Serum levels of interleukin-18 and sICAM-1 in patients affected by breast cancer: preliminary considerations

Interleukin-18 (IL-18), a cytokine that plays an important role in the T-cell-helper type 1 response, acts as an angiogenesis and tumor suppressor. Intercellular adhesion molecule-1 (ICAM-1) has a potential role in immunoregulation by mediating immune cell infiltration into the tissue. The aim of this study was to evaluate IL-18 and soluble (s) ICAM-1 serum levels in breast cancer (BCa) patients with liver (BCaM1 h) or bone (BCaM1 b) metastases compared to BCa patients without metastases (BCaM0) and healthy donors (HDs). Furthermore, since IL-18 enhances ICAM-1 expression, we investigated whether there was a direct correlation between sICAM-1 and IL-18 serum levels. Serum IL-18 and sICAM-1 levels were assayed by immunoenzymatic methods. The serum sICAM-1 levels in the three groups of cancer patients were significantly higher (p<0.05) than those of HDs. Serum IL-18 levels were significantly higher (p<0.05) in BCaM1h and BCaM1b patients compared to BCaM0 patients and HDs. sICAM-1 proved to be closely correlated with serum IL-18 levels in HDs, whereas a weaker correlation was found in BCaM1h, BCaM1b and BCaM0 patients. The defective correlation between sICAM-1 and IL-18 found in cancer patients may contribute to our understanding of the immunity upset occurring in cancer. Our data suggest that IL-18, irrespective of its biological activity, could represent a marker for metastatic breast cancer.     

Influence of 5-fluorouracil and folinic acid on interleukin-18 production in colorectal cancer patients

AIMS AND BACKGROUND: This study was carried out to evaluate the IL-18 blood concentrations of operated colorectal cancer patients and their possible variation in response to combination chemotherapy with 5-fluorouracil (5-FU) and folinic acid. METHODS: IL-18 levels were assayed in sera of 18 healthy donors and 18 surgical colorectal cancer patients before and after adjuvant chemotherapy with 5-fluorouracil and folinic acid. An ELISA kit for human IL-18 was used for the assay. RESULTS: Colorectal cancer patients showed significantly higher baseline levels of IL-18 than healthy donors (p<0.005). Furthermore, serum IL-18 levels increased significantly with respect to baseline in patients receiving adjuvant chemotherapy (p<0.005). CONCLUSIONS: This study suggests that treatment with 5-fluorouracil and folinic acid may provoke an increase in IL-18 serum levels in colorectal cancer patients. This increase may help to explain the efficacy of adjuvant chemotherapy with 5-FU in colorectal cancer.     

Elevated levels of circulating interleukin-18 in human immunodeficiency virus-infected individuals: role of peripheral blood mononuclear cells and implications for AIDS pathogenesis

Originally identified as the gamma interferon-inducing factor, interleukin-18 (IL-18) was rediscovered as a proinflammatory cytokine related to the IL-1 family of cytokines that plays an important role in both innate and adaptive immune responses against viruses and intracellular pathogens. Despite its importance in inducing and regulating immune responses, relatively little is known about its production in HIV infection. We report here significantly (P < 0.05) elevated levels of this cytokine in the sera of human immunodeficiency virus (HIV)-infected/AIDS patients compared to those of HIV-seronegative healthy persons. Surprisingly, the peripheral blood mononuclear cells (PBMC) from HIV-infected/AIDS patients were compromised in the ability to upregulate IL-18 gene expression and produce this cytokine with and without lipopolysaccharide (LPS) stimulation. A significant positive correlation (P < 0.05) existed between the concentration of IL-18 in serum and its production from PBMC of HIV-seronegative healthy individuals but not those of HIV-infected/AIDS patients. Furthermore, the patients' PBMC expressed relatively reduced levels of activated caspase-1 constitutively as well as in response to LPS stimulation. Our data suggest the involvement of transforming growth factor beta (TGF-beta) in suppressing IL-18 production from the patients' PBMC for the following reasons. (i) In in vitro studies it suppressed the production of IL-18 from PBMC. (ii) Its levels were significantly higher in the plasma of patients compared to that of control subjects. (iii) A significant negative correlation existed between the concentrations of TGF-beta in plasma and of IL-18 in serum of the patients. The elevated levels of IL-18 in the serum of HIV-infected individuals may contribute to AIDS pathogenesis, whereas its compromised production from their PBMC in response to stimuli may reduce their innate defense to opportunistic intracellular pathogens.     

