共查询到20条相似文献,搜索用时 15 毫秒
1.
Elena Tassi Marco Braga Renato Longhi Francesca Gavazzi Giorgio Parmiani Valerio Di Carlo Maria Pia Protti 《PloS one》2009,4(10)
Background
Pancreatic cancer is a very aggressive disease with dismal prognosis; peculiar is the tumor microenvironment characterized by an extensive fibrotic stroma, which favors rapid tumor progression. We previously reported that pancreatic cancer patients have a selective Th2 skew in the anti-carcinoembryonic antigen (CEA) CD4+ T cell immunity, which correlates with the presence of a predominant GATA-3+ tumor lymphoid infiltrate. This has negative effects in both effective anti-tumor immunity and further favoring fibrinogenesis. Aim of this study was to evaluate whether the Th2 polarization of CEA-specific CD4+ T cells from pancreatic cancer patients is stable or can be reverted by immunomodulating cytokines.Methodology/Principal Findings
We first evaluated the influence of IL-12 and IL-27, as single agents and in association, on the polarization of CEA-specific Th2 CD4+ T cell clones from a pancreatic cancer patient. We found that only the combination of IL-12 and IL-27 modified the polarization of Th2 effectors by both reduction of IL-5, GM-CSF and IL-13 and induction of IFN-γ production, which lasted after cytokine removal. Second, we evaluated the effect of the combined treatment on polyclonal CEA-specific CD4+ T cells in short-time re-stimulation assays. In agreement with the data obtained with the clones, we found that the combined treatment functionally modulated the Th2 polarization of CEA-specific CD4+ T cells and enhanced pre-existing Th1 type immunity.Conclusions/Significance
Collectively, our results demonstrate that tumor antigen specific Th2 CD4+ T cells in pancreatic cancer are endowed with functional plasticity. Hence, loco-regional cytokines delivery or targeted therapy based on antibodies or molecules directed to the tumor stroma might improve anti-tumor immunity and ameliorate fibrosis, without systemic toxicity. 相似文献2.
Irma Airoldi Emma Di Carlo Claudia Cocco Emanuela Caci Michele Cilli Carlo Sorrentino Gabriella Sozzi Silvano Ferrini Sandra Rosini Giulia Bertolini Mauro Truini Francesco Grossi Luis Juan Vicente Galietta Domenico Ribatti Vito Pistoia 《PloS one》2009,4(7)
Background
Non small cell lung cancer (NSCLC) is a leading cause of cancer death. We have shown previously that IL-12rb2 KO mice develop spontaneously lung adenocarcinomas or bronchioalveolar carcinomas.Aim of the study was to investigate i) IL-12Rβ2 expression in human primary lung adenocarcinomas and in their counterparts, i.e. normal bronchial epithelial cells (NBEC), ii) the direct anti-tumor activity of IL-12 on lung adenocarcinoma cells in vitro and vivo, and the mechanisms involved, and iii) IL-12 activity on NBEC.Methodology/Principal Findings
Stage I lung adenocarcinomas showed significantly (P = 0.012) higher frequency of IL-12Rβ2 expressing samples than stage II/III tumors. IL-12 treatment of IL-12R+ neoplastic cells isolated from primary adenocarcinoma (n = 6) inhibited angiogenesis in vitro through down-regulation of different pro-angiogenic genes (e.g. IL-6, VEGF-C, VEGF-D, and laminin-5), as assessed by chorioallantoic membrane (CAM) assay and PCR array. In order to perform in vivo studies, the Calu6 NSCLC cell line was transfected with the IL-12RB2 containing plasmid (Calu6/β2). Similar to that observed in primary tumors, IL-12 treatment of Calu6/β2+ cells inhibited angiogenesis in vitro. Tumors formed by Calu6/β2 cells in SCID/NOD mice, inoculated subcutaneously or orthotopically, were significantly smaller following IL-12 vs PBS treatment due to inhibition of angiogenesis, and of IL-6 and VEGF-C production. Explanted tumors were studied by histology, immuno-histochemistry and PCR array. NBEC cells were isolated and cultured from lung specimens of non neoplastic origin. NBEC expressed IL-12R and released constitutively tumor promoting cytokines (e.g. IL-6 and CCL2). Treatment of NBEC with IL-12 down-regulated production of these cytokines.Conclusions
This study demonstrates that IL-12 inhibits directly the growth of human lung adenocarcinoma and targets the adjacent NBEC. These novel anti-tumor activities of IL-12 add to the well known immune-modulatory properties of the cytokine and may provide a rational basis for the development of a clinical trial. 相似文献3.
