Citations of BMS215/2
Newborn patients exhibit an unusual pattern of interleukin 10 and interferon {gamma} serum levels in response to cardiac surgery
Alcaraz,A.J.; Sancho,L.; Manzano,L.; Esquivel,F.; Carrillo,A.; Prieto,A.; Bernstein,E.D.; Alvarez-Mon,M.
Journal of Thoracic and Cardiovascular Surgery 2002;123:451-458.
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Abstract
Objective: The aim of this study was to determine the clinical significance of serum levels of interleukin 10 and interferon {gamma} in pediatric patients undergoing cardiopulmonary bypass. Methods: We divided the patients into 2 groups: 8 neonates and 19 nonnewborn children. Interleukin 10 and interferon {gamma} serum levels were quantified before sternotomy, at admission to the pediatric intensive care unit (30 minutes postoperatively), 24 hours after the onset of the operation, and 3 days after the operation. Results: Newborn patients displayed significantly greater amounts of serum interleukin 10 than older children, not only in regard to the peak level achieved but also at every postoperative time point analyzed. In contrast, no significant changes in interferon {gamma} serum levels were observed in neonates at any time point, whereas nonnewborn pediatric patients showed a significant increase in interferon {gamma} serum concentrations immediately after the operation. This unusual pattern of cytokine response in newborn patients was not associated with modifications in cortisol serum levels. Furthermore, although neonates had significantly different surgical and clinical variables than did the nonnewborn pediatric patients, the variation in interleukin 10 production in neonates could not be accounted for by differences in the magnitude of surgical injury. In the group of neonates, there were significant positive correlations between peak interleukin 10 serum levels and both partial pressure of arterial oxygen/fraction of inspired oxygen ratio and postoperative body weight gain. Conclusions: Newborn patients undergoing cardiopulmonary bypass exhibit a distinctive biologic response pattern characterized by high levels of serum interleukin 10 without changes in serum interferon {gamma}. This cytokine imbalance could have potential clinical implications
1460
Immunodeficiency associated with anorexia nervosa is secondary and improves after refeeding
ALLENDE; CORELL; MANZANARES; MADRUGA; MARCOS; MADRONO; LOPEZ,G.O.Y.A.; GARCIA,P.E.R.E.; MORENO; RODRIGO; SANZ; ARNAIZ,V.I.L.L.
Immunology 1998;94:543-551.
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Abstract
Several studies have addressed the question of starvation effects on immune function by means of changes in lymphocyte subsets, cytokine induction or lymphocyte activation. Anorexia nervosa (AN) patients are severely malnourished and contradictory results have been obtained regarding the accompanying immunodeficiency, including its assignation as a part of the primary nervous disorder. In the present work, an extensive immunological function examination was carried out on 40 AN patients who were compared with a control group of 14 healthy girls. The AN patients were also classified according to their nutritional status (by the Body Mass Index: BMI), this being critical for a better understanding of these secondary immunodeficiency bases. Moreover, another immune system study was performed on five patients after refeeding. Lymphocyte subsets and function, cytokine induction and peripheral blood concentrations, and innate as well as humoral immunity were evaluated. Deregulation in the cytokine network, owing to the interaction of the central nervous (CNS) and immune systems, seems to be the initial immune alteration in AN immunodeficiency but it has not been disproved that the immunodeficiency is a direct consequence of the original psychiatric perturbation. Spontaneous high levels of circulating interleukin-1beta (IL-1beta) and tumour necrosis factor-alpha (TNF-alpha) have been observed; this is probably one of the causes of the anomalies found in the T-cell subpopulations (mainly the naive CD4+CD45RA+ reduction and the cytotoxic CD8+ increase) and T-cell activation status (mainly the down-regulation of the CD2 and CD69 activation pathways). This finally leads to an impairment, not only in T-cell function but also in T-cell to B-cell co-operation. The AN specificity of these results is confirmed by the fact that these immune alterations improve after refeeding and when nutritional status becomes less critical, which also suggests that AN immunodeficiency is indeed secondary to malnutrition
594
Preoperative prediction of pediatric patients with effusions and edema following cardiopulmonary bypass surgery by serological and routine laboratory data
Bocsi,József; Hambsch,Jörg; Osmancik,Pavel; Schneider,Peter; Valet,Günter; Tárnok,Attila
Critical Care 2002;6:226-233.
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Abstract
Aim Postoperative effusions and edema and capillary leak syndrome in children after cardiac surgery with cardiopulmonary bypass constitute considerable clinical problems. Overshooting immune response is held to be the cause. In a prospective study we investigated whether preoperative immune status differences exist in patients at risk for postsurgical effusions and edema, and to what extent these differences permit prediction of the postoperative outcome. Method One-day preoperative serum levels of immunoglobulins, complement, cytokines and chemokines, soluble adhesion molecules and receptors as well as clinical chemistry parameters such as differential counts, creatinine, blood coagulation status (altogether 56 parameters) were analyzed in peripheral blood samples of 75 children (aged 318 years) undergoing cardiopulmonary bypass surgery (29 with postoperative effusions and edema within the first postoperative week). Results Preoperative elevation of the serum level of C3 and C5 complement components, tumor necrosis factor-¦, percentage of leukocytes that are neutrophils, body weight and decreased percentage of lymphocytes (all P < 0.03) occurred in children developing postoperative effusions and edema. While single parameters did not predict individual outcome, >86% of the patients with postoperative effusions and oedema were correctly predicted using two different classification algorithms. Data mining by both methods selected nine partially overlapping parameters. The prediction quality was independent of the congenital heart defect. Conclusion Indicators of inflammation were selected as risk indicators by explorative data analysis. This suggests that preoperative differences in the immune system and capillary permeability status exist in patients at risk for postoperative effusions. These differences are suitable for preoperative risk assessment and may be used for the benefit of the patient and to improve cost effectiveness.
907
Suboptimal Activation of CD8+ T Cells by Melanoma-derived Altered Peptide Ligands: Role of Melan-A/MART-1 Optimized Analogues
Carrabba,Matteo G.; Castelli,Chiara; Maeurer,Markus J.; Squarcina,Paola; Cova,Agata; Pilla,Lorenzo; Renkvist,Nicolina; Parmiani,Giorgio; Rivoltini,Licia
Cancer Research 2003;63:1560-1567.
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Abstract
Suboptimal activation of T lymphocytes by tumor cells may contribute to the failure of the immune system to control tumor growth. We recently demonstrated that Melan-A/MART-1-reactive CTLs can be anergized by peptide analogues with partial agonist/antagonist functions, which selectively impair interleukin (IL)-2 release. Here we analyze the potential expression of partial agonist/antagonist peptides by tumor cells and their role in suboptimal T-cell activation. HLA-bound peptide fractions were eluted from HLA-A*0201/Melan-A/MART-1+ melanoma cells and analyzed for reconstitution of the MART-1-specific T-cell epitope. Among the peptide fractions able to induce IFN-{gamma} release by MART-1-specific T cells, only fraction 43-44 activated IL-2 production by anti-MART-1 T cells, whereas the remaining two fractions acted as peptide antagonists by inhibiting IL-2 release in response to the native epitope. A comparable down-modulation of IL-2 release could also be induced by the MART-1-derived peptide 32-40, previously identified in one of the two anergizing fractions. A substantial deficit in IL-2 release was additionally detected in tumor-specific CD8+ T cells infiltrating melanoma lesions. To overcome IL-2 impairment by peptide antagonists, anti-MART-1 T cells were generated by in vitro sensitization with the two optimized analogues Melan-A/MART-127-35 1L (with superagonist features) and Melan-A/MART-126-35 2L (with improved HLA-A*0201 binding). T cells raised with the superagonist Melan-A/MART-127-35 1L showed resistance to the inhibition of IL-2 release mediated by melanoma-derived peptide fractions, whereas Melan-A/MART-126-35 2L-specific T cells appeared to be as sensitive as T cells raised with the parental epitope. This resistance was associated with the enhanced ability of Melan-A/MART-127-35 1L-specific T cells to release IL-2. Taken together, these data indicate that melanoma cells can process and present on their surface peptides inhibiting optimal T-cell activation against immunodominant epitopes and that the usage of optimized peptide analogues could represent a promising approach for overcoming tumor-induced immunosuppression and possibly designing more successful vaccines for cancer patients
68
Altered T helper 1 reaction but not increase of virus load in patients with dengue hemorrhagic fever
Chen,R.F.; Liu,J.W.; Yeh,W.T.; Wang,L.; Chang,J.C.; Yu,H.R.; Cheng,J.T.; Yang,K.D.