The significance of an increase in soluble interleukin-2 receptor level in colorectal cancer and its biological regulating role in the physiological switching of the immune response cytokine network from TH1 to TH2 and back

 Current research has still not clarified the biological role of soluble interleukin(IL)-2 receptor (sIL-2R) and the significance of its increase in the serum of colon cancer patients compared to healthy subjects. To address these questions at the immunological level in a group of patients and healthy subjects, we determined the sIL-2R level in the serum and its release from peripheral blood mononuclear cells (PBMC) as a function of tumour necrosis factor (TNF) α, IL-1α, IL-1β, IL-2, interferon (IFN) γ, IL-4, IL-6 and IL-10 levels in the serum and PBMC production; and PBMC proliferative responses to IL-2, IL-4 and anti-CD3 monoclonal antibody (CD3), variously combined. The level of sIL-2R in patients’ serum was higher than in healthy subjects and correlated with the stage of advancement. Moreover, while in healthy subjects the serum level of sIL-2R was not significantly correlated with other parameters, in patients it was positively related to IL-4, IL-6 and IL-10 serum levels, PBMC IL-4 production and to the PBMC proliferative response to CD3 and CD3+IL-2; it was negatively correlated to IL-2 serum level and IL-1β PBMC release. A negative connection between IFNγ serum level and the PBMC production of sIL-2R was also found. This suggests that the increase of sIL-2R in the serum of patients, compared to healthy subjects, is involved in the inappropriate expansion of the T helper (TH2) suppressive immune response, which we previously reported. The multivariate statistical method supported the above suggestions and we also found that, in healthy subjects, the up- and down-regulation of sIL-2R in the serum within the physiological ranges seems to have a regulating role in the relationships between TNFα, IFNγ and IL-4, IL-6, contributing to the operation of the cytokine network between TH1 and TH2 cells. However, in patients compared to healthy subjects the increased sIL-2R serum level seems to direct the immune response towards a suppressive type, which may be due to an alteration in the above-mentioned physiological regulating role. Received: 12 April 1997 / Accepted: 4 September 1997     

Serum levels of interleukin-18 in patients with uncomplicated Plasmodium falciparum malaria

Interleukin (IL)-18, a newly discovered cytokine produced primarily by macrophages, has been shown to induce gamma interferon (IFN-gamma) production by natural killer cells, to induce the T helper type 1 response. To further elucidate the role of this cytokine in uncomplicated malaria caused by Plasmodium falciparum, serum levels of IL-18, and gamma interferon (IFN-gamma), determined by an immunoenzymatic assay, were analyzed in 40 adult patients, and in 15 healthy control subjects. A significant increase in serum levels of IL-18 was observed in patients with uncomplicated P. falciparum malaria on admission, whereas serum levels of IFN-gamma tended to increase although not significantly. Serum levels of IL-18 decreased three days later, but still remained significantly high, whereas IFN-gamma levels returned to normal levels compared to the controls. No significant correlation was found between parasitemia and serum levels of IL-18 and IFN-gamma. The increase of IL-18 levels during acute and recovery phases of uncomplicated P. falciparum malaria may reflect a proinflammatory role of IL-18 in these patients. An early and effective immune response regulated by proinflammatory Th1 cytokines, including tumor necrosis factor (TNF), interleukin (IL)-12, and possibly IFN-gamma may limit the progression from uncomplicated malaria to severe and life-threatening complications.     

