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Lorenzo Piemonti,
Matthew J Everly,
Paola Maffi,
Marina Scavini,
Francesca Poli,
Rita Nano,
Massimo Cardillo,
Raffaella Melzi, Alessia Mercalli,
Valeria Sordi,
Vito Lampasona,
Alejandro Espadas de Arias,
Mario Scalamogna,
Emanuele Bosi,
Ezio Bonifacio,
Antonio Secchi,
Paul I Terasaki
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ABSTRACT: Long-term clinical outcome of islet transplantation is hampered by the rejection and recurrence of autoimmunity. Accurate monitoring may allow for early detection and treatment of these potentially compromising immune events. Islet transplant outcome was analyzed in 59 consecutive pancreatic islet recipients in whom baseline and de novo posttransplant autoantibodies (GAD antibody, insulinoma-associated protein 2 antigen, zinc transporter type 8 antigen) and donor-specific allo antibodies (DSA) were quantified. Thirty-nine recipients (66%) showed DSA or autoantibody increases (de novo expression or titer increase) after islet transplantation. Recipients who had a posttransplant antibody increase showed similar initial performance but significantly lower graft survival than patients without an increase (islet autoantibodies P < 0.001, DSA P < 0.001). Posttransplant DSA or autoantibody increases were associated with HLA-DR mismatches (P = 0.008), induction with antithymocyte globulin (P = 0.0001), and pretransplant panel reactive alloantibody >15% in either class I or class II (P = 0.024) as independent risk factors and with rapamycin as protective (P = 0.006) against antibody increases. DSA or autoantibody increases after islet transplantation are important prognostic markers, and their identification could potentially lead to improved islet cell transplant outcomes.
Diabetes 12/2012; · 8.29 Impact Factor
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Rita Nano,
Leda Racanicchi,
Raffaella Melzi, Alessia Mercalli,
Paola Maffi,
Valeria Sordi,
Zhidong Ling,
Marina Scavini,
Olle Korsgren,
Barbara Celona,
Antonio Secchi,
Lorenzo Piemonti
[show abstract]
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ABSTRACT: High levels of donor-derived high-mobility group box-1 protein (HMGB1) have been associated with poor islet graft outcome in a mouse model. The aim of our work was to determine whether HMGB1 released by human islets had independent pro-inflammatory effects that influence engraftment in humans. Human islet preparations contained and released HMGB1 in different amounts, as determined by Western Blot and ELISA (median 17 pg/ml/IEQ/24h; min-max 0-211, n=74). HMGB1 release directly correlated with brain death, donor hyperamilasemia and factors related to the pancreas digestion procedure (collagenase and digestion time). HMGB1 release was significantly positively associated with the release of other cytokines/chemokines, in particular with the highly released "pro inflammatory" CXCL8/IL-8, CXCL1/GRO-α and with the IFNγ inducible chemokines CXCL10/IP-10 and CXCL9/MIG. HMGB1 release was not modulated by Toll Like Receptor-2,-3,-4,-5,-9 agonists or by exposure to IL-1β. When evaluated after islet transplantation, pre-transplant HMGB1 release was weekly associated to the activation of the coagulation cascade (evaluated as serum crosslinked fibrin products), but not with the immediate post transplant inflammatory response. Concordantly, HMGB1 did not impact short-term human islet function. Our data show that human islet HMGB1 release is a sign of "damaged" islets, although without any independent direct role in graft failure.