FEMS Immunology and Medical Microbiology 2005;44:43-50.
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Abstract
To investigate whether dengue-2 patients with and without dengue hemorrhagic fever had different virus load, immune mediators, or T helper (Th) reaction, we simultaneously measured virus load, immune mediators and the Th1/Th2 transcription factors T-bet/GATA-3 mRNA expression in a large outbreak of dengue-2 infections in Southern Taiwan. Results showed that virus load was not significantly different between patients with and without dengue hemorrhagic fever. Patients with dengue fever had higher IFN-? levels, but patients with dengue hemorrhagic fever had significantly higher IL-10 levels. Further studies showed that patients with dengue hemorrhagic fever had a significantly lower T-bet than those with dengue fever, but GATA-3 mRNA expression in peripheral blood leukocytes was not significant difference between both groups. In conclusion, altered Th1 reaction as reflected by lower T-bet mRNA expression associated with higher IL-10 levels might be involved in the pathogenesis of dengue hemorrhagic fever.
918
Altered T helper 1 reaction but not increase of virus load in patients with dengue hemorrhagic fever
Chen,Rong Fu; Liu,Jien Wei; Yeh,Wen Ting; Wang,Lin; Chang,Jen Chieh; Yu,Hong Ren; Cheng,Jiin Tsuey; Yang,Kuender D.
FEMS Immunology and Medical Microbiology 2005;44:43-50.
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Abstract
Abstract To investigate whether dengue-2 patients with and without dengue hemorrhagic fever had different virus load, immune mediators, or T helper (Th) reaction, we simultaneously measured virus load, immune mediators and the Th1/Th2 transcription factors T-bet/GATA-3 mRNA expression in a large outbreak of dengue-2 infections in Southern Taiwan. Results showed that virus load was not significantly different between patients with and without dengue hemorrhagic fever. Patients with dengue fever had higher IFN-gamma levels, but patients with dengue hemorrhagic fever had significantly higher IL-10 levels. Further studies showed that patients with dengue hemorrhagic fever had a significantly lower T-bet than those with dengue fever, but GATA-3 mRNA expression in peripheral blood leukocytes was not significant difference between both groups. In conclusion, altered Th1 reaction as reflected by lower T-bet mRNA expression associated with higher IL-10 levels might be involved in the pathogenesis of dengue hemorrhagic fever
652
Leukemia-Derived Immature Dendritic Cells Differentiate into Functionally Competent Mature Dendritic Cells That Efficiently Stimulate T Cell Responses
Cignetti,Alessandro; Vallario,Antonella; Roato,Ilaria; Circosta,Paola; Allione,Bernardino; Casorzo,Laura; Ghia,Paolo; Caligaris-Cappio,Federico
The Journal of Immunology 2004;173:2855-2865.
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Abstract
Primary acute myeloid leukemia cells can be induced to differentiate into dendritic cells (DC). In the presence of GM-CSF, TNF-{alpha}, and/or IL-4, leukemia-derived DC are obtained that display features of immature DC (i-DC). The aim of this study was to determine whether i-DC of leukemic origin could be further differentiated into mature DC (m-DC) and to evaluate the possibility that leukemic m-DC could be effective in vivo as a tumor vaccine. Using CD40L as maturating agent, we show that leukemic i-DC can differentiate into cells that fulfill the phenotypic criteria of m-DC and, compared with normal counterparts, are functionally competent in vitro in terms of: 1) production of cytokines that support T cell activation and proliferation and drive Th1 polarization; 2) generation of autologous CD8+ CTLs and CD4+ T cells that are MHC-restricted and leukemia-specific; 3) migration from tissues to lymph nodes; 4) amplification of Ag presentation by monocyte attraction; 5) attraction of naive/resting and activated T cells. Irradiation of leukemic i-DC after CD40L stimulation did not affect their differentiating and functional capacity. Our data indicate that acute myeloid leukemia cells can fully differentiate into functionally competent m-DC and lay the ground for testing their efficacy as a tumor vaccine
378
Human immunodeficiency virus (HIV) phenotype and interleukin-2/ interleukin-10 ratio are associated markers of protection and progression in HIV infection
Clerici,M.; Balotta,C.; Salvaggio,A.; Riva,C.; Trabattoni,D.; Papagno,L.; Berlusconi,A.; Rusconi,S.; Villa,M.L.; Moroni,M.; Galli,M.
Blood 1996;88:574-579.
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Abstract
Human immunodeficiency virus (HIV) isolability, rate of viral replication, HIV phenotype, type 1 and type 2 cytokine production, and CD4 counts were cross sectionally analyzed in 63 HIV seropositive (HIV+) individuals to establish possible correlations between virologic and immunologic markers of protection and progression. We observed that these markers are tightly correlated. Thus, lack or low prevalence of HIV isolability and the presence of nonsyncitium inducing strains are associated with the strongest type 1 cytokine production, the weakest type 2 cytokine production, and highest CD4 counts. Conversely, the isolation of highly replicating, syncitium-inducing HIV strains is associated with the weakest type 1 cytokine production, the strongest type 2 cytokine production, and lowest CD4 counts. Additionally, it was determined that the interleukin (IL)-10/IL-2 ratio best discriminates among different virologic scenarios. These data suggest that the virologic and immunologic correlates of disease protection and progression might be associated variables that define two different subsets of HIV+ individuals and lend support to a viro-immunologic hypothesis of HIV infection
331
Safety and efficacy of recombinant granulocyte colony-stimulating factor as an adjunctive therapy for Streptococcus pneumoniae meningitis in non-neutropenic adult patients: a pilot study
de Lalla,Fausto; Nicolin,Roberto; Lazzarini,Luca
The Journal of Antimicrobial Chemotherapy 2000;46:843-846.
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Abstract
Twenty-two non-neutropenic adult patients with Streptococcus pneumoniae meningitis received granulocyte-colony stimulating factor (G-CSF) (300-450 Ig/day subcutaneously for 6 days) in addition to cefotaxime plus dexamethasone (9-12 g/day for 10 days and 16 mg/day for 3 days iv, respectively). Patients recovered without evident sequelae in all cases but one (with bilateral hearing deficit). No adverse event was recorded. Improvement of inflammation indices in the cerebrospinal fluid was rapid. The most rapid improvement was seen in glucose concentration, which returned to normal ranges within 24-48 h of treatment. In this study G-CSF administration appeared to be safe and effective; further controlled clinical trials are justified
205
Cancer cachexia is associated with the IL10 -1082 gene promoter polymorphism in patients with gastroesophageal malignancy
Deans,DA Chris; Tan,Benjamin HL; Ross,James A.; Rose-Zerilli,Matthew; Wigmore,Stephen J.; Howell,W.Martin; Grimble,Robert F.; Fearon,Kenneth CH
American Journal of Clinical Nutrition 2009;89:1164-1172.