Abnormal production of interleukin (IL)-11 and IL-8 in polycythaemia vera

We studied the production of interleukin (IL)-11 and IL-8, two cytokines known to affect erythropoiesis, in polycythemia vera (PV). In vivo, IL-11 was detected more frequently in serum and bone marrow (BM) plasma of PV patients than in controls (healthy donors and patients with idiopathic erythrocytosis (IE)). In addition, serum IL-11 levels of PV patients were higher than those of controls. IL-8 was elevated in serum of both PV and IE patients (respective median levels: 38.6 and 242pg/ml, vs 4.4pg/ml for healthy donors). BM plasma IL-8 levels of PV patients (508pg/ml) were significantly higher than those of IE patients (120pg/ml). In vitro, bone marrow (BM) stromal cells (BMSC) of PV patients produced significantly more IL-11 (x6.4) and IL-8 (x8.3) than BMSC of healthy donors or IE patients. In conclusion, both IL-11 and IL-8 are overproduced in PV, apparently by BMSC; IL-8 is also overproduced in IE, by cells other than BMSC.     

Serum IL-18 levels are not increased in patients with untreated Graves' ophthalmopathy.

OBJECTIVE: Cytokines play an important role in autoimmune thyroid diseases, and serum levels may reflect the activity of the immune process. This is particularly interesting in Graves' ophthalmopathy, where a reliable serum activity marker is warranted. Interleukin-18 (IL-18) is a potent Th1 cytokine, known to induce interferon (IFN)-gamma and the aim of this study was to evaluate serum IL-18 levels in Graves' ophthalmopathy. METHODS: Serum IL-18 was measured by ELISA in 52 patients with untreated Graves' ophthalmopathy (who all had been rendered euthyroid with antithyroid drugs), 52 healthy controls matched for sex, age, and smoking habits, and 15 euthyroid patients who had been treated for Graves' hyperthyroidism and ophthalmopathy in the past. RESULTS: Serum IL-18 (median values in pg/ml with range) levels did not differ between the untreated Graves' ophthalmopathy patients-226 (61-704) pg/ml, matched healthy controls-194 (17-802) pg/ml, and Graves' ophthalmopathy patients treated in the past-146 (0-608) pg/ml. No correlation was observed between serum IL-18 levels and thyroid function or antithyroid antibodies. There was no correlation between serum IL-18 levels and smoking habits. CONCLUSION: We conclude that Graves' ophthalmopathy does not affect serum IL-18.     

Increased Soluble CD155 in the Serum of Cancer Patients

Emerging evidence suggests that DNAM-1 (CD226) play an important role in the recognition of tumor cells and their lysis by cytotoxic T lymphocytes (CTL) and NK cells. Although the DNAM-1 ligand CD155 is ubiquitously expressed in various tissues, many human tumors significantly upregulate the expression of CD155; DNAM-1 on CTL and NK cells may be involved in tumor immunity. However, unlike those in mice, human tissues also express soluble isoforms of CD155 (sCD155) that lack the transmembrane region. Here, we show that sCD155 levels were significantly higher in the sera of 262 patients with lung, gastrointestinal, breast, and gynecologic cancers than in sera from healthy donors. In addition, the sCD155 levels were significantly higher in patients with early stage (stages 1 and 2) gastric cancer than in healthy donors, and were significantly higher in patients with advanced stage (stages 3 and 4) disease than in patients in those with early stage disease and healthy donors. Moreover, the sCD155 levels were significantly decreased after surgical resection of cancers. Thus, sCD155 level in serum may be potentially useful as a biomarker for cancer development and progression.     

Serum and urinary levels of IL-18 and its inhibitor IL-18BP in systemic lupus erythematosus

Overproduction of inflammation-related cytokines plays an important role in systemic lupus erythematosus (SLE). A crucial cytokine is IL-18, a member of the IL-1 family involved in the regulation of both innate and acquired immune responses. The aim of this study was to evaluate free IL-18 levels in the serum and urine of SLE patients, in order to establish their relationship with other biomarkers of disease activity. Serum and urine levels of IL-18 and IL-18BP were measured by ELISA in 50 SLE patients and in 32 healthy subjects; free IL-18 was calculated using the law of mass action. Serum levels of total IL-18, IL-18BP and free IL-18 were higher in SLE patients than in healthy controls. Total and free serum IL-18 levels were higher in patients with active disease (with nephritis or active non-renal disease), and correlated with the ECLAM score. Urinary levels of total and free IL-18 were higher in patients than in controls, but did not correlate with disease activity. The data collected in this study show that increased levels of both IL-18 and its natural inhibitor IL-18BP, characterise SLE. Despite the overproduction of IL-18BP, free IL-18 is still significantly higher in SLE patients than in controls, and its serum levels are a marker of disease activity.     

