1: Clin Exp Immunol. 2004 Nov;138(2):348-56. 

Interleukin (IL)-10, IL-1ra and IL-12 profiles in active and quiescent systemic
lupus erythematosus: could longitudinal studies reveal patient subgroups of
differing pathology?

Capper ER, Maskill JK, Gordon C, Blakemore AI.

Section of Medical Genetics, Imperial College London, London, UK.

Several cytokines have been implicated individually in the pathogenesis of
systemic lupus erythematosus (SLE) and some, including interleukin (IL)-10,
IL-12 and IL-1ra are raised during flares of disease activity. Few studies have
been directed at examining the interactions between these cytokines and how
their combined profile relates to disease activity. We have examined serum
levels of IL-10, IL-12 and IL-1ra in a cohort of SLE patients obtained from the
Queen Elizabeth Hospital, Birmingham in cross-sectional and, in a smaller group,
longitudinal analyses. In the cross-sectional study, there were significant
correlations between levels of the three cytokines. There were also significant
correlations between levels of each cytokine and measures of disease activity.
IL-10 levels correlated with ESR, anti-dsDNA antibody titres and C3D, IL-12
levels with anti-dsDNA antibody titres and IL-1ra levels with ESR, anti-dsDNA
antibody titres and C3D. IL-1ra levels also correlated with CRP. Circulating
IL-10 and IL-1ra levels were higher in patients with SLE than in normal
controls, although in this study group they did not reach significance.
Circulating IL-12 levels were, however, significantly higher in SLE compared to
controls. This was true both in patients with active disease and those sampled
during a quiescent phase. These data add to the evidence that cytokines such as
IL-10, IL-12 and IL-1ra are important in SLE pathogenesis. In a retrospective
study of serial serum samples from seven patients, we found two patients whose
cytokine profile was very different from the rest of the group. In most patients
normalized IL-10, IL-12 and IL-1ra levels mirrored BILAG scores closely, but in
these two patients, IL-10, IL-12 and IL-1ra levels did not fluctuate with
disease activity. It is possible that there is a subgroup of SLE patients whose
cytokine profile could be an important indicator of their pathology. In order to
confirm this and determine the frequency of such patients this study needs to be
repeated with a much larger subject group. The coexistence of patient groups
with different patterns of cytokine activity might explain conflicting reports
of associations of levels of particular cytokines with SLE. As the observed
differences could reflect different aetiologies of SLE, this information could
reveal valuable endophenotypes for genetic and functional studies of SLE and
might, ultimately, inform therapeutic management.

PMID: 15498048 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


2: Invest Clin. 2004 Sep;45(3):243-56. 

[Serum values of cytokines in children with vitamin A deficiency disorders]

[Article in Spanish]

Leal JY, Castejon HV, Romero T, Ortega P, Gomez G, Amaya D, Estevez J.

Laboratorio de Investigacion en Malnutricion Infantil y Retardo Mental, Hospital
de Especialidades Pediatricas de Maracaibo, Instituto de Investigaciones
Biologicas, Facultad de Medicina, Universidad del Zulia, Maracaibo, Venezuela.
jyleal@hotmail.com

Vitamin A Deficiency Disorders (VADD) have been associated with alterations of
cellular differentiation, regulatory functions of the immune system and
increased children morbidity and mortality rates due to acute respiratory and
intestinal infections. The aim of the present study was to determine serum
concentrations of Thl-Th2 cytokines in VADD children. The sample consisted of
138 children (F=72; M=66; 4-7 y old) living in slums in Maracaibo, Venezuela,
with an adequate nutrition assessed by clinics and anthropometry. Vitamin A
status was assessed by the Conjunctival Impression Cytology (CIC) technique
following the ICEPO methodology, which determines Normal CIC = control or
Abnormal CIC = VADD. The cytokines IL-10, IL-4 and IFN-gamma (pg/mL) were
analyzed by the ELISA method; and IL-2 (U/mL) by the EAISA method. The Student's
t test was applied to detect differences between values (p<0.05). No one child
presented clinical evidence of VADD; 71 children (51.40%) exhibited normal CIC
(control), whereas 67 children (48.60%) presented abnormal CIC indicative of
sub-clinical manifestation of VADD. The prevalence was higher, although non
significant, in females, 5-6 y old children and amerindians (51.39%, 64.18% and
60.40%, respectively). A diminished serum concentration of IL-10 was detected in
VADD children, in comparison with the control group (4.41 +/- 1.27 pg/mL vs.
6.03 +/- 3.90 pg/mL) (p<0.03). The rest of studied cytokines were not
significantly different with respect to control. The IL-10 diminution in VADD
children would be related to the alteration of the inflammatory response at the
level of respiratory and intestinal epithelia affected by infections.

PMID: 15469069 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


3: Nature. 2004 Aug 5;430(7000):604-5. 