Chun K Wong Da P Chen Lai S Tam Edmund K Li Yi B Yin Christopher WK Lam 《Arthritis research & therapy》2010,12(4):R129-15
Introduction
Interleukin (IL)-27 is a novel member of the IL-6/IL-12 family cytokines that are produced early by antigen-presenting cells in T helper (Th)1-mediated inflammation. Elevated expression of IL-27 has been detected in the synovial membranes and fluid of rheumatoid arthritis (RA). 相似文献4.
Maria C Lebre Christina L Jonckheere Maarten C Kraan Arno WR van Kuijk Jan D Bos Menno de Rie Danielle M Gerlag Paul P Tak 《Arthritis research & therapy》2012,14(5):R200
Introduction
Psoriatic arthritis (PsA) is an inflammatory joint disease associated with psoriasis. Alefacept (a lymphocyte function-associated antigen (LFA)-3 Ig fusion protein that binds to CD2 and functions as an antagonist to T-cell activation) has been shown to result in improvement in psoriasis but has limited effectiveness in PsA. Interleukin-20 (IL-20) is a key proinflammatory cytokine involved in the pathogenesis of psoriasis. The effects of alefacept treatment on IL-20 expression in the synovium of patients with psoriasis and PsA are currently unknown.Methods
Eleven patients with active PsA and chronic plaque psoriasis were treated with alefacept (7.5 mg per week for 12 weeks) in an open-label study. Skin biopsies were taken before and after 1 and 6 weeks, whereas synovial biopsies were obtained before and 4 and 12 weeks after treatment. Synovial biopsies from patients with rheumatoid arthritis (RA) (n = 10) were used as disease controls. Immunohistochemical analysis was performed to detect IL-20 expression, and stained synovial tissue sections were evaluated with digital image analysis. Double staining was performed with IL-20 and CD68 (macrophages), and conversely with CD55 (fibroblast-like synoviocytes, FLSs) to determine the phenotype of IL-20-positive cells in PsA synovium. IL-20 expression in skin sections (n = 6) was analyzed semiquantitatively.Results
IL-20 was abundantly expressed in both PsA and RA synovial tissues. In inflamed PsA synovium, CD68+ macrophages and CD55+ FLSs coexpressed IL-20, and its expression correlated with the numbers of FLSs. IL-20 expression in lesional skin of PsA patients decreased significantly (P = 0.04) 6 weeks after treatment and correlated positively with the Psoriasis Area and Severity Index (PASI). IL-20 expression in PsA synovium was not affected by alefacept.Conclusions
Conceivably, the relatively limited effectiveness of alefacept in PsA patients (compared with anti-tumor necrosis factor (TNF) therapy) might be explained in part by persistent FLS-derived IL-20 expression. 相似文献5.
M Benito-Miguel Y García-Carmona A Balsa MB Bautista-Caro I Arroyo-Villa T Cobo-Ibáñez MG Bonilla-Hernán C Pérez de Ayala P Sánchez-Mateos E Martín-Mola ME Miranda-Carús 《PloS one》2012,7(7):e40620
Introduction
The purpose of this study was to examine the role of RA Synovial Fibroblast (RASFib) IL-15 expression on B cell survival.Methods
Magnetically sorted peripheral blood memory B cells from 15 healthy subjects were cocultured with RASFib.Results
RASFib constitutively expressed membrane IL-15. Survival of isolated B cells cultured for 6 days, below 5%, was extended in coculture with RASFib to 52+/−8% (p<0.001). IL-15 neutralizing agents but not isotype controls, reduced this rate to 31+/−6% (p<0.05). Interestingly, rhIL-15 had no effect on isolated B cells but significantly increased their survival in coculture with RASFib. In parallel, B cell IL-15R chains were upregulated in cocultures. BAFF and VCAM-1, that are expressed on RASFib, were tested as potential candidates involved in upregulating B cell IL-15R. Culture of B cells in the presence of rhBAFF or rhVCAM-1 resulted in significantly increased survival, together with upregulation of all three IL-15R chains; in parallel, rhIL-15 potentiated the anti-apoptotic effect of BAFF and VCAM-1. Both BAFF and VCAM-1 neutralizing agents downmodulated the effect of RASFib on B cell survival and IL-15R expression. In parallel, rhIL-15 had a lower effect on the survival of B cells cocultured with RASFib in the presence of BAFF or VCAM-1 neutralizing agents. Peripheral blood B cells from 15 early RA patients demonstrated an upregulated IL-15R and increased survival in cocultures.Conclusion
IL-15 expression on RASFib significantly contributes to the anti-apoptotic effect of RASFib on B cells. IL-15 action is facilitated by BAFF and VCAM-1 expressed on RASFib, through an upregulation of IL-15R chains. 相似文献6.