Involvement of fractalkine and macrophage inflammatory protein-1 alpha in moderate-severe depression

Moderate-severe depression (MSD) is linked to overexpression of proinflammatory cytokines and chemokines. Fractalkine (FKN) and macrophage inflammatory protein-1 alpha (MIP-1alpha) are, respectively, members of CX3C and C-C chemokines, and both are involved in recruiting and activating mononuclear phagocytes in the central nervous system. We analysed the presence of FKN and MIP-1alpha in sera of untreated MSD patients and healthy donors. High FKN levels were observed in all MSD patients as compared with values only detectable in 26% of healthy donors. MIP-1alpha was measurable in 20% of patients, while no healthy donors showed detectable chemokine levels. In conclusion, we describe a previously unknown involvement of FKN in the pathogenesis of MSD, suggesting that FKN may represent a target for a specific immune therapy of this disease.     

Serum IL-18 levels in patients with type 1 diabetes: relations to metabolic control and microvascular complications

The study was designed to examine serum IL-18 level and its relation to metabolic control parameters and microvascular complications in type 1 diabetes mellitus (DM). Sixty two patients with type 1 DM and 30 healthy individuals were enrolled in the study. Serum IL-18 levels of patients with type 1 DM were significantly increased compared to controls (293.4+/-133.4 vs 211.2+/-63.9 pg/ml, P=0.003). Patients with poor glycemic control had higher levels of IL-18 than patients with well glycemic control (329.9+/-141.0 vs 226.3+/-89.6 pg/ml, P=0.02). There was no significant difference between the serum IL-18 levels of patients with microvascular complications and those of patients without microvascular complications (307.6+/-127.6 vs 293.2+/-145.6 pg/ml, P>0.05). IL-18 correlated positively with HbA(1c) (r=0.32, P=0.01) and postprandial blood glucose (PPBG) (r=0.26, P=0.02); and negatively with HDL-cholesterol (HDL-C) (r=-0.38, P=0.007). By linear regression analysis, PPBG was determined as the most explanatory parameter for the alterations in serum IL-18 levels (P=0.02). High levels of IL-18 in patients with type 1 DM is related to short and long term glycemic control and HDL-C levels but not to microvascular complications.     

The Expression of Tristetraprolin and Its Relationship with Urinary Proteins in Patients with Diabetic Nephropathy

Objective

Tristetraprolin (TTP), also known as zinc finger protein 36, is an RNA binding protein that has a significant role in regulating the expression of mRNAs containing AU-rich elements. We postulated that TTP might regulate interleukin (IL)-6 and IL-18 expression in diabetes. This study aimed to test the hypothesis that the levels of TTP are correlated with nephropathy in patients with type 2 diabetes.

Methods

Eighty-seven patients (61.3±9.6 years old) who had been diagnosed with type 2 diabetes mellitus and 41 age and sex matched healthy control subjects were enrolled. The diabetes patients were classified into those without proteinuria, with microalbuminuria, and with clinical proteinuria groups according to the ratio of urinary excretion of albumin/creatinine (ACR).

Results

Serum and urinary levels of IL-6 and IL-18 were significantly elevated, but those of TTP were significantly decreased in patients with diabetes as compared with control subjects. In addition, serum and urinary levels of IL-6 and IL-18 were significantly higher, but those of TTP were significantly lower in patients with proteinuria than in patients without proteinuria or with microalbuminuria. There was a significant correlation between serum TTP and IL-6/IL-18 (correlation coefficients of -0.572 and -0.685, P < 0.05).