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Abstract
Background: The genetic predisposition of the host to local or systemic inflammation may contribute to the effect of cancer cachexia. Objective: We investigated the relation between cytokine polymorphisms (IL1B -511, IL6 -174, IL10 -1082, TNFA -308, and LTA +252) and markers of nutritional status among patients with gastroesophageal cancer to determine whether any such association was reflected by cytokine concentrations in the tumor or plasma compartments. Design: Patients (n = 203) with a diagnosis of gastroesophageal cancer underwent nutritional assessment (body mass index, anthropometric measures, dysphagia scoring, and estimation of dietary intake). Single nucleotide polymorphism genotyping was performed by TaqMan allelic discrimination genotyping. Serum cytokine and C-reactive protein concentrations were determined by enzyme-linked immunosorbent assay. Tumor tissue cytokine protein concentrations (n = 56) were determined by using the Cytometric Bead Array System. Results: IL10 GG and IL6 CC polymorphisms were associated with elevated serum C-reactive protein concentrations, and the IL6 CC genotype was also associated with elevated tumor tissue cytokine concentrations. At diagnosis, the IL10 GG, but not the IL6, genotype was linked with increased total weight loss: 4.9% for AA, 7.1% for AG, and 12.0% for GG (P = 0.007). Serum C-reactive protein concentrations correlated with increased weight loss (r = 0.24, P < 0.001). Compared with other genotypes, the IL10 GG genotype retained an independent association in determining the extent of weight loss on multivariate analysis (95% CI: 0.52, 3.43; P = 0.008). Possession of the GG allele was associated with a 2.3 times increased risk of developing cachexia (95% CI: 1.2, 4.3; P = 0.014). Conclusion: These data suggest that the IL10 genotype of the host can influence the development of cachexia among patients with gastroesophageal malignancy
2352
A homozygous Fas ligand gene mutation in a patient causes a new type of autoimmune lymphoproliferative syndrome
Del Rey,Manuel; Ruiz-Contreras,Jesus; Bosque,Alberto; Calleja,Sara; Gomez-Rial,Jose; Roldan,Ernesto; Morales,Pablo; Serrano,Antonio; Anel,Alberto; Paz-Artal,Estela; Allende,Luis M.
Blood 2006;108:1306-1312.
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Abstract
Autoimmune lymphoproliferative syndrome (ALPS) is characterized by lymphoproliferation and autoimmune clinical manifestations and is generally caused by defective Fas-mediated apoptosis. This report describes the first homozygous FASL gene mutation in a woman with clinical and immunologic features of ALPS. T-cell blasts from the patient did not induce FasL-mediated apoptosis on Fas-transfected murine L1210 or on Jurkat cells, and activation-induced cell death was impaired. Furthermore, Fas-dependent cytotoxicity was drastically reduced in COS cells transfected with the mutant FasL. In addition, FasL expression on T-cell blasts from the patient was similar to that observed in a healthy control, despite its bearing the high-producer genotype -844C/C in the FASL promoter. Sequencing of the patient's FASL gene revealed a new mutation in exon 4 (A247E). The location of A247E in the FasL extracellular domain and the conservation of the protein sequence of that region recorded in 8 species different from humans support the essential role of FasL COOH terminal domain in Fas/FasL binding. These findings provide evidence that inherited nonlethal FASL abnormalities cause an uncommon apoptosis defect producing lymphoproliferative disease, and they highlight the need for a review of the current ALPS classification to include a new ALPS type Ic subgroup
707
Autoimmune lymphoproliferative syndrome (ALPS) in a patient with a new germline Fas gene mutation
Del-Rey,M.J.; Manzanares,J.; Bosque,A.; Aguilo,J.I.; Gomez-Rial,J.; Roldan,E.; Serrano,A.; Anel,A.; Paz-Artal,E.; Allende,L.M.
Immunobiology 2007;212:73-83.
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Abstract
Autoimmune lymphoproliferative syndrome (ALPS) is a rare genetic disorder characterized by chronic lymphoproliferation, autoimmune manifestations and expansion of TCRaß+CD4-CD8- lymphocytes. The main pathogenic factor is a defective Fas-mediated apoptosis generally caused by mutations in the Fas gene. This report describes a new heterozygous Fas gene mutation in a boy with clinical and immunological features of ALPS. In vitro, T-cell blasts from the patient are completely resistant to the effects on the anti-Fas cytotoxic mAb CH-11, they also have a higher proliferation rate than T cells from healthy donors, while PHA-induced AICD is normal. The location of the mutation (I246S) found in the intracytoplasmic death domain, and the conservation of that residue in four different species from human suggest that I246 is an essential amino acid for Fas function. The patient has inherited the mutation from his father who also shows defective Fas-mediated apoptosis but the clinical and immunological manifestations are much less severe. These results provide evidence that the penetrance of genetic defects in Fas is variable and that other factors may influence the phenotype of the disease.
937
Mechanism of Complement Activation and Its Role in the Inflammatory Response After Thoracoabdominal Aortic Aneurysm Repair
Fiane,Arnt E.; Videm,Vibeke; Lingaas,Per S.; Heggelund,Lars; Nielsen,Erik W.; Geiran,Odd R.; Fung,Michael; Mollnes,Tom E.
Circulation 2003;108:849-856.
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Abstract
Background-- Complement activation contributes to ischemia-reperfusion injury. Patients undergoing thoracoabdominal aortic aneurysm (TAAA) repair suffer extensive ischemia-reperfusion and considerable systemic inflammation. Methods and Results-- The degree and mechanism of complement activation and its role in inflammation were investigated in 19 patients undergoing TAAA repair. Patients undergoing open infrarenal aortic surgery (n=5) or endovascular descending aortic aneurysm repair (n=6) served as control subjects. Substantial complement activation was seen in TAAA patients but not in controls. C1rs-C1-inhibitor complexes increased moderately, whereas C4bc, C3bBbP, C3bc, and the terminal SC5b-9 complex (TCC) increased markedly after reperfusion, reaching a maximum 8 hours after reperfusion. Interleukin (IL)-1{beta}, tumor necrosis factor {alpha} (TNF-{alpha}), and IL-8 increased significantly in TAAA patients but not in controls, peaking at 24 hours postoperatively and correlating closely with the degree of complement activation. IL-6 and IL-10 increased to a maximum 8 hours after reperfusion in the TAAA patients, were not correlated with complement activation, and increased moderately in the control subjects. Myeloperoxidase and lactoferrin increased markedly before reperfusion in all groups, whereas sICAM-1, sP-selectin, and sE-selectin were unchanged. No increase was observed in complement activation products, IL-1{beta}, TNF-{alpha}, or IL-8 in a mannose-binding lectin (MBL)-deficient TAAA patient, whereas IL-6, IL-10, myeloperoxidase, and lactoferrin increased as in the controls. Two other MBL-deficient TAAA patients receiving plasma attained significant MBL levels and showed complement and cytokine patterns identical to the MBL-sufficient TAAA patients. Conclusions-- The data suggest that complement activation during TAAA repair is MBL mediated, amplified through the alternative pathway, and responsible in part for the inflammatory response
32
Simultaneous detection of multiple cytokines and chemokines from nonhuman primates using luminex technology
Giavedoni,L.D.
Journal of Immunological Methods 2005;301:89-101.
