. albicans with human leukocytes and serum. J Bacteriol. 1968;98:996-1002.
20.
Fauci AS.
The human immunodeficiency virus: infectivity and mechanism of pathogenesis.
Science.
1988;239:617-622 21. Flo RW, Naess A, Nilsen A, Harthug S, Solberg CO. A longitudinal study of phagocyte function in HIV-infected patients. AIDS. 1994;8:771-777[Medline] [Order article via Infotrieve]. 22. Vecchiarelli A, Monari C, Baldelli F, et al. Beneficial effect of recombinant human granulocyte colony-stimulating factor on fungicidal activity of polymorphonuclear leukocytes from patients with AIDS. J Infect Dis. 1995;171:1448-1454[Medline] [Order article via Infotrieve]. 23. Tascini C, Baldelli F, Monari C, et al. Inhibition of fungicidal activity of polymorphonuclear leukocytes from HIV-infected patients by interleukin (IL)-4 and IL-10. AIDS. 1996;10:477-483[Medline] [Order article via Infotrieve].
24.
Vàzquez N, Walsh TJ, Friedman D, Chanock SJ, Lyman CA.
Interleukin-15 augments superoxide production and microbicidal activity of human monocytes against Candida albicans.
Infect Immun.
1998;66:145-150
25.
Badolato R, Ponzi AN, Millesimo M, Notarangelo LD, Musso T.
Interleukin-15 (IL-15) induces IL-8 and monocyte chemotactic protein 1 production in human monocytes.
Blood.
1997;90:2804-2809
26.
Girard D, Paquet M-E, Paquin R, Beaulieu AD.
Differential effect of interleukin-15 (IL-15) and IL-2 on human neutrophils: modulation of phagocytosis, cytoskeleton rearrangement, gene expression, and apoptosis by IL-15.
Blood.
1996;88:3176-3184 27. Chehimi J, Marshall JD, Salvucci O, et al. IL-15 enhances immune functions during HIV infection. J Immunol. 1997;158:5978-5987[Abstract].
28.
Seder RA, Grabstein KH, Berzofsky JA, MacDyer JF.
Cytokine interaction in HIV-infected individuals: role of IL-2, IL-12 and IL-15.
J Exp Med.
1995;182:1067-1078 29. Kanai T, Thomas EK, Yasutomi Y, Letvin NL. IL-15 stimulates the expansion of AIDS-virus-specific CTL. J Immunol. 1996;157:3681-3687[Abstract]. 30. Kacani L, Sprinzl GM, Erdei A, Dierich MP. Interleukin-15 enhances HIV-1-driven polyclonal B-cell response in vitro. Exp Clin Immunogenet. 1999;16:162-172[Medline] [Order article via Infotrieve]. 31. Naora H, Gougeon ML. Enhanced survival and potent expansion of the natural killer cell population of HIV-infected individuals by exogenous interleukin-15. Immun Lett. 1999;68:359-367[Medline] [Order article via Infotrieve]. 32. Lin SJ, Roberts RL, Ank BJ, Nguyen QH, Thomas AK, Stiehm ER. Human immunodeficiency virus (HIV) type-1 gp120-specific cell-mediated cytotoxicity (CMC) and natural killer (NK) activity in HIV-infected (HIV+) subjects: enhancement with interleukin-(IL-2), IL-12 and IL-15. Clin Immunol Immunopathol. 1997;82:163-173[Medline] [Order article via Infotrieve]. 33. Loubeau M, Ahmad A, Toma E, Menezes J. Enhancement of natural killer and antibody-dependent cytolytic activities of the peripheral blood mononuclear cells of HIV-infected patients by recombinant IL-15. J Acquired Immune Defic Syndr Hum Retrovirol. 1997;16:137145. 34. Allavena P, Giradina G, Bianchi G, Mantovani A. IL-15 is chemotactic for natural killer cells and stimulates their adhesion to vascular endothelium. J Leuk Biol. 1997;61:729-735[Abstract]. 35. Oppenheimer-Marks N, Brezinschek RI, Mohamadzadeh M, Vita R, Lipsky PE. Interleukin 15 is produced by endothelial cells and increases the transendothelial migration of T cells in vitro and in the SCID mouse-human rheumatoid arthritis model in vivo. J Clin Invest. 1998;101:1261-1272[Medline] [Order article via Infotrieve].
36.