Cell Transplantation 10/2012; · 5.13 Impact Factor
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Antonio Citro,
Elisa Cantarelli,
Paola Maffi,
Rita Nano,
Raffaella Melzi, Alessia Mercalli,
Erica Dugnani,
Valeria Sordi,
Paola Magistretti,
Luisa Daffonchio,
Pier Adelchi Ruffini,
Marcello Allegretti,
Antonio Secchi,
Ezio Bonifacio,
Lorenzo Piemonti
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ABSTRACT: Although long considered a promising treatment option for type 1 diabetes, pancreatic islet cell transformation has been hindered by immune system rejection of engrafted tissue. The identification of pathways that regulate post-transplant detrimental inflammatory events would improve management and outcome of transplanted patients. Here, we found that CXCR1/2 chemokine receptors and their ligands are crucial negative determinants for islet survival after transplantation. Pancreatic islets released abundant CXCR1/2 ligands (CXCL1 and CXCL8). Accordingly, intrahepatic CXCL1 and circulating CXCL1 and CXCL8 were strongly induced shortly after islet infusion. Genetic and pharmacological blockade of the CXCL1-CXCR1/2 axis in mice improved intrahepatic islet engraftment and reduced intrahepatic recruitment of polymorphonuclear leukocytes and NKT cells after islet infusion. In humans, the CXCR1/2 allosteric inhibitor reparixin improved outcome in a phase 2 randomized, open-label pilot study with a single infusion of allogeneic islets. These findings indicate that the CXCR1/2-mediated pathway is a regulator of islet damage and should be a target for intervention to improve the efficacy of transplantation.
The Journal of clinical investigation 09/2012; 122(10):3647-51. · 15.39 Impact Factor
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ABSTRACT: In this study we examined the effect of rapamycin (RAPA), a key component of the immunosuppressive regimen in clinical islet transplantation, on islet engraftment and function in vivo.
Diabetic C57BL/6 or BALB/C recipient mice were transplanted with 350 syngeneic islets through the portal vein (PV-Tx; C57BL/6 n = 60; BALB/C n = 22) and treated with once-daily oral RAPA (1 mg/kg) or vehicle. No differences in post-transplant blood glucose concentrations and glucose tolerance were observed between RAPA- and vehicle-treated mice. The impact of RAPA on human islet engraftment was assessed in 10 patients with type 1 diabetes treated with : 0.1 mg/kg/day rapamycin before islet transplantation. Compared to non pre-treated islet transplant recipients (n = 12), RAPA pre-treated patients had increased blood RAPA concentrations (p = 0.006) and fasting C-peptide concentrations (p = 0.005) in the two weeks post-transplant. RAPA pre-treatment was associated with a reduction in chemokines CCL2 and CCL3 concentrations pre-transplant (p < 0.01), and a dampened chemokine response (p = 0.005) post-transplant. Concordantly, in vitro RAPA inhibited the secretion of CCL2 and CCL3 by monocytes.
Rapamycin does not adversely affect intrahepatic islet engraftment in the mouse, and potentially improves islet engraftment in humans by an anti-inflammatory mechanism.
Islets 11/2010; 1(1):42-9.
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Valeria Sordi,
Raffaella Melzi, Alessia Mercalli,
Roberta Formicola,
Claudio Doglioni,
Francesca Tiboni,
Giuliana Ferrari,
Rita Nano,
Karolina Chwalek,
Eckhard Lammert,
Ezio Bonifacio,
Danielle Borg,
Lorenzo Piemonti
Stem Cells 02/2010; 28(2):386. · 7.78 Impact Factor
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Raffaella Melzi, Alessia Mercalli,
Valeria Sordi,
Elisa Cantarelli,
Rita Nano,
Paola Maffi,
Giovanni Sitia,
Luca G Guidotti,
Antonio Secchi,
Ezio Bonifacio,
Lorenzo Piemonti
[show abstract]
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ABSTRACT: High levels of donor-derived CCL2 have been associated with poor islet allograft outcome in patients with type 1 diabetes. The aim of our work was to determine whether CCL2 secreted by the islet has independent proinflammatory effects that influence engraftment and graft acceptance. Both in mice and humans CCL2 is significantly positively associated with other cytokines/chemokines, in particular with the highly released "proinflammatory" IL-6 and CXCL8 or CXCL1. Transplantation of CCL2-/- islets into syngenic recipients did not improve the transplant function. Transplantation of islets into CCL2-/- syngenic recipients led to a significant improvement of transplant function and partial abrogation of local hepatic inflammation. When evaluated in human islets CCL2 release was strongly related to the immediate local inflammatory response in the liver and impacted short-term human islet function dependently by the induced inflammatory response and independently by the immunosuppressive therapy. The data showed that islet CCL2 release is a sign of "inflamed" islets without having a direct role in graft failure. On the other hand, a causal effect for developing detrimental proinflammatory conditions after transplant was proved for recipient CCL2. Strategies to selectively decrease recipient, but not donor, CCL2 release may increase the success of islet transplantation.