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Abstract
Cytokines and chemokines are soluble mediators of the immune system that play a crucial role in intercellular signaling, and in the recruitment of cells to inflammation sites. Identification of these molecules in nonhuman primates (NHP) is crucial for the understanding of complex physiological and pathological mechanisms that occur in these species, and to demonstrate whether these mechanisms function similarly in humans. The Luminex100 system is a bench-top flow cytometer that allows the user to perform up to 100 tests simultaneously in a single tube. Recently, a significant number of commercial vendors have developed kits for the simultaneous detection of multiple cytokines and chemokines of human origin with the Luminex system. These kits were tested for their capacity to recognize chemokines and cytokines of nonhuman primate origin. ELISA and ELISPOT assays were also adapted to the Luminex format, and novel assays based on new combinations of antibodies were developed. PBMC were isolated from blood from chimpanzees, rhesus macaques, baboons, cynomolgus macaques, pig-tailed macaques, and African green monkeys; these cells were stimulated in vitro and culture supernatants were used for the determination of cytokines and chemokines. Crossreactivity tables were prepared based on the ability of the reagents to detect cytokines and chemokines in NHP samples with similar intensity to the ones observed in human samples. By mixing commercially available reagents and newly developed ones, a combination has been created that allows for the detection of 20 NHP chemokines and cytokines in a single sample, including G-CSF, GM-CSF, IFN-?, IL-1ß, IL-1Ra, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12 (p40), IL-17, IL-18, MCP-1, MIP-1a, MIP-1ß, RANTES, TNF-a, and TNF-ß. These reagents may become a very useful resource for scientists working with these NHP species, which are relevant pre-clinical models for human diseases and transplantation because they approximate humans in physiology and genetics more closely than any other animal.
952
Regulatory T Cells Recruited through CCL22/CCR4 Are Selectively Activated in Lymphoid Infiltrates Surrounding Primary Breast Tumors and Lead to an Adverse Clinical Outcome
Gobert,Michael; Treilleux,Isabelle; Bendriss-Vermare,Nathalie; Bachelot,Thomas; Goddard-Leon,Sophie; Arfi,Vanessa; Biota,Cathy; Doffin,Anne Claire; Durand,Isabelle; Olive,Daniel; Perez,Solene; Pasqual,Nicolas; Faure,Christelle; Ray-Coquard,Isabelle; Puisieux,Alain; Caux,Christophe; Blay,Jean Yves; Menetrier-Caux,Christine
Cancer Research 2009;69:2000-2009.
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Abstract
Immunohistochemical analysis of FOXP3 in primary breast tumors showed that a high number of tumor-infiltrating regulatory T cells (Ti-Treg) within lymphoid infiltrates surrounding the tumor was predictive of relapse and death, in contrast to those present within the tumor bed. Ex vivo analysis showed that these tumor-infiltrating FOXP3+ T cells are typical Treg based on their CD4+CD25highCD127lowFOXP3+ phenotype, their anergic state on in vitro stimulation, and their suppressive functions. These Ti-Treg could be selectively recruited through CCR4 as illustrated by (a) selective blood Treg CCR4 expression and migration to CCR4 ligands, (b) CCR4 down-regulation on Ti-Treg, and (c) correlation between Ti-Treg in lymphoid infiltrates and intratumoral CCL22 expression. Importantly, in contrast to other T cells, Ti-Treg are selectively activated locally and proliferate in situ, showing T-cell receptor engagement and suggesting specific recognition of tumor-associated antigens (TAA). Immunohistochemical stainings for ICOS, Ki67, and DC-LAMP show that Ti-Treg were close to mature DC-LAMP+ dendritic cells (DC) in lymphoid infiltrates but not in tumor bed and were activated and proliferating. Furthermore, proximity between Ti-Treg, CD3+, and CD8+ T cells was documented within lymphoid infiltrates. Altogether, these results show that Treg are selectively recruited within lymphoid infiltrates and activated by mature DC likely through TAA presentation, resulting in the prevention of effector T-cell activation, immune escape, and ultimately tumor progression. This study sheds new light on Treg physiology and validates CCR4/CCL22 and ICOS as therapeutic targets in breast tumors, which represent a major health problem. [Cancer Res 2009;69(5):2000-9]
2372
Alterations in the number of circulating leucocytes, phenotype of monocyte and cytokine production in patients undergoing cardiothoracic surgery
HIESMAYR,M.J.; SPITTLER,A.; LASSNIGG,A.; BERGER,R.; LAUFER,G.; KOCHER,A.; ARTEMIOU,O.; BOLTZ-NITULESCU,G.; ROTH,E.
Clinical and Experimental Immunology 1999;115:315-323.
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Abstract
Changes in the differential blood cell count, monocyte phenotype and the cytokine plasma levels in a group of seven patients with cardiac surgery/cardiopulmonary bypass (CPB) and nine patients with thoracic surgery/without CPB, both receiving identical opioid-based anaesthetic technique, were assessed. A significant reduction in the number of circulating lymphocytes and monocytes was observed after anaesthesia and surgery. Interestingly, at the end of surgery as well as 1 day post-surgery a marked increase in the number of granulocytes was noted. General anaesthesia and surgery caused a significant reduction of HLA-DR and CD11c/CD18 molecules, starting immediately after induction of anaesthesia, and an increase of CD64 at day 1 after anaesthesia. The use of a CPB was followed by a significant reduction of CD32, CD16, CD54 and HLA-ABC antigens expression at the end of surgery. One day after surgery these parameters returned nearly to baseline values with the exception of CD54. A monocyte subpopulation, characterized by low CD14, high CD16 and HLA-DR expression (CD14+CD16+HLA-DR++) was found in both groups at each time point, and the percentage of this cell subset decreased from baseline to 24 h. The plasma concentrations of IL-6 and IL-10 increased considerably during CPB. No dynamic changes of IL-1 level due to surgery or CPB were found. We conclude that anaesthesia as well as the use of CPB induced profound alterations in the number of circulating leucocytes, and in the phenotype of monocyte and cytokine production
1506
Interleukin-10 is localized to and released by human lung mast cells
Ishizuka; Okayama; Kobayashi; Mori
Clinical & Experimental Allergy 1999;29:1424-1432.
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Abstract
Background Mast cells control the local inflammation by producing many kinds of cytokines. Interleukin (IL)-10 is one of the important cytokine that upregulate or downregulate inflammation. Objective The aim of this study is to ascertain whether IL-10 is produced from human lung mast cells by cross-linkage of high-affinity Fcepsilon receptors (FcepsilonRI). Methods Mast cells were purified using affinity magnetic selection with mAb YB5.B8 (> 93% pure). Mast cells were precultured with human myeloma IgE (3 mug/mL) for 16 h and then washed, and stimulated with anti-IgE in the presence or absence of recombinant human stem cell factor (rhSCF). We have studied the production of IL-10 by using reverse transcription-PCR, enzyme-linked immunosorbent assay and immunocytochemistry. Results We found that human lung mast cells were immunocytochemically stained with anti-IL-10 mAb after IgE-dependent stimulation. The activation of mast cells via FcepsilonRI enhanced the intensity of the IL-10 mRNA signal. Anti-IgE (1 mug/mL) induced a median IL-10 release of 301.7 (7.8-1532.4) pg/106 mast cells/24 h. In contrast, mast cells released only a small amount of IL-10 in the absence of anti-IgE. This difference was statistically significant (P = 0.02, n = 11). Conclusion Our findings indicate that human lung mast cells are capable of producing IL-10 in response to IgE-dependent stimulation
666
IL-12-Impaired and IL-12-Secreting Dendritic Cells Produce IL-23 upon CD154 Restimulation
Jasny,Edith; Eisenblatter,Martin; Matz-Rensing,Kerstin; Tenner-Racz,Klara; Tenbusch,Matthias; Schrod,Annette; Stahl-Hennig,Christiane; Moos,Verena; Schneider,Thomas; Racz,Paul; Uberla,Klaus; Kaup,Franz Josef; Ignatius,Ralf
The Journal of Immunology 2008;180:6629-6639.