Conclusion

These results show that diabetes with clinical proteinuria is accompanied by decreased urinary and serum level of TTP and increased levels of IL-6 and IL-18. Decreased TTP expression might occur prior to the increase in IL-6 and IL-18, and decrease of TTP might provide an earlier marker for glomerular dysfunction than IL-6 and IL-18.     

B cell-derived IL-15 enhances CD8 T cell cytotoxicity and is increased in multiple sclerosis patients

Multiple lines of evidence suggest that CD8 T cells contribute to the pathogenesis of multiple sclerosis (MS). However, the sources and involvement of cytokines such as IL-15 in activating these cells is still unresolved. To investigate the role of IL-15 in enhancing the activation of CD8 T cells in the context of MS, we determined cell types expressing the bioactive surface IL-15 in the peripheral blood of patients and evaluated the impact of this cytokine on CD8 T cell cytotoxicity and migration. Flow cytometric analysis showed a significantly greater proportion of B cells and monocytes from MS patients expressing IL-15 relative to controls. We established that CD40L activation of B cells from healthy donors increased their IL-15 levels, reaching those of MS patients. We also demonstrated an enhanced cytotoxic profile in CD8 T cells from MS patients upon stimulation with IL-15. Furthermore, we showed that IL-15 expressed by B cells and monocytes is sufficient and functional, enhancing granzyme B production by CD8 T cells upon coculture. Exposure of CD8 T cells to this cytokine enhanced their ability to kill glial cells as well as to migrate across an in vitro inflamed human blood-brain barrier. The elevated levels of IL-15 in patients relative to controls, the greater susceptibility of CD8 T cells from patients to IL-15, in addition to the enhanced cytotoxic responses by IL-15-exposed CD8 T cells, stresses the potential of therapeutic strategies to reduce peripheral sources of IL-15 in MS.     

High levels of circulating interleukin-10 in diabetic nephropathy patients

AIMS: The aim of our study was to analyse the level of circulating interleukin-10 (IL-10) and relate it to the grade of albuminuria in patients with diabetic nephropathy (DN) due to type 1 diabetes mellitus (DM). Since IL-10 has met the criteria for an anti-inflammatory and an immunosuppressive cytokine, its activity may be important for clinical outcome of DN. METHODS: The IL-10 level was measured by ELISA in serum samples from thirty patients with DN due to type 1 DM, and compared with thirty patients with type 1 DM without DN and a control group of thirty, healthy, age- and sex-matched people. RESULTS: We observed a greatly elevated concentration of circulating IL-10 in 30/30 DM patients with DN (mean 140 pg/mL +/- 102), compared to DM patients without DN in whom IL-10 was detectable in only 11/30 patients (0.79 pg/mL +/- 1.24), and the group of healthy people in whom IL-10 was detectable in only 3/30 donors (0.92 pg/mL +/- 0.17). IL-10 appeared to be the strongest independent predictor of albuminuria, followed by HbA1c, diastolic blood pressure and DN duration. There was a positive correlation between the values of IL-10 and albuminuria in DM patients with DN. The patients in the fourth quartile of albuminuria had a distinctly higher concentration of IL-10 than those in the lower quartiles. CONCLUSIONS: The increased concentration of IL-10 in the serum samples from DM patients with DN seems to depend on the severity of the nephropathy. The excessive IL-10 production may indirectly contribute towards DN progression. On the other hand, it may explain the relatively long course of diabetic nephropathy.     

Interleukin-15 modulates interferon-gamma and beta-chemokine production in patients with HIV infection: implications for immune-based therapy