Polyxeni T. Mantani Pontus Dunér Eva Bengtsson Ragnar Alm Irena Ljungcrantz Ingrid S?derberg Lena Sundius Fong To Jan Nilsson Harry Bj?rkbacka Gunilla Nordin Fredrikson 《PloS one》2015,10(1)
Objective
IL-25 has been implicated in the initiation of type 2 immunity and in the protection against autoimmune inflammatory diseases. Recent studies have identified the novel innate lymphoid type 2 cells (ILC2s) as an IL-25 target cell population. The purpose of this study was to evaluate if IL-25 has any influence on atherosclerosis development in mice.Methods and Results
Administration of 1 μg IL-25 per day for one week to atherosclerosis-prone apolipoprotein (apo)E deficient mice, had limited effect on the frequency of T cell populations, but resulted in a large expansion of ILC2s in the spleen. The expansion was accompanied by increased levels of anti-phosphorylcholine (PC) natural IgM antibodies in plasma and elevated levels of IL-5 in plasma and spleen. Transfer of ILC2s to apoE deficient mice elevated the natural antibody-producing B1a cell population in the spleen. Treatment of apoE/Rag-1 deficient mice with IL-25 was also associated with extensive expansion of splenic ILC2s and increased plasma IL-5, suggesting ILC2s to be the source of IL-5. Administration of IL-25 in IL-5 deficient mice resulted in an expanded ILC2 population, but did not stimulate generation of anti-PC IgM, indicating that IL-5 is not required for ILC2 expansion but for the downstream production of natural antibodies. Additionally, administration of 1 μg IL-25 per day for 4 weeks in apoE deficient mice reduced atherosclerosis in the aorta both during initiation and progression of the disease.Conclusions
The present findings demonstrate that IL-25 has a protective role in atherosclerosis mediated by innate responses, including ILC2 expansion, increased IL-5 secretion, B1a expansion and natural anti-PC IgM generation, rather than adaptive Th2 responses. 相似文献7.
Background
Recently, growing evidence suggests the involvement of PI 3-K/Akt in IL-6-dependent survival and proliferative responses in several types of cells. However, whether PI 3-K/Akt plays the same role in IL-6-dependent growth of 7TD1 mouse-mouse B cell hybridoma is not known. 相似文献8.
Mario Weinhold Martin Eisenbl?tter Edith Jasny Michael Fehlings Antje Finke Hermine Gayum Ursula Rüschendorf Pablo Renner Viveros Verena Moos Kristina Allers Thomas Schneider Ulrich E. Schaible Ralf R. Schumann Martin E. Mielke Ralf Ignatius 《PloS one》2013,8(6)
Background
Bacterial vectors have been proposed as novel vaccine strategies to induce strong cellular immunity. Attenuated strains of Brucella abortus comprise promising vector candidates since they have the potential to induce strong CD4+ and CD8+ T-cell mediated immune responses in the absence of excessive inflammation as observed with other Gram-negative bacteria. However, some Brucella strains interfere with the maturation of dendritic cells (DCs), which is essential for antigen-specific T-cell priming. In the present study, we investigated the interaction of human monocyte-derived DCs with the smooth attenuated B. abortus strain (S) 19, which has previously been employed successfully to vaccinate cattle.Methodology/Principal findings
We first looked into the potential of S19 to hamper the cytokine-induced maturation of DCs; however, infected cells expressed CD25, CD40, CD80, and CD86 to a comparable extent as uninfected, cytokine-matured DCs. Furthermore, S19 activated DCs in the absence of exogeneous stimuli, enhanced the expression of HLA-ABC and HLA-DR, and was able to persist intracellularly without causing cytotoxicity. Thus, DCs provide a cellular niche for persisting brucellae in vivo as a permanent source of antigen. S19-infected DCs produced IL-12/23p40, IL-12p70, and IL-10, but not IL-23. While heat-killed bacteria also activated DCs, soluble mediators were not involved in S19-induced activation of human DCs. HEK 293 transfectants revealed cellular activation by S19 primarily through engagement of Toll-like receptor (TLR)2.Conclusions/Significance
Thus, as an immunological prerequisite for vaccine efficacy, B. abortus S19 potently infects and potently activates (most likely via TLR2) human DCs to produce Th1-promoting cytokines. 相似文献9.