Cell Transplantation 01/2010; 19(8):1031-46. · 5.13 Impact Factor
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Raffaella Melzi,
Barbara Antonioli, Alessia Mercalli,
Manuela Battaglia,
Andrea Valle,
Stefano Pluchino,
Rossella Galli,
Valeria Sordi,
Emanuele Bosi,
Gianvito Martino,
Ezio Bonifacio,
Claudio Doglioni,
Lorenzo Piemonti
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ABSTRACT: Data available on the immunomodulatory properties of neural stem/precursor cells (NPC) support their possible use as modulators for immune-mediated process. The aim of this study was to define whether NPC administered in combination with pancreatic islets prevents rejection in a fully mismatched allograft model.
Diabetic Balb/c mice were co-transplanted under the kidney capsule with pancreatic islets and GFP(+) NPC from fully mismatched C57BL/6 mice. The following 4 groups of recipients were used: mice receiving islets alone; mice receiving islets alone and treated with standard immunosuppression (IL-2Ralpha chain mAbs + FK506 + Rapamycin); mice receiving a mixed islet/NPC graft under the same kidney capsule (Co-NPC-Tx); mice receiving the islet graft under the left kidney capsule and the NPC graft under the right kidney capsule (NPC-Tx). Our results demonstrate that only the co-transplantation and co-localization of NPC and islets (Co-NPC-Tx) induce stable long-term graft function in the absence of immunosuppression. This condition is associated with an expansion of CD4(+)CD25(+)FoxP3(+) T regulatory cells in the spleen. Unfortunately, stable graft function was accompanied by constant and reproducible development of NPC-derived cancer mainly sustained by insulin secretion.
These data demonstrate that the use of NPC in combination with islets prevents graft rejection in a fully mismatched model. However, the development of NPC-derived cancer raises serious doubts about the safety of using adult stem cells in combination with insulin-producing cells outside the original microenvironment.
PLoS ONE 01/2010; 5(4):e10357. · 4.09 Impact Factor
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Valeria Sordi,
Raffaella Melzi, Alessia Mercalli,
Roberta Formicola,
Claudio Doglioni,
Francesca Tiboni,
Giuliana Ferrari,
Rita Nano,
Karolina Chwalek,
Eckhard Lammert,
Ezio Bonifacio,
Lorenzo Piemonti
[show abstract]
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ABSTRACT: Adherent fibroblast-like cells have been reported to appear in cultures of human endocrine or exocrine pancreatic tissue during attempts to differentiate human β cells from pancreatic precursors. A thorough characterization of these mesenchymal cells has not yet been completed, and there are no conclusive data about their origin.We demonstrated that the human mesenchymal cells outgrowing from cultured human pancreatic endocrine or exocrine tissue are pancreatic mesenchymal stem cells (pMSC) that propagate from contaminating pMSC. The origin of pMSC is partly extrapancreatic both in humans and mice, and by using green fluorescent protein (GFP+) bone marrow transplantation in the mouse model, we were able to demonstrate that these cells derive from the CD45+ component of bone marrow. The pMSC express negligible levels of islet-specific genes both in basal conditions and after serum deprivation or exogenous growth factor exposure, and might not represent optimal candidates for generation of physiologically competent β-cells. On the other hand, when cotransplanted with a minimal pancreatic islet mass, pMSC facilitate the restoration of normoglycemia and the neovascularization of the graft. These results suggest that pMSCs could exert an indirect role of “helper” cells in tissue repair processes. STEM CELLS 2010;28:140–151
Stem Cells 12/2009; 28(1):140 - 151. · 7.78 Impact Factor
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Valeria Sordi,
Raffaella Melzi, Alessia Mercalli,
Roberta Formicola,