The medals and the damage done.

Giles J.

Publication Types:
    News

PMID: 15295567 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


4: Zhonghua Wai Ke Za Zhi. 2004 May 22;42(10):617-21. 

[Postoperative analgesic and anti-inflammatory effects of rofecoxib after total
knee replacement]

[Article in Chinese]

Feng Y, Ju H, Yang BX, An HY, Zhou YY.

Department of Anesthesiology, Peking University People's Hospital, Beijing
100044, China.

OBJECTIVE: To evaluate the analgesic efficacy and systemic anti-inflammation of
preoperative cyclooxygenase-2 nonsteroidal antiinflammatory drug, rofecoxib,
after total knee replacement (TKR). METHODS: Thirty patients underwent elective
knee replacement were randomly given oral rofecoxib 25 mg (group RE, n = 15) or
placebo (group E, n = 15) 1 hour prior to surgery. All patients received
epidural combined isoflurane anesthesia during surgery and patient-controlled
epidural analgesia after surgery for 72 hrs (0.1 mg/ml morphine + 1.2 mg/ml
bupivacaine + 0.02 mg/ml droperidol). Modified verbal rate scale was used to
evaluate postoperative pain intensity. The outcomes included pain scores during
rest and movement of knee joints and analgesia satisfaction. Daily morphine
consumption was recorded. Circulation leucocyte and serum cytokine
concentrations (including interleukin 6, interleukin 8, interleukin 10, Tumor
necrosis factor-alpha) were determined before surgery, at the end of surgery, 2
h, 6 h, 12 h, 24 h and 48 h after surgery in two groups using RIA. The amount of
intraoperative blood loss and postoperative drainage from the knees were
measured. RESULTS: The pain scores were significantly less in the group RE than
in group E during rest and knee joints movement on the first and second
postoperative day, with an improvement in total analgesia satisfaction (P <
0.05). The mean dose of morphine for first 24 h was (8.1 +/- 1.5) mg in the E
group and (6.8 +/- 0.7) mg in the RE group (t = -2.71, P < 0.01). Leucocyte and
neutrophil counts were much higher in group E than in group RE at 12 h, 24 h
post-operatively (P < 0.05). Serum TNF-alpha concentration was significantly
lower in group RE than group E at the end of surgery, 6 h, 12 h postoperatively,
as well as IL6 at 48 h, IL8 at 24h after surgery (P < 0.05). There were no
significant differences in respect to the amount of intraoperative and
postoperative blood loss between two groups (P > 0.05). CONCLUSION: Preoperative
cyclooxygenase-2-specific nonsteroidal anti-inflammatory drug rofecoxib
increases analgesia satisfaction, reduces opioid requirement and demonstrates a
systemic anti-inflammatory effect after TKR.

PMID: 15265408 [PubMed - in process]


---------------------------------------------------------------


5: J Interferon Cytokine Res. 2004 Apr;24(4):245-51. 

IL-10 promoter nt -1082A/G polymorphism and human papillomavirus infection in
cytologic abnormalities of the uterine cervix.

Szoke K, Szalmas A, Szladek G, Veress G, Gergely L, Toth FD, Konya J.

Department of Medical Microbiology, Medical and Health Science Center,
University of Debrecen, Debrecen, Hungary.

The role of A/G polymorphism at nucleotide -1082 in the interleukin-10 (IL-10)
promoter was assessed by following the disease course of 253 patients who had
had a routine diagnostic Hybrid Capture human papillomavirus (HPV) test because
of cytologic or colposcopic abnormalities of the uterine cervix. At baseline, 97
(78%) of the 125 high-risk HPV-positive and 83 (65%) of the 128 HPV-negative
patients had equivocal cytologic atypia classified as P3 by the Papanicolaou
classification, and the rest of the patients had mild colposcopic atypia with
cytologic results of no oncogenic significance. In the high-risk HPV-infected
patients, the frequency distribution of the nt -1082 genotypes (A/A: 28%; A/G:
52%; G/G: 20%) did not differ significantly from that in the controls (A/A: 25%;
A/G: 51%; G/G: 24%; p = 0.70). On the other hand, the nt -1082 G allele tended
to decrease susceptibility to equivocal cytologic atypia unrelated to HPV
infection (A/G: OR = 0.56 [95% CI: 0.31-1.02], G/G: OR = 0.27 [95% CI:
0.11-0.63], p for trend = 0.05). With respect to the development of high-grade
cervical intraepithelial neoplasia (CIN), the established risk factors, such as
high-risk HPV infection (RR = 104.6, 95% CI: 14.2-769.9) and cytologic atypia
(RR = 9.6, 95% CI: 2.34-39.7) but not the various nt -1082 genotypes (A/A:
reference; A/G: RR = 1.11 [95% CI: 0.59-2.08]; G/G: RR = 0.62 [95% CI:
0.25-1.50]) were found to increase the risk for high-grade CIN. In conclusion,
the nt -1082 polymorphism had no influence on the early phase of cervical
carcinogenesis but may determine different susceptibilities to cervical
abnormalities unrelated to HPV infection.