Interleukin (IL)-15 is a cytokine that has lymphocyte stimulatory activity similar to that of IL-2, and plays important immunoregulatory functions during HIV disease. To evaluate the role of IL-15 in HIV infection the following patients were studied: 18 antiretroviral-naive patients with advanced disease; 19 patients with continuous viral suppression and immunological response after 48-120 weeks of highly active antiretroviral therapy (HAART); and 12 patients with evidence of virological and immunological HAART treatment failure. Nineteen healthy blood donors were included as controls. The production of IL-15 by human peripheral blood monocytes stimulated with lipopolysaccharide and Mycobacterium avium complex, the priming effect of IL-15 on IFN-gamma production from purified CD4(+) and CD8(+) T cells, and the ability of IL-15 to stimulate the beta-chemokine release from purified CD4(+) and CD8(+) T cells were analyzed. In the present work IL-15 production by human peripheral blood monocytes was significantly increased in HIV-infected patients with long-term virological and immunological response to HAART. IL-15 enhanced the in vitro priming of CD4(+) and CD8(+) T cells for IFN-gamma production, also in patients receiving HAART. Finally, IL-15 had positive effects on RANTES, MIP-1alpha, and MIP-1beta release by CD4(+) and CD8(+) T cells. In conclusion IL-15 could affect the immune response of HIV-infected patients by augmenting and/or modulating IFN-gamma production and beta-chemokine release. These data about functional properties of IL-15 could provide new implications for immune-based therapies in HIV infection.     

Development of CD8+ effector T cells is differentially regulated by IL-18 and IL-12

We investigated the effects of IL-18 on the development of CD8+ effector T cells in DBA/2 anti-BDF1 whole spleen cell MLC and compared the results with those of IL-12. Addition of IL-18 to the MLC resulted in a twofold increase in CD8/CD4 ratios compared with the control cultures when cells were expanded in IL-2-containing medium following MLC. Purified CD8+ T cells recovered from the IL-18-stimulated MLC produced 20- to 30-fold more IFN-gamma after secondary stimulation with C57BL/6 spleen cells or anti-CD3 mAb, and exhibited strong allospecific CTL activity. Neither IL-18 nor IL-18-supplemented culture supernatants from DBA/2 anti-BDF1 MLC induced type I CD8+ effector T cells when purified CD8+ T cells were used as responder cells in primary MLC. Furthermore, CD4+ T cell depletion from the responder cells abrogated the IL-18-induced increase in secondary IFN-gamma production by CD8+ T cells, suggesting that IL-18-induced type I effector CD8+ T cell development was CD4+ T cell dependent. In marked contrast, adding IL-12 to primary MLC decreased CD8/CD4 ratios by 50% and suppressed secondary IFN-gamma production and CTL activity by CD8+ T cells regardless of concentration, whereas Th1 development was promoted by IL-12. Moreover, both IL-12 and IL-18 efficiently induced type I CD8+ effector T cells in C57BL/6 anti-BDF1 MLC. These findings show that IL-18 plays an important role in the generation of type I CD8+ effector T cells, and further suggest that functional maturation of CD8+ T cells is differentially regulated by IL-18 and IL-12.     

CD14 is an acute-phase protein

The origin of soluble CD14 (sCD14) in the circulation is uncertain. To examine whether CD14 could be an acute-phase protein (APP), the levels of sCD14, IL-6, and C-reactive protein were determined by ELISA in serum and synovial fluid (SF) of patients with various arthropathies, and the regulation of CD14 synthesis was examined in liver cells. In patients with crystal-mediated or immunologically mediated arthritis (rheumatoid arthritis), serum levels of sCD14 were higher than or similar to those found in infection-mediated arthritis (reactive arthritis), precluding a relation with bacteria exposure. Levels of sCD14 were similar in SF and serum, and did not correlate with the number of SF leukocytes, excluding an important source from leukocyte membrane-bound CD14, by protease-mediated shedding. In contrast, serum levels of sCD14 in patients correlated with those of C-reactive protein, a classical APP, and IL-6, a cytokine known to regulate the synthesis of APP in the liver. Serum levels of sCD14 also correlated with disease activity in rheumatoid arthritis and reactive arthritis patients. IL-6 stimulated the production of CD14 by HepG2 hepatoma cells. By real-time PCR, the inducibility of CD14 by IL-6 was also observed at the mRNA level both in HepG2 cells and human primary hepatocytes. These in vitro results were confirmed by in vivo studies in IL-6(-/-) mice injected with turpentine, an experimental model of acute-phase response. Liver levels of CD14 mRNA increased in IL-6(+/+), but not in IL-6(-/-) mice. These results indicate that sCD14 can be considered as a type 2 APP.     