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Abstract
Experimental studies in monkeys on the basis of ex vivo-generated, reinjected dendritic cells (DCs) allow investigations of primate DC biology in vivo. To study in vitro and in vivo properties of DCs with a reduced capacity to produce IL-12, we adapted findings obtained in vitro with human cells to the rhesus macaque model. Following exposure of immature monocyte-derived monkey DCs to the immunomodulating synthetic polypeptide glatiramer acetate (GA) and to dibutyryl-cAMP (d-cAMP; i.e., a cAMP enhancer that activates DCs but inhibits the induction of Th1 immune responses), the resulting DCs displayed a mature phenotype with enhanced Ag-specific T cell stimulatory function, notably also for memory Th1 cells. Phosphorylation of p38 MAPK was not induced in GA/d-cAMP-activated DCs. Accordingly, these cells secreted significantly less IL-12p40 (p [≤] 0.001) than did cytokine-activated cells. However, upon restimulation with rhesus macaque CD154, GA/d-cAMP-activated DCs produced IL-12p40/IL-23. Additionally, DCs activated by proinflammatory cytokines following protocols for the generation of cells used in clinical studies secreted significantly more IL-23 upon CD154 restimulation than following prior activation. Two days after intradermal injection, GA/d-cAMP-activated fluorescence-labeled DCs were detected in the T cell areas of draining lymph nodes. When similarly injected, GA/d-cAMP as well as cytokine-activated protein-loaded DCs induced comparable Th immune responses characterized by secretion of IFN-{gamma}, TNF, and IL-17, and transiently expanded FOXP3+ regulatory T cells. Reactivation of primate DCs through CD154 considerably influences their immmunostimulatory properties. This may have a substantial impact on the development of innovative vaccine approaches
2330
Phosphodiesterase 4 Inhibitors Prevent Cytokine Secretion by T Lymphocytes by Inhibiting Nuclear Factor-kappa B and Nuclear Factor of Activated T Cells Activation
Jimenez,Jose Luis; Punzon,Carmen; Navarro,Joaquin; Munoz-Fernandez,M.Angeles; Fresno,Manuel
Journal of Pharmacology and Experimental Therapeutics 2001;299:753-759.
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Abstract
Blockade of phosphodiesterase 4 with rolipram reduced the production of tumor necrosis factor (TNF)-[alpha], interleukin (IL)-5, IL-10, and IL-2 but poorly inhibited cell proliferation and interferon-[gamma] (IFN-[gamma]) production by activated human T cells. Addition of dibutyryl cAMP mimicked rolipram inhibitions on proliferation, IL-2, TNF-[alpha], and IFN-[gamma] but not on IL-10 or IL-5 production. Moreover, the inhibitory effects of rolipram on proliferation, IFN-[gamma], and TNF-[alpha] but not of IL-10 production can be prevented by a specific protein kinase A inhibitor. Rolipram and pentoxifylline, a nonspecific phosphodiesterase inhibitor, decreased transcription of IL-2 and TNF-[alpha] promoters in transiently transfected normal T cells. Moreover, they inhibited the activation of nuclear factor-[kappa]B (NF-[kappa]B) and nuclear factor of activated T cells (NFAT) and stimulated activator protein-1 (AP-1) and cAMP response element-binding proteins (CREBs). In contrast, dibutyryl cAMP inhibited NF-[kappa]B but not NFAT activation. Thus, our data indicate that blockade of phosphodiesterase 4 regulates transcription of a particular cytokine through inhibition of NF-[kappa]B and NFAT, and stimulation of AP-1 and CREB
158
Extracellular Branched-Chain Amino Acids, Especially Valine, Regulate Maturation and Function of Monocyte-Derived Dendritic Cells
Kakazu,Eiji; Kanno,Noriatsu; Ueno,Yoshiyuki; Shimosegawa,Tooru
The Journal of Immunology 2007;179:7137-7146.
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Abstract
The functions of dendritic cells (DCs) are impaired in patients with liver cirrhosis. It is well-known that cirrhotic patients show decreased levels of plasma branched-chain amino acids (BCAA). Although amino acids are associated with maintaining the cell structure and function in many organs, limited data are available regarding the role of amino acids including BCAA in the immune system. We aimed to investigate the roles of BCAA in the function of human monocyte-derived DCs (MoDC). CD14-positive monocytes (CD14 +) were isolated from PBMC from healthy volunteers and hepatitis C virus (HCV) cirrhotic patients. In medium deprived of BCAA or valine, monocytes were able to differentiate into immature, but not into mature, DCs and showed weak expression of CD83. The deprivation of leucine or isoleucine did not affect this process. The MoDC allostimulatory capacity was significantly decreased in medium deprived of BCAA or valine (p = 0.017, p = 0.012, Bonferroni's analysis, respectively). Annexin VFITC/propidium iodide staining showed that the DC yield and viability were not significantly different under any medium. Immunoblotting demonstrated that depletion of valine or leucine decreased phospho-S6 kinase expression. Valine increased dose-dependently the allostimulatory capacity and IL-12 production of MoDC from both healthy volunteers and HCV cirrhotic patients. An elevated extracellular concentration of valine could improve the DC function in cirrhotic patients. These data provide a rationale for nutrition therapy that could be beneficial to patients with cirrhosis
2467
Role of amiodarone on the systemic inflammatory response induced by cardiac surgery: proinflammatory actions: [Role de l'amiodarone sur la reaction inflammatoire systemique provoquee par la chirurgie cardiaque : actions pro-inflammatoires]
Karth,Georg Delle; Buberl,Anton; Nikfardjam,Mariam; Meyer,Brigitte; Wollenek,Gregor; Grimm,Michael; Lassnigg,Andrea; Brannath,Werner; Hiesmayr,Michael; Heinz,Gottfried
Canadian Journal of Anesthesia 2007;54:262-268.
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Abstract
Purpose: Amiodarone (AMIO), a widely used anti-arrhythmic drug, has been shown to reduce the incidence of atrial fibrillation after cardiac surgery and also to exert immunomodulatory actions in vitro and proinflammatory effects in vivo. The present study investigated the immunomodulatory properties of AMIO in the inflammatory response induced by cardiac surgery with cardiopulmonary bypass (CPB). Methods: In this double-blind, placebo-controlled trial, 20 patients undergoing elective coronary artery bypass graft were randomized to receive placebo or AMIO 600 mg{middle dot}day-1 orally for seven days before surgery and 45 mg{middle dot}hr-1 intravenously for 48 hr postoperatively. Plasma levels of the proinflammatory markers C-reactive protein (CRP), fibrinogen (FBG), tumour necrosis factor (TNF)-{alpha}, interleukin (IL)-6 and monocyte chemoattractant protein (MCP)-1, and the antiinflammatory marker IL-10, were compared before and after surgery. Results: Ninety-six hours after start of surgery, plasma levels of FBG had more than doubled (2.2 {+/-} 0.5-fold increase, P < 0.0001). Overall, FBG formation was significantly increased in the AMIO group (P = 0.048). Monocyte chemoattractant protein 1 secretion transiently increased four hours after start of surgery (6.6 {+/-} 4.5-fold increase) but rapidly declined thereafter, (P < 0.0001). There was a trend toward higher MCP-1 plasma concentrations in the AMIO group (P = 0.13). The plasma levels of CRP, TNF-{alpha}, IL-6 and Il-10 changed significantly over time, but were not altered by AMIO treatment. Conclusion: In the inflammatory response induced by cardiac surgery with CPB, our data suggest that AMIO treatment is associated with a selective trend toward proinflammatory actions
822
Aqueous and Serum Interferon {gamma}, Interleukin (IL) 2, IL-4, and IL-10 in Patients With Uveitis
Lacomba,Manuel Santos; Martin,Carmen Marcos; Chamond,Rafael Ramirez; Galera,Jose Maria Gallardo; Omar,Mohamed; Estevez,Eduardo Collantes
Archives of Ophthalmology 2000;118:768-772.