PMID: 15144570 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


6: AACN Clin Issues. 2004 Jan-Mar;15(1):74-82. 

Inactivity and inflammation: selected cytokines as biologic mediators in muscle
dysfunction during critical illness.

Winkelman C.

Case Western Reserve University, Frances Payne Bolton School of Nursing,
Cleveland, Ohio, USA. chris.winkelman@case.edu

Muscle dysfunction leads to activity intolerance, prolonged hospitalization, and
additional days of mechanical ventilation. The etiology of muscle dysfunction in
the critically ill patient is multifactoral. Inactivity and inflammation, common
phenomena to patients in the intensive care unit, are associated with myopathy
and muscle dysfunction. Cytokines are small biological active molecules that
regulate inflammation and have a direct effect on muscle wasting. The purpose of
this article is to describe selected cytokines (ie, interleukin-1,
interleukin-6, interleukin-10, and tumor necrosis factor), explain their role in
muscle dysfunction, and explore the role of therapeutic activity as a moderator
of muscle dysfunction and cytokine-mediated muscle damage.

Publication Types:
    Review
    Review, Tutorial

PMID: 14767366 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


7: Clin Cancer Res. 2003 Jan;9(1):76-83. 

Repeated administrations of interleukin (IL)-12 are associated with persistently
elevated plasma levels of IL-10 and declining IFN-gamma, tumor necrosis
factor-alpha, IL-6, and IL-8 responses.

Portielje JE, Lamers CH, Kruit WH, Sparreboom A, Bolhuis RL, Stoter G, Huber C,
Gratama JW.

Department of Medical Oncology, Erasmus MC - Daniel den Hoed, 3075 EA Rotterdam,
the Netherlands.

PURPOSE: Repeated administrations of recombinant human interleukin-12 (rHuIL-12)
to cancer patients are characterized by a reduction of side effects during
treatment. Induction of IFN-gamma, considered a key mediator of antitumor
effects of IL-12, is known to decline on repeated administrations. We studied
whether other immunological effects of rHuIL-12 are tapered in the course of
treatment. EXPERIMENTAL DESIGN: In a Phase I study of 26 patients with advanced
renal cell cancer, rHuIL-12 was administered s.c. on day 1, followed by 7 days
rest and six injections administered over a 2-week time period. Plasma
concentrations of various cytokines were monitored, as well as absolute counts
of circulating leukocyte and lymphocyte subsets. RESULTS: The first injection of
IL-12 was accompanied by rapid, transient, and dose-dependent increments of
plasma levels IFN-gamma, tumor necrosis factor-alpha, IL-10, IL-6, IL-8, but not
IL-4, as well as rapid, transient, and dose-dependent reductions of lymphocyte,
monocyte, and neutrophil counts. The major lymphocyte subsets, i.e., CD4+ and
CD8+ T cells, B cells, and natural killer cells, followed this pattern. On
repeated rHuIL-12 injections, IL-10 concentrations increased further, whereas
the transient increments of IFN-gamma, tumor necrosis factor-alpha, IL-6, and
IL-8 concentrations, as well as the fluctuations of the leukocyte subset counts,
were tapered. Dose escalation of IL-12 within clinically tolerable margins did
not reduce the decline of these immunological effects. CONCLUSIONS: Induction of
pro-inflammatory cytokines and associated fluctuations in leukocyte subset
counts decrease on repeated administrations of rHuIL-12. The steady increment of
IL-10 plasma levels may mediate the observed down-regulation of clinical and
immunological effects.

Publication Types:
    Clinical Trial
    Clinical Trial, Phase I

PMID: 12538454 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


8: Am Heart J. 2002 Nov;144(5):811-7. 

Elevation of serum levels of the anti-inflammatory cytokine interleukin-10 and
decreased risk of coronary events in patients with unstable angina.

Anguera I, Miranda-Guardiola F, Bosch X, Filella X, Sitges M, Marin JL, Betriu
A, Sanz G.

Institut de Malalties Cardiovasculars, Hospital Clinic, University of Barcelona,
Barcelona, Spain.