10.
Bangwei Cao Linzhong Zhu Shengtao Zhu Danping Li Chuanzhen Zhang Changqing Xu Shutian Zhang 《Cancer immunology, immunotherapy : CII》2010,59(12):1851-1857
Purpose
T cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3) could weaken the Th1-mediated anti-tumor responses and accelerate the tumor cell proliferation by inhabiting the production of IL-2 or IFN-γ. This study was to assess the association between TIM-3 genetic variations and the development of gastric cancer. 相似文献11.
12.
Complex interactions between effector T cells and Foxp3+ regulatory T cells (Treg) contribute to clinical outcomes in cancer, and autoimmune and infectious diseases. Previous work showed that IL-12 reversed Treg-mediated suppression of CD4+Foxp3− T cell (Tconv) proliferation. We and others have also shown that Tregs express T-bet and IFN-γ at sites of Th1 inflammation and that IL-12 induces IFN-γ production by Tregs in vitro. To investigate whether loss of immunosuppression occurs when IFN-γ is expressed by Tregs we treated mouse lymphocyte cultures with IL-12. IFN-γ expression did not decrease the ability of Tregs to suppress Tconv proliferation. Rather, IL-12 treatment decreased Treg frequency and Foxp3 levels in Tregs. We further showed that IL-12 increased IL-2R expression on Tconv and CD8 T cells, diminished its expression on Tregs and decreased IL-2 production by Tconv and CD8 T cells. Together, these IL-12 mediated changes favored the outgrowth of non-Tregs. Additionally, we showed that treatment with a second cytokine, IL-27, decreased IL-2 expression without augmenting Tconv and CD8 T cell proliferation. Notably, IL-27 only slightly modified levels of IL-2R on non-Treg T cells. Together, these results show that IL-12 has multiple effects that modify the balance between Tregs and non-Tregs and support an important role for relative levels of IL-2R but not for IFN-γ expression in IL-12-mediated reversal of Treg immunosuppression. 相似文献
13.
Aims
Although showing an anti-tumor activity, evodiamine also up-regulated IL-8 production of human gastric cancer AGS cells. This study aimed to assess this effect and to examine whether co-administration with berberine counteracts it.Main methods
MTT assay was used to assess the cell proliferation and adhesive ability. Flow cytometry was performed to measure the cell cycle distribution. Wound healing assay was used to detect the migration ability of cells. IL-8 production was determined by ELISA. Levels of mRNA expression of IL-8, VCAM-1 and ICAM-1 were measured by real-time PCR. Molecular pathways involved were evaluated by ELISA and western-blotting methods.Key findings
Evodiamine triggered proliferative inhibition and cell cycle arrest, and decreased migration of AGS cells. IL-8 expression and the adhesive ability of AGS cells to HUVECs were significantly increased by evodiamine, but were inhibited after being co-treated with berberine in AGS cells. As IL-8 was neutralized, increased adhesion of AGS cells to HUVECs induced by evodiamine was abolished. Berberine significantly suppressed the up-regulation of VCAM-1 and the down-regulation of ICAM-1 induced by evodiamine. Evodiamine provoked IL-8 secretion via ERK1/2, SAPK/JNK, JAK2 and AP-1 pathways which could be counteracted by berberine.Significance
Although showing anti-proliferative and anti-migratory activities in AGS cells, evodiamine displayed a potential tendency to promote metastasis of gastric cancer cells by increasing IL-8 secretion and adhesion molecules. However, berberine could counteract the side-effect and simultaneously keep anti-proliferative and anti-migratory properties of evodiamine on AGS cells, which reduces the risk to use evodiamine in therapy of gastric cancers. 相似文献14.