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Abstract
Objective To determine the cytokine profile in aqueous humor and peripheral blood from patients with uveitis. Methods Cytokines (interferon [IFN]-{gamma}, interleukin [IL] 2, IL-4, and IL-10) were measured in aqueous humor and peripheral blood samples from 23 patients with uveitis and 16 patients undergoing operation for uncomplicated cataracts (control group) by means of an enzyme-linked immunosorbent assay. Results Aqueous and serum samples from patients with uveitis showed higher levels of IFN-{gamma} and IL-2 than those of controls (P<.001). Similarly, serum IL-10 levels were slightly higher in the uveitis group (P=.002). No differences were found between uveitis and control groups for aqueous and serum IL-4 or aqueous IL-10 levels. In patients with uveitis, IFN-{gamma} levels were significantly higher in serum than aqueous (P<.001), whereas IL-2 levels were higher in aqueous than in serum (P<.001). Serum IFN-{gamma} levels correlated with severe visual damage (r=0.44; P=.03). Conclusions Aqueous and serum levels of IFN-{gamma} and IL-2 were elevated in patients with uveitis, suggesting a predominantly type 1 response (high IFN-{gamma} and low IL-4 levels). Elevated serum IFN-{gamma} level seems to predispose the patient to more serious loss of vision
225
Characterization of type 1 and type 2 cytokine production profile in physiologic and pathologic human pregnancy
MARZI,M.; VIGANO,A.; Trabattoni,D.; Villa,M.L.; Salvaggio,A.; CLERICI,E.; Clerici,M.
Clinical and Experimental Immunology 1996;106:127-133.
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Abstract
Antigen- and mitogen-stimulated cytokine production by peripheral blood mononuclear cells (PBMC) of 50 pregnant women and 31 age- and sex-matched non-pregnant controls were analysed to determine whether changes in cytokine production occur during normal and pathologic human gestation. The pregnant women, consecutively enrolled during a 3-month period, were undergoing a normal, non-pathologic pregnancy at the time of entry into the study, and underwent ultrasound examination to ascertain the exact week of pregnancy and the vitality of the fetus. Forty of the 50 pregnancies (80%) terminated physiologically with the birth of normal babies. Spontaneous abortions were observed in 5/50 (10%) women, and five women gave birth to newborns small for gestational age (SGA). A decrease in the production of IL-2 and interferon-gamma (IFN-gamma) accompanied by an increase in production of IL-4 and IL-10, was observed in normal pregnancy, with the lowest quantities of IL-2 and IFN-gamma and the highest quantities of IL-4 and IL-10 present in the third trimester of pregnancy. Statistically significant increased production of both IL-2 and IFN-gamma and reduced production of IL-10 characterized pathologic pregnancies and distinguished them from normal pregnancies. These preliminary data suggest that a type 2 cytokine profile may be associated with normal human pregnancy, whereas the lack of a dominant type 2 cytokine profile may be indicative of a pathologic pregnancy
639
Cutting Edge: Abortive Proliferation of CD46-Induced Tr1-Like Cells due to a Defective Akt/Survivin Signaling Pathway
Meiffren,Gregory; Flacher,Monique; Azocar,Olga; Rabourdin-Combe,Chantal; Faure,Mathias
The Journal of Immunology 2006;177:4957-4961.
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Abstract
T regulatory cell 1 (Tr1) are low proliferating peripherally induced suppressive T cells. Engaging CD3 and CD46 on human CD4+ T cells induces a Tr1-like phenotype. In this study, we report that human Tr1-like cells do not sustain proliferation over time. The weak proliferation of these cells results first from their inability to sustain expression of various cell cycle-associated proteins, to efficiently degrade the inhibitor of cell cycle progression p27/Kip1 and, as a consequence, in their accumulation in the G0-G1 phase. Also, the reduced proliferation of Tr1-like cells results from their increased sensitivity to death as they divide, through a mechanism that is neither Fas-mediated nor Bcl2/Bcl-xL related. Both properties, impaired cell cycle and death sensitivity, are explained by a specific defective activation of Akt that impairs the expression of Survivin. Thus, our results show that CD3/CD46-induced Tr1-like cells die through a process of abortive proliferation
739
Chemotherapy induces inflammatory response in breast cancer patients
Michlmayr A.,S.Baumann,M.Zellner,C.Burghuber,P.Schuch,C.Wenzel,R.Bartsch,U.Pluschnig,I.Rech-Weichselbraun,G.Steger,R.Jakesz,M.Gnant and T.Bachleitner-Hofmann,M.Bergmann,R.Oehler
Keystonesymposia, Inflammation, Microenvironment and Cancer 2008;Abstract
Chemotherapeutic treatment of breast cancer patients supposedly mediates its effect via direct elimination of tumor cells. However, there is growing evidence that activation of immune cells in the tumor micro environment is essential for tumor regression. We investigated whether chemotherapy is associated with an inflammatory response which is detectable also in the peripheral blood. Blood was taken from 24 breast cancer patients before and 4 days after receiving the first course of neoadjuvant chemotherapy (epirubicin/docetaxel). This combination therapy leads to substantial tumor regression in about 50% of patients. To assess the inflammatory response we performed an analysis of 17 different inflammatory mediators using a beads based multiplex immunoassay. Systemic IL-6 and IL-10 levels increased in response to chemotherapy while sPECAM and sICAM-3 levels decreased. These results were verified by ELISA (p<0.01). To get a broader view of the effect of chemotherapy a proteomic analysis was performed using 2D-DIGE. Thirty-one out of 642 protein spots showed a more than 1.4 fold (p < 0.05) change within 4 days of chemotherapy including complement factors C1, C3 and C4, alpha2HSglycoprotein, and alpha1-anti chymotrypsin. These proteins are induced in the course of acute phase response during inflammation. These data show that chemotherapy induces inflammation in breast cancer patients. However, it cannot be concluded whether this occurs due to a direct effect of treatment on cancer cells or to a side effect on other tissues. The degree of protein induction varied between patients. Future studies are planned to clarify whether such variations are associated with the clinical response rate to therapy.
1288
Microbial Immune Suppression Mediated by Direct Engagement of Inhibitory Fc Receptor
Monari,Claudia; Kozel,Thomas R.; Paganelli,Francesca; Pericolini,Eva; Perito,Stefano; Bistoni,Francesco; Casadevall,Arturo; Vecchiarelli,Anna
The Journal of Immunology 2006;177:6842-6851.
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Abstract
A microbial polysaccharide (glucuronoxylomannan (GXM)) exerts potent immunosuppression by direct engagement to immunoinhibitory receptor Fc{gamma}RIIB. Activation of Fc{gamma}RIIB by GXM leads to the recruitment and phosphorylation of SHIP that prevents I{kappa}B{alpha} activation. The Fc{gamma}RIIB blockade inhibits GXM-induced IL-10 production and induces TNF-{alpha} secretion. GXM quenches LPS-induced TNF-{alpha} release via Fc{gamma}RIIB. The addition of mAb to GXM reverses GXM-induced immunosuppression by shifting recognition from Fc{gamma}RIIB to Fc{gamma}RIIA. These findings indicate a novel mechanism by which microbial products can impair immune function through direct stimulation of an inhibitory receptor. Furthermore, our observations provide a new mechanism for the ability of specific Ab to reverse the immune inhibitory effects of certain microbial products
742
Lipid metabolism and TNF-alpha secretion in response to dietary sterols in human monocyte derived macrophages
Napolitano,M.; Bravo,E.
European Journal of Clinical Investigation 2005;35:482-490.