BACKGROUND: Inflammation is an important phenomenon in atherosclerotic plaque
growth and in plaque instability. Cytokines are nuclear mediators in the
inflammatory response; some have proinflammatory and others anti-inflammatory
roles. Proinflammatory cytokines have been associated with worse outcomes in
unstable angina. The aims of this study were to determine the role of the
anti-inflammatory cytokine interleukin (IL)-10 and the proinflammatory to
anti-inflammatory ratios in the short-term prognosis of patients with unstable
angina. METHODS: Serum levels of proinflammatory cytokines IL-1beta, IL-6, and
IL-8, and of the anti-inflammatory cytokine IL-10 were determined on admission
in 127 consecutive patients with severe unstable angina, and comparisons were
made between patients who had cardiovascular events (death, nonfatal myocardial
infarction, readmission for refractory angina) (n = 20) and patients without
coronary events (n = 107) during a follow-up period of 3 months. RESULTS: IL-10
levels were lower (0.67 +/- 1.13 vs 1.33 +/- 1.67 pg/mL, P =.04) and IL-8 levels
were higher (3.6 +/- 2.41 vs 2.23 +/- 2.47 pg/mL, P =.029) in patients in whom
cardiovascular events subsequently developed compared with those without events,
with resulting higher proinflammatory to anti-inflammatory cytokine ratios in
the former group, whereas no significant differences were seen in IL-1beta or
IL-6 levels between the groups, except for the subgroup of patients with
prolonged rest angina and persistent electrocardiographic changes. A greater
ratio of IL-8 to IL-10 serum levels was observed in patients who had coronary
events (28 +/- 25 vs 12 +/- 21, P =.007). The risk of subsequent coronary events
increased in patients in the highest quartile of proinflammatory to
anti-inflammatory cytokine ratio (IL-8/IL-10). Patients in the highest quartile
had a relative risk 3.8 times higher than those in the lowest quartile (P =.01).
CONCLUSIONS: Lower levels of IL-10, with higher proinflammatory to
anti-inflammatory cytokine ratios, were observed on admission in patients with
unstable angina who subsequently had cardiovascular events. Higher levels of the
anti-inflammatory cytokine IL-10 may be needed to provide protection in unstable
angina.

PMID: 12422149 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


9: Clin Sci (Lond). 2002 Mar;102(3):315-20. 

Response of tumour necrosis factor-alpha to delayed in vitro monocyte
stimulation in patients with septic shock is related to outcome.

Appoloni O, Vincent JL, Duchateau J.

Department of Intensive Care, Erasme University Hospital, Route de Lennik 808,
B-1070 Brussels, Belgium.

We hypothesized that cytokine production following delayed in vitro cell
stimulation (to reproduce physiological cellular status at baseline) may be
related to outcome in patients with septic shock. A total of 20 patients were
included in a prospective clinical study, conducted in a medico-surgical
intensive care unit in a university hospital. Blood samples were obtained at the
onset of septic shock; these were treated to retain the cells, but to wash out
autologous plasma (containing potential inflammatory stimuli such as cytokines,
bacterial products and drugs) and replace it with foetal calf serum. Each
treated sample was divided into two sets of four aliquots, to be stimulated
either immediately or after an overnight period of resting incubation at 37
degrees C. The rest period was to allow recovery from potentially reversible
endogenous or pharmacologically induced alterations in cellular response, in
order to reproduce a near physiological state at baseline. In vitro cellular
challenges used low-dose (0.2 ng/ml) or high-dose (1 ng/ml) CD14-dependent
lipopolysaccharide and CD14-independent pokeweed mitogen to induce the
production of tumour necrosis factor-alpha (TNF-alpha), and interleukins-1 beta
and -10. Levels of TNF-alpha, interleukin-1 beta and interleukin-10 were
significantly higher (P<0.05) when cell stimulation was delayed for 16 h,
indicating a functional down-regulation of cells during septic shock. Moreover,
TNF-alpha responses obtained with high-dose lipopolysaccharide were
significantly greater in cells from patients who subsequently survived septic
shock (n=13; median value 1392 pg/ml; range 592-2048 pg/ml) than in cells from
non-survivors (n=7; median value 708 pg/ml; range 520-1344 pg/ml). These
observations support the existence of individual differences in the inflammatory
response that could influence patient outcome following septic shock.

PMID: 11869172 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


10: Pflugers Arch. 2000;441(2-3 Suppl):R79-84. 

Head-down tilt bed rest and immune responses.

Schmitt DA, Schwarzenberg M, Tkaczuk J, Hebrard S, Brandenberger G, Mauco G,
Cogoli-Greuter M, Abbal M.

ESA-ESTEC, MSM-GS, Noordwijk, The Netherlands.