Sancho D, Yanez-Mò M, Tejedor R, Sanchez-Madrid F.
Activation of peripheral blood T cells by interaction and migration through endothelium: role of lymphocyte function antigen-1/intercellular adhesion molecule-1 and interleukin-15.
Blood.
1999;93:886-896
37.
Agostini C, Zambello R, Facco M, et al.
CD8 T-cell infiltration in extravascular tissues of patients with human immunodeficiency virus infection: interleukin-15 upmodulates costimulatory pathways involved in the antigen-presenting cells-T-cell interaction.
Blood.
1999;93:1277-1286
38.
McDonald PP, Russo MP, Ferrini S, Cassatella MA.
Interleukin-15 (IL-15) induces NF-
39.
Roilides E, Venzon D, Pizzo PA, Rubin M.
Effects of antiretroviral dideoxynucleosides on polymorphonuclear leukocyte function.
Antimicrob Agents Chemother.
1990;34:1672-1677 40. Mastroianni CM, Lichtner M, Mengoni F, et al. Effect of HIV protease inhibitors on neutrophil apoptosis. Presented at: 39th Interscience Conference on Antimicrobial Agents and Chemotherapy San Francisco: CA; 1999; abstract 1830.
© 2000 by The American Society of Hematology.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
|
 |
|
  Z. Ye, E. J. Kerschen, D. A. Cohen, A. M. Kaplan, N. van Rooijen, and S. C. Straley Gr1+ Cells Control Growth of YopM-Negative Yersinia pestis during Systemic Plague Infect. Immun., September 1, 2009; 77(9): 3791 - 3806. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. A. Stoklasek, K. S. Schluns, and L. Lefrancois Combined IL-15/IL-15R{alpha} Immunotherapy Maximizes IL-15 Activity In Vivo J. Immunol., November 1, 2006; 177(9): 6072 - 6080. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Heit, G. Jones, D. Knight, J. M. Antony, M. J. Gill, C. Brown, C. Power, and P. Kubes HIV and Other Lentiviral Infections Cause Defects in Neutrophil Chemotaxis, Recruitment, and Cell Structure: Immunorestorative Effects of Granulocyte-Macrophage Colony-Stimulating Factor J. Immunol., November 1, 2006; 177(9): 6405 - 6414. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Marquis, D. Lewandowski, V. Dugas, F. Aumont, S. Senechal, P. Jolicoeur, Z. Hanna, and L. de Repentigny CD8+ T Cells but Not Polymorphonuclear Leukocytes Are Required To Limit Chronic Oral Carriage of Candida albicans in Transgenic Mice Expressing Human Immunodeficiency Virus Type 1 Infect. Immun., April 1, 2006; 74(4): 2382 - 2391. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Gill, K. L. Rosenthal, and A. A. Ashkar NK and NKT Cell-Independent Contribution of Interleukin-15 to Innate Protection against Mucosal Viral Infection J. Virol., April 1, 2005; 79(7): 4470 - 4478. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Lum, D. J. Schnepple, Z. Nie, J. Sanchez-Dardon, G. L. Mbisa, J. Mihowich, N. Hawley, S. Narayan, J. E. Kim, D. H. Lynch, et al. Differential Effects of Interleukin-7 and Interleukin-15 on NK Cell Anti-Human Immunodeficiency Virus Activity J. Virol., June 1, 2004; 78(11): 6033 - 6042. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Kubes, B. Heit, G. van Marle, J. B. Johnston, D. Knight, A. Khan, and C. Power In Vivo Impairment of Neutrophil Recruitment during Lentivirus Infection J. Immunol., November 1, 2003; 171(9): 4801 - 4808. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. T. Goldenberg, G. N. Holland, W. G. Cumberland, T. C. Fisher, I.-C. Folz, R. C. Wang, B. G. Terry, A. A. Moe, F. Kramer, J. I. Lim, et al. An Assessment of Polymorphonuclear Leukocyte Rigidity in HIV-Infected Individuals after Immune Recovery Invest. Ophthalmol. Vis. Sci., June 1, 2002; 43(6): 1857 - 1861. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|||||||
 |
 |
 |
 |
 |
 |
 |
 |
||
| Copyright © 2000 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Top
Abstract
Introduction
-helix bundle cytokine family and plays an important role in
the early steps of the innate immune response to
infections.
- and 
B activation and IL-8 production in human neutrophils.
Blood.
1998;92:4828-4835