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Abstract
Abstract Background The postprandial phase is characterized by the circulation of atherogenic dietary-triacylglycerol rich lipoproteins. Little is known about the modulation of lipid and immune functions in macrophages by these particles or of the role of the oxysterols found in food such as 7beta-hydroxycholesterol and 7-ketocholesterol. Materials and methods Human macrophages were tested with different concentrations of chylomicron remnant-like particles (CRLP) with or without incorporated oxysterols to study their uptake by the cells, and their effects on cholesteryl ester and triacylglycerol synthesis and the secretion of inflammatory mediators, including tumour necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6) and interleukin 10 (IL-10). Results Independently of the presence of oxysterols, CRLP caused cholesterol accumulation. However, the dose-dependent increase in [3H]cholesterol internalization by macrophages after incubation with [3H]cholesteryl ester-labelled CRLP was abolished by the presence of oxysterols in the particles. TNF-alpha secretion was decreased and that of IL-10 unaffected by CRLP independently of the presence of oxysterol. Exposure to CRLP containing 7beta-hydroxysterol, but not to CRLP or 7-ketosterol-containing CRLP, reduced IL-6 secretion with respect to cells not exposed to any particles. Because TNF-alpha levels have been related to scavenger receptor expression, we tested the uptake of modified LDL in macrophages exposed to human postprandial triacylglycerol-rich lipoproteins and found it to be markedly increased. Conclusions Cholesterol loading as a result of dietary lipids depresses the inflammatory response of macrophages and the presence of 7beta-hydroxysterol may exacerbate this effect. In addition, exposure to dietary lipids enhances scavenger receptor activity in macrophages. These results suggest that changes induced by dietary lipids in human macrophage function are related to an increased propensity of the cells to accumulate lipids during the postprandial phase. Eur J Clin Invest 2005; 35 (8): 482 -490
626
Inhibition of Phosphodiesterase Type IV Suppresses Human Immunodeficiency Virus Type 1áReplication and Cytokine Production in Primary T Cells: Involvement of NF-kappa B and NFAT
Navarro,Joaquin; Punzon,Carmen; Jimenez,Jose Luis; Fernandez-Cruz,Eduardo; Pizarro,Angel; Fresno,Manuel; Munoz-Fernandez,M.Angeles
Journal of Virology 1998;72:4712-4720.
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Abstract
Rolipram, a phosphosdiesterase type IV-specific inhibitor, prevented p24 antigen release from anti-CD3-activated human immunodeficiency virus (HIV)-infected T cells and CD4+-cell depletion associated with viral replication in a dose-responsive manner but minimally inhibited T-cell proliferation. Moreover, rolipram reduced the production of tumor necrosis factor alpha (TNF-[alpha]) and interleukin-10 (IL-10) by HIV-infected T cells. The transcriptional ability of a luciferase reporter gene under control of the HIV long terminal repeat, induced by phorbol myristic acetate plus ionomycin or by TNF-[alpha], in primary T and Jurkat cells was also inhibited by rolipram. Rolipram inhibited NF-[kappa]B and NFAT activation induced by T-cell activation in Jurkat and primary T cells, as measured by transient transfection of reporter genes and electrophoretic mobility shift assays. Exogenous addition of TNF-[alpha] in the presence of rolipram restored NF-[kappa]B but not NFAT activation or p24 release. Addition of dibutyryl-cyclic AMP (dBcAMP) mimicked the effects of rolipram on p24 antigen release, NF-[kappa]B activation, and TNF-[alpha] secretion, but it did not affect NFAT activation or IL-10 production. The protein kinase A inhibitor KT5720 prevented the inhibition of TNF-[alpha] secretion but not that of HIV type 1 (HIV-1) replication caused by rolipram. Our data indicate that blockade of phosphodiesterase type IV could be of benefit against HIV-1 disease by modulating cytokine secretion and transcriptional regulation of HIV replication, and they suggest an important role of NFAT in HIV replication in primary T cells. Some of those activities cannot be ascribed solely to its ability to increase cAMP
298
Clinical Relevance of Cytokine Production in HIV-1 Infection in Children on Antiretroviral Therapy
Resino,S.; Bellon,J.Ma; Sanchez-Ramon,S.; Gurbindo,D.; Munoz-Fernandez,Ma A.
Scandinavian Journal of Immunology 2000;52:634-640.
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Abstract
In order to investigate the correlation among cytokine production and antiretroviral therapy (ART), viral load, CD4+ and CD8+ T lymphocytes, 55 human immunodeficiency virus (HIV)-1-infected children on ART or not, and 16 uninfected controls were studied. Peripheral blood mononuclear cells (PBMCs) of HIV-1-infected children and controls were cultured and spontaneous and mitogen-stimulated cytokines production was quantified in the supernatants. Viral load was quantified using standard molecular assay. CD4 and CD8 T-lymphocyte counts were determined by flow cytometry. Cytokine production by mitogen-stimulated PBMCs showed different profiles in HIV-1 children whether treated or not. The tumour necrosis factor (TNF)-alpha production was higher and the interleukin (IL)-10 production was lower in the HIV-1-untreated group than in the HIV-1-treated children and controls. The IL-2 production was reduced and the RANTES production was higher in both HIV-1 groups compared with the controls. The interferon (IFN)-gamma and the IL-5 production was significantly reduced in the HIV-1-treated children compared to the controls. Interestingly, the analysis of the correlation of HIV-1 phenotype with cytokine production indicated an increased RANTES production in relation to nonsyncytium-inducing viral phenotype with slow/low replication profile, whereas decreased IL-10 levels was associated to syncytium-inducing (SI) strains and rapid/high replication. Our findings suggest that AVT changes on the cytokine and chemokine production play an important role in the HIV pathogenesis
400
Features of the CD4^+ T-cell response in liver and peripheral blood of hepatitis C virus-infected patients with..
Rico,M.A.; Quiroga,J.A.; Subira,D.; Garcia,E.; Castanon,S.; Sallberg,M.; Leroux-Roels,G.; Weiland,O.; Pardo,M.; Carreno,V.
Journal of Hepatology 2002;36:408-416.
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Abstract
Background/Aims: The liver is the primary site of hepatitis C virus (HCV) replication; intrahepatic T-cell responses may influence liver disease severity. Methods: HCV-specific CD4+ T-cell reactivity was investigated ex vivo in paired liver tissue and peripheral blood from 42 chronic HCV patients. Results: The frequencies with which HCV-specific HLA class-II-restricted CD4+ T-cell proliferation were observed were 29% in liver and 36% in peripheral blood. Among responses, non-structural-3 protein (NS3)-specific T-cell proliferation was dominant but non-exclusive and did rarely occur concurrently in liver infiltrate and peripheral blood suggesting liver compartmentalization of a CD4+ T-cells population. Compared with 24 patients with abnormal ALT levels, 18 HCV carriers with persistently normal ALT levels had similar serum and liver viral loads but showed: (i) a low-activity grade and stage chronic hepatitis (P<0.001); (ii) less intrahepatic CD4+ T-lymphocytes (P<0.01); (iii) less frequent intrahepatic (17 vs. 33%) and peripheral (17 vs. 38%) NS3-specific CD4+ T-cell proliferation; (iv) less often in vitro T-helper (Th)1 (interferon-?) cytokine production (2 vs. 18%; P<0.001). Conclusions: Our data show a low frequency of intrahepatic HCV-specific HLA class-II-restricted CD4+ Th1 responses in patients with chronic HCV. However, these Th1 responses are detected more often in those patients with overt clinical and histological disease.
1062
In contrast to their murine counterparts, normal human keratinocytes and human epidermoid cell lines A431 and HaCaT fail to express IL-10 mRNA and protein
TEUNISSEN,M.B.M.; KOOMEN,C.W.; JANSEN,J.; WAAL MALEFYT,R.; SCHMITT,E.; VAN DEN WIJNGAARD,R.M.J.G.; DAS,P.K.; BOS,J.D.