Head-down tilt bed rest (HDT) is used as a model for studying the physiological
changes occurring in weightlessness during spaceflight. In the present study,
eight volunteers were subjected to a strict HDT of -6 degrees for 42 days. Blood
samples were obtained 37 and 13 days before, at days 13, 34, and 41 during, and
12, 33, and 47 days after HDT. FACScan analysis was used to determine cell
subpopulations. Plasma was used to quantify various circulating hormone levels.
Whole blood and reconstituted blood were stimulated with various activators such
as phytohaemagglutinin-P (PHA), PHA combined with phorbol-12-myristate
13-acetate (PMA), anti-CD2, anti-CD3, and lipopolysaccharide. Supernatants were
collected and analysed for the interleukins IL-1beta, IL-2, IL-6, and IL-10,
interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha). The
total number of T lymphocytes and monocytes did not change significantly,
whereas the number of polymorphonuclear cells increased during HDT. The
percentage of CD2+ and CD3+ cells was increased at day 35 of HDT. The percentage
and total number of natural killer cells (CD2+/CD3-/CD56+) was increased 12 days
before and 14 days after HDT. TNF-alpha secretion did not change significantly
during HDT. IL-2, IL-10 and IFN-gamma were increased at day 34 of HDT. IL-1beta
levels were increased before and during HDT compared to post-HDT measurements.
No significant changes were observed in plasma immunoglobulin, complement
factors and other factors of the inflammatory system. Prolactin levels increased
slightly but significantly at day 35 of HDT, thyreotropin and growth hormone
levels remained virtually unchanged. Cortisol decreased slightly but
significantly over the entire duration of the study. The changes observed during
HDT do not indicate that the immune system is blunted, and these changes do not
seem to correlate with the duration of HDT. Taken together these results show
that a HDT does not reproduce the changes in immune responses observed after
spaceflight.

PMID: 11200985 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


11: Genes Immun. 2000 Oct;1(7):442-50. 

Cloning, expression and initial characterization of interleukin-19 (IL-19), a
novel homologue of human interleukin-10 (IL-10).

Gallagher G, Dickensheets H, Eskdale J, Izotova LS, Mirochnitchenko OV, Peat JD,
Vazquez N, Pestka S, Donnelly RP, Kotenko SV.

University of Glasgow Department of Surgery, Queen Elizabeth Building, Glasgow
Royal Infirmary, 10 Alexandra Parade, Glasgow G312ER, Scotland, UK.
Grant@laboratory.gg

Interleukin-10 (IL-10) is a pleiotropic cytokine with important immunoregulatory
functions whose actions influence activities of many of the cell-types in the
immune system. We report here identification and cloning of a gene and
corresponding cDNAs encoding a novel homologue of IL-10, designated IL-19. IL-19
shares 21% amino acid identity with IL-10. The exon/intron structure of IL-19 is
similar to that of the human IL-10 gene, comprising five exons and four introns
within the coding region of the IL-19 cDNA. There are at least two distinct
IL-19 mRNA species that differ in their 5'-sequences, suggesting the existence
of an intron in the 5'-sequences of coding portion of the IL-19 gene. The longer
5'-sequence contains an alternative initiating ATG codon that is in-frame with
the rest of the coding sequence. The expression of IL-19 mRNA can be induced in
monocytes by LPS-treatment. The appearance of IL-19 mRNA in LPS-stimulated
monocytes was slightly delayed compared to expression of IL-10 mRNA: significant
levels of IL-10 mRNA were detectable at 2 h post-stimulation, whereas IL-19 mRNA
was not detectable until 4 h. Treatment of monocytes with IL-4 or IL-13 did not
induce de novo expression of IL-19, but these cytokines did potentiate IL-19
gene expression in LPS-stimulated monocytes. In addition, GM-CSF was capable of
directly inducing IL-19 gene expression in monocytes. IL-19 does not bind or
signal through the canonical IL-10 receptor complex, suggesting existence of an
IL-19 specific receptor complex, the identity of which remains to be discovered.

PMID: 11196675 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


12: Crit Care Med. 2000 Sep;28(9):3166-70. 

Comment in:
    Crit Care Med. 2001 May;29(5):1093.

Role of interleukin-10 on hyporesponsiveness of endotoxin during surgery.

Ogata M, Okamoto K, Kohriyama K, Kawasaki T, Itoh H, Shigematsu A.

Department of Anesthesiology, University of Occupational and Environmental
Health, Kitakyushu, Japan. mogata@med.uoeh-u.ac.jp

OBJECTIVE: To examine whether surgical stress causes blood cells to lose their
responsiveness to endotoxin during surgery. DESIGN: Prospective case series.
SETTING: A university hospital. PATIENTS: Sixteen volunteers classified as
American Society of Anesthesiologists physical status I-II who were scheduled
for elective distal partial gastrectomy. INTERVENTIONS: We studied nine patients
who underwent elective distal partial gastrectomy. Blood samples for tumor
necrosis factor (TNF) and interleukin (IL)-10 assay were obtained before
anesthesia, preincision, 2 hrs and 4 hrs postincision, postextubation, and 24
hrs postincision. The rest of each blood sample was diluted with 5 volumes of
endotoxin-free saline, incubated for 4 hrs in the presence of lipopolysaccharide
(LPS), centrifuged to remove cells, and assayed for TNF. In another seven
patients, antihuman IL-10 antibody was added into the diluted whole blood sample
before LPS stimulation. MEASUREMENTS AND MAIN RESULTS: TNF activity was not
detected in the blood of any patient throughout the study. In contrast, plasma
cortisol and IL-10 levels increased rapidly during surgery (p < .01, p < .05,
respectively). LPS-induced TNF activity in whole blood decreased significantly
during surgery (p < .01) and recovered to control levels by 24 hrs postincision.
The peak suppression of LPS-induced TNF and the peak value of plasma IL-10
levels occurred postextubation. Treatment with anti-IL-10 antibody partially
restored the ability of LPS to induce TNF activity postextubation (p < .05).
CONCLUSIONS: Surgical trauma rapidly induces a transient hyporesponsiveness of
blood cells to endotoxin. Plasma IL-10, which increases during surgery,
participates in this hyporesponsiveness.