IL-21 influences the frequency, phenotype, and affinity of the antigen-specific CD8 T cell response

IL-21, a newly described cytokine belonging to the IL-2 gamma-chain receptor cytokine family (that includes IL-2, IL-7, and IL-15), has been described as an important regulator of the cellular immune response. In this study, the role of IL-21 in the generation of a human Ag-specific CD8+ T cell response is characterized by tracking a rare, but measurable population of self-Ag-specific T cells in vitro. Autologous dendritic cells pulsed with the melanoma antigen recognized T cells 1 self-peptide were used to stimulate CD8+ T cells from HLA-A2+ healthy donors and melanoma patients. We demonstrate that exposure to IL-21 increased the total number of MART-1-specific CD8+ T cells that could be elicited by >20-fold and, at the clonal level, enriched for a population of high-affinity CD8+ T cells with a peptide dose requirement more than 1 log(10)-fold less than their untreated counterparts. Phenotypic analysis of T cells from IL-21-treated cultures revealed a unique population of CD45RO+ CD28(high) CD8+ T cells, a phenotype that was stable for at least 4 wk after IL-21 exposure. These CD28(high) CD8+ T cells produced IL-2 upon Ag stimulation and represent potential helper-independent CTLs. Our studies demonstrate a significant role for IL-21 in the primary Ag-specific human CTL response and support the use of IL-21 in the ex vivo generation of potent Ag-specific CTLs for adoptive therapy or as an adjuvant cytokine during in vivo immunization against tumor Ags.     

Regulatory effects of IL-18 on cytokine profiles and development of myocarditis during Trypanosoma cruzi infection

Chagas disease, caused by Trypanosoma cruzi (Tc), is an important cause of heart disease. Resistance to Tc infection is multifactorial and associated with Th1 response. IL-18 plays an important role in regulation of IFN-γ production/development of Th1 response. However, the role of IL-18 in the setting of Tc infection remains unclear. Therefore, we investigated the role of IL-18 in the modulation of immune response and myocarditis in Tc infection. C57BL/6 and IL-18 KO mice were infected with Tc (Y or Colombian strain) and parasitemia, immune response and pathology were evaluated. Y strain infection of IL-18 KO did not alter any parameters when compared with C57BL/6 mice. However, during the acute phase (20 and 40 days post infection-dpi), Colombian strain infected-IL-18 KO mice displayed higher serum levels of IL-12 and IFN-γ, respectively, and at the chronic phase (100 dpi) an increase in splenic IFN-γ-producing CD4⁺ and CD8⁺ T memory cells. There was an IL-10, FOXP3 and CD4⁺CD25⁺ cells reduction during acute infection in spleen. Additionally, there was a significant reduction in leukocyte infiltration and parasite load in myocardium of chronically infected IL-18 KO mice. Collectively, these data indicate that IL-18 contributes to the pathogenesis of Tc-induced myocarditis when infected with Colombian but not Y strain. These observations also underscore that parasite and host strain differences are important in evaluation of experimental Tc infection pathogenesis.     

Interleukin-17 in acute myeloid leukemia

There are several reports that angiogenesis plays important roles in hematological malignancies including acute myeloid leukemia (AML). Human interleukin-17 (IL-17) is a proinflammatory cytokine produced by activated CD4 T cells. IL-17 plays a potential role in T cell mediated angiogenesis. The role of IL-17 in pathologic angiogenesis has not been evaluated yet. The aim of the study was to determine plasma level of IL-17 in patients with AML. IL-17 levels were measured by ELISA in plasma samples taken from 68 adult patients with AML before chemotherapy was administered. In addition 20 out of 68 patients were reanalysed after achieving complete remission (CR). Ten samples from healthy volunteers were evaluated as the control. In this study we have demonstrated that serum level of IL-17 is not elevated in AML patients. These results suggest that angiogenesis in AML is not mediated by CD4 T cells. To our knowledge this is the first report about IL-17 serum level in acute leukemias. We are currently evaluating IL-17 levels in others haematological malignancies.