Sujata Sarkar Laura A Cooney Peter White Deborah B Dunlop Judith Endres Julie M Jorns Matthew J Wasco David A Fox 《Arthritis research & therapy》2009,11(5):R158-15
Introduction
Interleukin (IL)-17 plays an important role in the pathogenesis of rheumatoid arthritis and the mouse model collagen-induced arthritis (CIA). Interferon(IFN)-γ and IL-4 have been shown to suppress Th17 development in vitro, but their potential immunoregulatory roles in vivo are uncertain. The goals of this study were to determine the relationship between Th17 responses and disease severity in CIA and to assess regulation of IL-17 by endogenous IFN-γ and IL-4. 相似文献15.
Sharon H. Chou Aditya V. Shetty Yajun Geng Lipeng Xu Gnanasekar Munirathinam Anne Pipathsouk Isaiah Tan Timothy Morris Bin Wang Aoshuang Chen Guoxing Zheng 《Cancer immunology, immunotherapy : CII》2013,62(3):597-603
Purpose and experimental design
Recombinant human IL-2 (rhIL-2) is a potent cytokine and FDA-approved anticancer drug. However, its clinical use has been limited by severe toxicity, associated primarily with systemic administration with excess protein distributing freely throughout the body. We hypothesized that rhIL-2 in alternate forms permitting more restricted localization may exert stronger antitumor efficacy and less toxicity. Here, we have tested the utility of palmitate-derivatized rhIL-2. rhIL-2 was reacted with N-hydroxysuccinimide palmitate ester. The resultant lipidated rhIL-2 (pIL-2), when mixed with cells, could spontaneously transfer from solution to cell surfaces. Next, anticancer efficacy of pIL-2 was assessed in two modalities. For adoptive T cell therapy, antitumor cytotoxic T cells (CTLs) were protein transferred (“painted”) with pIL-2 and injected into mice bearing lymphoma. For in situ therapy, pIL-2 was injected intratumorally into mice bearing melanoma. Tumor growth and IL-2-associated toxicity were determined.Results
In the lymphoma model, painting of the antitumor CTLs with pIL-2 markedly increased their viability and titer. In the melanoma model, intratumoral injection of pIL-2, but not rhIL-2, increased the number of activated CD8+ T cells (IFN-γ+) in the spleen, reduced lung metastasis and prolonged the survival of treated mice. Moreover, while repeated intratumoral injection of rhIL-2 at an excessively high dose (10 injections of 10,000 IU/mouse) caused marked vascular leakage syndrome, the same regimen using pIL-2 caused no detectable toxicity.Conclusions
Transferring spontaneously from solution to cell surfaces, pIL-2 may bypass the current limitations of rhIL-2 and, thus, serve as a more effective and tolerable anticancer drug. 相似文献16.
Background
Toxic Shock Syndrome (TSS) is characterized by fever, rash, hypotension, constitutional symptoms, and multi-organ involvement and is caused by Staphylococcus aureus enterotoxins such as Staphylococcal Enterotoxin B (SEB). SEB binds to the MHC-IIα chain and is recognized by the TCRβ chain of the Vβ8 TCR+ T cells. The binding of SEB to Vβ chain results in rapid activation of T cells and production of inflammatory cytokines, such as Interleukin-2 (IL-2), Interferon-γ and Tumor Necrosis Factor-α which mediate TSS. Although IL2 was originally identified as the T cell growth factor and was proposed to contribute to T cell differentiation, its role in TSS remains unexplored.Methodology/Principal Findings
Mice were injected with D-Gal (25 mg/mouse). One hour after D-Galactosamine (D-Gal) injection each mouse was injected with SEB (20 µg/mouse. Mice were then observed for 72 hrs and death was recorded at different times. We tested Interleukin-12, IFNγ, and IL-2 deficient mice (IL-2−/−), but only the IL-2 deficient mice were resistant to SEB induced toxic shock syndrome. More importantly reconstitution of IL-2 in IL-2 deficient mice restored the shock. Interestingly, SEB induced IL-2 production from T cells was dependent on p38MAPK activation in macrophages as inhibition of it in macrophages significantly inhibited IL-2 production from T cells.Conclusion
This study shows the importance of IL -2 in TSS which has not been previously explored and it also shows that regulating macrophages function can regulate T cells and TSS. 相似文献17.