PMID: 11008976 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


13: Clin Cancer Res. 2000 Jul;6(7):2661-9. 

A dose-escalation and pharmacokinetic study of subcutaneously administered
recombinant human interleukin 12 and its biological effects in Japanese patients
with advanced malignancies.

Ohno R, Yamaguchi Y, Toge T, Kinouchi T, Kotake T, Shibata M, Kiyohara Y, Ikeda
S, Fukui I, Gohchi A, Sugiyama Y, Saji S, Hazama S, Oka M, Ohnishi K, Ohhashi Y,
Tsukagoshi S, Taguchi T.

Department of Medicine III, Hamamatsu University School of Medicine, Japan.
ohnoryu@hama-med.ac.jp

A pilot dose-escalation study of recombinant human interleukin 12 (rhIL-12) was
conducted in Japanese patients with advanced malignancies. Cohorts of three
patients received escalating doses of rhIL-12 that increased from 50 to 300
ng/kg/day s.c. three times a week for 2 weeks followed by 1-week rest. The same
dosage and schedule was repeated for two additional courses. Sixteen previously
treated patients were registered, and 15 were evaluated. Common toxicities were
fever and leukopenia; the abnormality of laboratory tests included elevations in
aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase,
C-reactive protein, and beta2-microglobin. Dose-limiting toxicity was the grade
3 elevation of aminotransferases, and was observed in two of six patients at the
300-ng/kg dose level after the first course in one patient and after the third
course in the other. Leukopenia was observed at all of the dose levels; two of
six patients at 300 ng/kg experienced grade 3 leukopenia. Thus, 300 ng/kg was
determined to be the maximum acceptable dose. Peak plasma levels of rhIL-12
decreased in the second courses, but the areas under the curve were almost the
same in the first and second courses. Biological effects included increases of
plasma levels of IFN-gamma, tumor necrosis factor-alpha, IL-6, IL-10, and
neopterin. In two patients with renal cell carcinoma, complete response and
partial response of metastatic tumors were observed with 50 and 300 ng/kg; the
responses lasted for 5 and 3.5 months, respectively. Although immunological
response to rhIL-12 varies depending on administration route and schedule and on
patients' physiological conditions, the recommended dose for Phase II studies is
300 ng/kg s.c. three times a week for 2 weeks followed by 1-week rest.

Publication Types:
    Clinical Trial
    Clinical Trial, Phase I
    Multicenter Study

PMID: 10914707 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


14: Nutrition. 2000 May;16(5):355-60. 

Modulating effects of the feeding route on stress response and endotoxin
translocation in severely stressed patients receiving thoracic esophagectomy.

Takagi K, Yamamori H, Toyoda Y, Nakajima N, Tashiro T.

First Department of Surgery, Chiba University School of Medicine, Chiba City,
Chiba, Japan.

Experimental studies have demonstrated that the route of nutritional supply
impacts the systemic metabolic responses after surgical injury. Intestinal
mucosal atrophy, as induced by total parenteral nutrition (TPN) or prolonged
bowel rest, has been reported to enhance bowel endotoxin translocation. The
operative procedure for thoracic esophageal cancer, including thoracotomy,
laparotomy, and three-field lymph-node dissection, is a particularly stressful
surgery that requires long-term aggressive nutritional support and often results
in the postoperative hypermetabolic state, leading to perturbation of
postoperative immune function. Interleukin-6 (IL-6) plays an important role in
host inflammatory responses, whereas IL-10 is linked to suppression of cellular
immunity. The aim of this study was to investigate how the antecedent
nutritional routes influence systemic IL-6 and IL-10 responses and endotoxin
translocation after an operation for thoracic esophageal cancer. Twenty-nine
patients who underwent esophagectomy with three-field lymphadenectomy were
investigated. They were assigned to groups receiving either TPN (n = 18) or
enteral nutrition (EN; n = 11) providing 35 kcal x kg(-1) x d(-1) of energy and
approximately 1.2-1.5 g x kg(-1) x d(-1) of amino acids. These nutritional
supports were conducted from 1 wk before the operation to 14 d after the
operation. Serum IL-6, IL-10, and endotoxin concentration were measured before
and during the operation and at 2 h and 1, 3, and 7 d after the operation. IL-6
in sera was significantly higher after the operation in both groups. In the EN
group, however, significantly less IL-6 production was observed on the third and
seventh postoperative days when compared with those patients in the TPN group.
Similarly, serum IL-10 concentration in the TPN group showed a significantly
higher level than that in the EN group. Serum IL-6 showed a significant positive
correlation with IL-10 at 2 h and at 7 d after the operation, suggesting that
the reduced inflammatory responses were related to the inhibition of the
development of postoperative immunosuppression. Endotoxin concentration in sera
was significantly lower in the EN group after the operation than in the TPN
group. Perioperative EN provides better regulation of inflammatory cytokine
responses and may contribute less to immunosuppression after major surgery than
parenteral nutrition. The attenuated production of endotoxin induced by EN may
play an important role in these phenomena.