Clinical and Experimental Immunology 1997;107:213-223.
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Abstract
In mice, keratinocyte-derived IL-10 is up-regulated by ultraviolet-B (UVB) radiation and plays a major role in UVB-induced immunosuppression. The present study was designed to examine whether a comparable phenomenon can be detected in man. Freshly isolated or cultured normal human keratinocytes (NHK) and keratinocyte cell lines A431 and HaCaT were stimulated with graded doses of UVB (up to 200 J/m2) or with a variety of other stimuli. RNA was extracted at various time points post-stimulation and analysed by reverse transcriptase-polymerase chain reaction (RT-PCR) using four different IL-10-specific primer pairs and RNA from monocytes or T cells as positive controls. We failed to detect IL-10 mRNA in NHK from 40 different donors (breast, abdomen, leg, scalp, foreskin) and in A431 and HaCaT cells, irrespective of the stimulation used and despite successful stimulation. Supernatants of NHK, A431 and HaCaT cultures were negative for IL-10 protein, as tested by four different ELISAs and a bioassay. Murine keratinocytes, stimulated under comparable conditions and tested by the same techniques, displayed a strong expression of IL-10 mRNA and protein. Remarkably, an IL-10 mRNA signal could be detected in NHK after a second round of PCR amplification. Because NHK suspensions are contaminated with Langerhans cells, melanocytes and possibly fibroblasts, we tested pure populations of each individual cell type to determine the origin of this IL-10 mRNA. Our results clearly indicate that NHK, Langerhans cells and fibroblasts fail to express IL-10 and that melanocytes are the principal source of IL-10 mRNA in normal human epidermis
1570
Low CD4 counts rather than superantigenic-like effects account for differences in expressed T-cell receptor (TCR) repertoires between HIV-1 seropositive long-term non-progressors and individuals with progressive disease
Westby,Michael; Vaughan,Andrew N.; Balotta,Claudia; Galli,Massimo; Clerici ,Mario; Dalgleish,Angus G.
British Journal of Haematology 1998;102:1187-1196.
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Abstract
Analysis of HIV-infected individuals who have stable CD4 counts many years after seroconversion may provide an insight as to how the host's immune system can successfully control HIV infection. In this study we analysed the T-cell receptor (TCR) Vbeta repertoire in 13 HIV+ individuals, seven of whom were classed as long-term non-progressors (LTNP), using a technique which couples anchor PCR (AnPCR) amplification of beta-chain cDNA to differential probe hybridization with non-radioactively labelled Vbeta family specific oligonucleotide probes. There were no significant differences in the expressed TCR repertoires between the LTNP group and the other HIV-infected individuals. However, there was a statistically significant inverse correlation between CD4 count and the number of Vbeta family-specific perturbations in the recent seroconverters (SC) and those with progressive infection (PI), consistent with other shared features of clinical disease progression (Th1/Th2 switch and high frequency of viral isolation). We conclude that long-term clinical non-progression in HIV-1 infection is not associated with the loss or expansion of a particular Vbeta family; instead, low CD4 count in the PI and SC individuals was correlated with increased number of Vbeta family-specific perturbations relative to the LTNP group and that it is hence unlikely that HIV encodes a superantigen
677
Role of osteopontin in amplification and perpetuation of rheumatoid synovitis
Xu,Guangwu; Nie,Hong; Li,Ningli; Zheng,Wenxin; Zhang,Dongqing; Feng,Guozhang; Ni,Liqing; Xu,Rong; Hong,Jian; Zhang,Jingwu Z.
Journal of Clinical Investigation 2005;115:1060-1067.
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Abstract
Osteopontin (OPN) is an extracellular matrix protein of pleiotropic properties and has been recently recognized as a potential inflammatory cytokine. In this study, we demonstrate, for the first time to our knowledge, that overexpression of OPN in synovial T cells is associated with local inflammatory milieu and that OPN acts as an important mediator in amplification and perpetuation of rheumatoid synovitis. The study revealed that mRNA expression of OPN was highly elevated in CD4+ synovial T cells derived from patients with RA, which correlated with increased OPN concentrations in synovial fluid (SF). The pattern of OPN overexpression was confined to rheumatoid synovium and correlated with coexpression of selected OPN receptors in synovial T cells, including integrins {alpha}v and {beta}1 and CD44. RA-derived SF stimulated the expression of OPN in T cells, which was attributable to IL-10 present in SF and abrogated by anti-IL-10 antibody. Among the more than 300 autoimmune and inflammatory response genes examined, OPN selectively induced the expression of proinflammatory cytokines and chemokines known to promote migration and recruitment of inflammatory cells. Furthermore, it was evident that OPN activated transcription factor NF-{kappa}B in mononuclear cells. The study has important implications for understanding the role of OPN in rheumatoid synovitis and other inflammatory conditions
444
Implications of previous subclinical dengue infection but not virus load in dengue hemorrhagic fever
Yeh,Wen Ting; Chen,Rong Fu; Wang,Lin; Liu,Jien Wei; Shaio,Men Fang; Yang,Kuender D.
FEMS Immunology & Medical Microbiology 2006;48:84-90.
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Abstract
Abstract In a study comparing the virus load and immune reaction between patients with primary and secondary dengue-2 (DEN-2) infections in a hospital-based analysis, we found that 40.7% (55/135) of the 135 patients had secondary DEN-2 infection following a DEN-2 outbreak in southern Taiwan. Most of the secondary infections had subclinical primary dengue infections (78.2%; 43/55). Patients with secondary DEN-2 infections had lower platelet counts, and blood interferon-alpha and virus load, but significantly higher interleukin-10 (P=0.030) and anti-DEN-1 neutralization titers (P=0.013) than those with primary infection. Patients with secondary DEN-2 infection also had a higher rate of dengue hemorrhagic fever (DHF) (61.7% vs. 36.3%). A previous subclinical dengue infection is involved in the secondary DEN-2 infection associated with altered immune reaction and higher DHF rate, but lower blood virus load
1453
Interleukin-10 gene promoter polymorphisms and their protein production in peritoneal fluid in patients with endometriosis
Zhang,X.; Hei,P.; Deng,L.; Lin,J.
Molecular Human Reproduction 2007;13:135-140.
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Abstract
Although associations of interleukin-10 (IL-10) gene promoter polymorphisms and their protein production with endometriosis risk have been reported, the correlations remain controversial. The objective of this study was to determine IL-10 gene promoter polymorphisms at -1082, -819 and -592 sites and their protein production in peritoneal fluid (PF) in patients with and without endometriosis. IL-10 gene promoter polymorphisms at -1082 site were detected by amplification refractory mutation system (ARMS)-PCR and that at -819 and -592 sites was genotyped by restriction fragment length polymorphism (RFLP)-PCR. Protein levels of IL-10 in PF were measured by enzyme-linked immunosorbent assay (ELISA). There were no significant differences in the genotype and allele frequencies of IL-10 gene promoter polymorphisms at position -1082 between the endometriosis and the control groups. However, the frequency of -819 or -592 C alleles was significantly increased in patients with endometriosis compared with controls. The protein levels of IL-10 in PF were statistically higher in the endometriosis group than in the control group. Moreover, the polymorphisms at -1082, -819 and -592 sites were associated with protein levels of IL-10 in PF in the endometriosis group while in the control group only the polymorphisms at position -1082 correlated with protein levels. Increased frequency of -819 or -592 C allele and increased protein production of IL-10 in PF in patients with endometriosis compared with controls and correlations of polymorphisms at -819 and -592 sites with protein levels of IL-10 in PF in patients with endometriosis may suggest that polymorphisms at -819 and -592 sites and their protein production are associated with endometriosis risk
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