Lotte Wieten Suzanne E. Berlo Corlinda B. ten Brink Peter J. van Kooten Mahavir Singh Ruurd van der Zee Tibor T. Glant Femke Broere Willem van Eden 《PloS one》2009,4(1)
Background
The anti-inflammatory capacity of heat shock proteins (HSP) has been demonstrated in various animal models of inflammatory diseases and in patients. However, the mechanisms underlying this anti-inflammatory capacity are poorly understood. Therefore, the possible protective potential of HSP70 and its mechanisms were studied in proteoglycan (PG) induced arthritis (PGIA), a chronic and relapsing, T cell mediated murine model of arthritis.Methodology/Principal Findings
HSP70 immunization, 10 days prior to disease induction with PG, inhibited arthritis both clinically and histologically. In addition, it significantly reduced PG-specific IgG2a but not IgG1 antibody production. Furthermore, IFN-γ and IL-10 production upon in vitro restimulation with HSP70 was indicative of the induction of an HSP70-specific T cell response in HSP70 immunized mice. Remarkably, HSP70 treatment also modulated the PG-specific T cell response, as shown by the increased production of IL-10 and IFN-γ upon in vitro PG restimulation. Moreover, it increased IL-10 mRNA expression in CD4+CD25+ cells. HSP70 vaccination did not suppress arthritis in IL-10−/− mice, indicating the crucial role of IL-10 in the protective effect.Conclusions/Significance
In conclusion, a single mycobacterial HSP70 immunization can suppress inflammation and tissue damage in PGIA and results in an enhanced regulatory response as shown by the antigen-specific IL-10 production. Moreover, HSP70 induced protection is critically IL-10 dependent. 相似文献18.
Naeem K. Patil Liming Luan Julia K. Bohannon Yin Guo Antonio Hernandez Benjamin Fensterheim Edward R. Sherwood 《PloS one》2016,11(2)
Background
Severely burned patients are highly susceptible to opportunistic infections and sepsis, owing to the loss of the protective skin barrier and immunological dysfunction. Interleukin-15 (IL-15) belongs to the IL-2 family of common gamma chain cytokines and stimulates the proliferation and activation of T (specifically memory CD8), NK and NKT cells. It has been shown to preserve T cell function and improve survival during cecal ligation and puncture (CLP)-induced sepsis in mice. However, the therapeutic efficacy of IL-15 or IL-15 superagonist (SA) during infection after burn injury has not been evaluated. Moreover, very few, if any, studies have examined, in detail, the effect of burn injury and infection on the adaptive immune system. Thus, we examined the effect of burn and sepsis on adaptive immune cell populations and the effect of IL-15 SA treatment on the host response to infection.Methods
Mice were subjected to a 35% total body surface area burn, followed by wound infection with Pseudomonas aeruginosa. In some experiments, IL-15 SA was administered after burn injury, but before infection. Leukocytes in spleen, liver and peritoneal cavity were characterized using flow cytometry. Bacterial clearance, organ injury and survival were also assessed.Results
Burn wound infection led to a significant decline in total white blood cell and lymphocyte counts and induced organ injury and sepsis. Burn injury caused decline in CD4+ and CD8+ T cells in the spleen, which was worsened by infection. IL-15 treatment inhibited this decline and significantly increased cell numbers and activation, as determined by CD69 expression, of CD4+, CD8+, B, NK and NKT cells in the spleen and liver after burn injury. However, IL-15 SA treatment failed to prevent burn wound sepsis-induced loss of CD4+, CD8+, B, NK and NKT cells and failed to improve bacterial clearance and survival.Conclusion
Cutaneous burn injury and infection cause significant adaptive immune dysfunction. IL-15 SA does not augment host resistance to burn wound sepsis in mice despite inducing proliferation and activation of lymphocyte subsets. 相似文献19.