PMID: 10793304 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


15: J Interferon Cytokine Res. 1999 Sep;19(9):1025-30. 

Interleukin-10 inhibits spontaneous sleep in rabbits.

Kushikata T, Fang J, Krueger JM.

Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology,
Washington State University, Pullman 99164-6520, USA.

Proinflammatory cytokines, including interleukin-1beta(IL-1beta) and tumor
necrosis factor-alpha (TNF-alpha) are involved in sleep regulation. IL-10 is an
anti-inflammatory cytokine that inhibits proinflammatory cytokine production. We
hypothesized that IL-10 could attenuate sleep. Thirty-one male rabbits were
used. Three doses of IL-10 (5 ng, 50 ng, and 250 ng) were injected
intracerebroventricularly during the rest (light) period. One dose of IL-10 (250
ng) was injected during the active (dark) cycle. Appropriate time-matched
control injections of saline were given to the same rabbits on different days.
The two highest doses of IL-10 significantly inhibited spontaneous nonrapid eye
movement sleep if IL-10 was given during the light cycle. The highest dose of
IL-10 (250 ng) also significantly decreased rapid eye movement sleep. IL-10
administered at dark onset had no effect on sleep. The sleep inhibitory
properties of IL-10 provide additional evidence for the hypothesis that a brain
cytokine network is involved in regulation of physiologic sleep.

PMID: 10505745 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


16: Parasite Immunol. 1997 Aug;19(8):347-53. 

IL-10 deficit correlates with chronic, hypersplenomegaly syndrome in male CBA/J
mice infected with Schistosoma mansoni.

Bosshardt SC, Freeman GL Jr, Secor WE, Colley DG.

Immunology Branch, Centers for Disease Control and Prevention, USA Public Health
Service, Atlanta, GA 30341, USA.

Twenty weeks after moderate level infections with Schistosoma mansoni,
approximately 20% of male CBA/J mice develop hypersplenomegaly syndrome (HSS)
while the rest present with moderate splenomegaly syndrome (MSS). HSS and MSS
mice differ pathophysiologically (degree of splenomegaly, anaemia, ascites,
periportal fibrosis, portal hypertension) and immunologically with regard to
antibodies (idiotypic expression, isotype levels) to schistosome soluble egg
antigens (SEA), and spleen cell phenotypic profiles. This study compared in
vitro proliferative responses and IL-2, IFN gamma, IL-4, and IL-10 production by
spleen cells from uninfected mice and mice with acute (8 wk), MSS or HSS
schistosomiasis mansoni, upon exposure to anti-CD3 epsilon or SEA, Spleen cells
from uninfected mice produce Il-2 to anti-CD3 epsilon but exposure of cells from
all three groups of infected mice to anti-CD3 epsilon or SEA led to only very
low levels of supernatant IL-2. Anti-CD3 epsilon- or SEA-stimulated production
of IFN gamma or Il-4, and anti-CD3 epsilon-stimulated production of IL-10,
displayed similar patterns: highest cytokine production by cells from mice with
acute infections and lower levels of production that did not differ between the
two chronic groups. In contrast, while SEA-stimulated IL-10 production was again
highest with cells from mice with acute infections, spleen cells from mice with
MSS produced significantly more IL-10 than did those from mice with HSS. This
association of low levels of antigen-induced IL-10 with severe pathology is
consistent with the theory that IL-10 plays a role in the immunoregulation that
occurs in chronic schistosomiasis.

PMID: 9292893 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


17: J Exp Med. 1994 Apr 1;179(4):1397-402. 

Induction of hapten-specific tolerance by interleukin 10 in vivo.

Enk AH, Saloga J, Becker D, B1P6madzadeh M, Knop J.

Dermatology Department, University of Mainz, Germany.

Interleukin 10 (IL-10) is released during the induction phase of contact
sensitivity and was shown in prior functional studies to convert epidermal
Langerhans cells (LC) from potent inducers of primary immune responses to
specifically tolerizing cells in vitro. To investigate whether IL-10 also
subserves the function of a tolerizing agent in vivo ears of BALB/c or C3H mice
were injected intradermally with 1-2 micrograms of recombinant mouse (rm)IL-10 8
h before epicutaneous application of 3% trinitrochlorobenzene (TNCB; a contact
allergen). As a control, mice were injected with phosphate-buffered saline or
IL-10 plus neutralizing amounts of anti-IL-10 mAb. 5 d later, mice were
challenged with 1% TNCB on contralateral ears and ear swelling response was
measured 24 h later. Whereas control-treated mice showed a normal ear swelling
response to epicutaneous challenge (delta mm-2 = 25 +/- 5), ear swelling
response of IL-10-treated animals was significantly inhibited (delta mm-2 = 3
+/- 2). Coinjection of IL-10-specific mAb together with rmIL-10 completely
abrogated this effect. To differentiate between a state of nonresponsiveness and
induction of tolerance by IL-10, mice initially treated with IL-10 and TNCB were
resensitized with 3% TNCB in the absence of any treatment after 14 d of rest
(group 1). Again mice were challenged 5 d later and ear swelling responses were
tested. Whereas control mice treated with allergen alone (group 2) showed a good
swelling response (delta mm-2 = 28 +/- 6), IL-10-treated mice (group 1) showed a
minimal response towards application of allergen (delta mm-2 = 4 +/- 2). To show
that anergy induction by IL-10 was antigen-specific, mice initially treated with
IL-10 plus TNCB were exposed to 0.5% dinitrofluorobenzene (DNFB) 14 d later
(group 1). After challenge with 0.1% DNFB, IL-10-treated mice showed an ear
swelling response (delta mm-2 = 13 +/- 3; group 1) similar to that of control
mice only sensitized with DNFB (delta mm-2 = 14 +/- 3; group 3). In an attempt
to show the induction of antigen-specific tolerance in these mice in vitro,
regional lymph nodes of mice initially treated with TNCB plus IL-10 (group 1)
and control-treated mice (groups 2 and 3) were prepared and cultured in the
presence of TNBS, dinitrobenzene sulfonate (DNBS), or medium to measure
antigen-specific proliferation.(ABSTRACT TRUNCATED AT 400 WORDS)

PMID: 8145053 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


18: J Immunol. 1993 Sep 1;151(5):2390-8. 

Inhibition of Langerhans cell antigen-presenting function by IL-10. A role for
IL-10 in induction of tolerance.

Enk AH, Angeloni VL, Udey MC, Katz SI.

Dermatology Branch, National Cancer Institute, National Institutes of Health,
Bethesda, MD 20892.

IL-10 is a product of activated keratinocytes and is released during the
induction phase of contact sensitivity. As IL-10 effects have been described as
being mediated by APC, we investigated effects of IL-10 on epidermal Langerhans
cells (LC), the resident APC in the epidermis. Initial studies failed to
demonstrate effects of IL-10 on MHC class II Ag expression by LC or anti-CD3
mAb- or alloantigen-induced LC-dependent T cell proliferation. However,
production of IFN-gamma and IL-2, (but not IL-6) was markedly reduced in these
assays. When the soluble-protein Ag specific T cell clones AE7 (Th1) and D10.G4
(Th2) were substituted for unprimed T cells, differential effects of IL-10 on
T-cell proliferation were observed. Whereas IL-10-pretreated and untreated LC
supported Th2 cell proliferation equally well, IL-10-pretreated LC were
essentially unable to induce Th1 cell proliferation in response to native
protein or peptide Ag. The inhibitory influence of IL-10 on Th1 cells was
observed when fresh or 1 day cultured LC were used; 2- or 3-day cultured LC were
affected to a much lesser extent by IL-10 pretreatment. Further, coculture
experiments using IL-10-pretreated or untreated LC of a different haplotype
suggest that IL-10 negatively regulates a costimulatory signal required for
induction of Th1 cell proliferation. To assess whether T cells incubated with Ag
and IL-10-pretreated LC were responsive to further stimulation, T cells were
rescued after 1 day of coculture with IL-10-pretreated LC and restimulated,
either immediately or after 1 to 5 days of rest, with untreated LC in the
presence of Ag. T cells incubated with IL-10-pretreated LC were found to be
anergic, whereas T cells incubated with untreated LC proliferated normally after
further stimulation. However, anergic T cells responded vigorously to IL-2.
These data indicate that although IL-10-pretreated LC are effective APC for Th2
cells, they fail to induce Th1 cell proliferation and rather induce clonal
anergy in these cells.

PMID: 8103065 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------