Claudio Doglioni,
Francesca Tiboni,
Giuliana Ferrari,
Rita Nano,
Karolina Chwalek,
Eckhard Lammert,
Ezio Bonifacio,
Danielle Borg,
Lorenzo Piemonti
[show abstract]
[hide abstract]
ABSTRACT: Adherent fibroblast-like cells have been reported to appear in cultures of human endocrine or exocrine pancreatic tissue during attempts to differentiate human beta cells from pancreatic precursors. A thorough characterization of these mesenchymal cells has not yet been completed, and there are no conclusive data about their origin.We demonstrated that the human mesenchymal cells outgrowing from cultured human pancreatic endocrine or exocrine tissue are pancreatic mesenchymal stem cells (pMSC) that propagate from contaminating pMSC. The origin of pMSC is partly extrapancreatic both in humans and mice, and by using green fluorescent protein (GFP(+)) bone marrow transplantation in the mouse model, we were able to demonstrate that these cells derive from the CD45(+) component of bone marrow. The pMSC express negligible levels of islet-specific genes both in basal conditions and after serum deprivation or exogenous growth factor exposure, and might not represent optimal candidates for generation of physiologically competent beta-cells. On the other hand, when cotransplanted with a minimal pancreatic islet mass, pMSC facilitate the restoration of normoglycemia and the neovascularization of the graft. These results suggest that pMSCs could exert an indirect role of "helper" cells in tissue repair processes.
Stem Cells 11/2009; 28(1):140-51. · 7.78 Impact Factor
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Elisa Cantarelli,
Raffaella Melzi, Alessia Mercalli,
Valeria Sordi,
Giuliana Ferrari,
Carsten Werner Lederer,
Emanuela Mrak,
Alessandro Rubinacci,
Maurilio Ponzoni,
Giovanni Sitia,
Luca G Guidotti,
Ezio Bonifacio,
Lorenzo Piemonti
[show abstract]
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ABSTRACT: The liver is the current site for pancreatic islet transplantation, but has many drawbacks due to immunologic and nonimmunologic factors. We asked whether pancreatic islets could be engrafted in the bone marrow (BM), an easily accessible and widely distributed transplant site that may lack the limitations seen in the liver. Syngeneic islets engrafted efficiently in the BM of C57BL/6 mice rendered diabetic by streptozocin treatment. For more than 1 year after transplantation, these animals showed parameters of glucose metabolism that were similar to those of nondiabetic mice. Islets in BM had a higher probability to reach euglycemia than islets in liver (2.4-fold increase, P = .02), showed a compact morphology with a conserved ratio between alpha and beta cells, and affected bone structure only very marginally. Islets in BM did not compromise hematopoietic activity, even when it was strongly induced in response to a BM aplasia-inducing infection with lymphocytic choriomeningitis virus. In conclusion, BM is an attractive and safe alternative site for pancreatic islet transplantation. The results of our study open a research line with potentially significant clinical impact, not only for the treatment of diabetes, but also for other diseases amenable to treatment with cellular transplantation.
Blood 09/2009; 114(20):4566-74. · 9.90 Impact Factor
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ABSTRACT: Monocyte chemoattractant protein-1 (MCP-1/CCL2) is a chemokine involved into the pathogenesis of atherosclerosis and has prognostic value in the acute and chronic phases in patients with acute coronary syndromes.
MCP-1/CCL2 concentration was measured in plasma fractions of 363 middle-aged overweight/obese individuals (aged 61 +/- 12 years, BMI 30.1 +/- 6.6 kg/m(2), 15% with type 2 diabetes, and 12% with impaired glucose tolerance) of a population survey carried out in 1990-1991 in Lombardy, Italy (Cremona Study), and cardiovascular disease (CVD) mortality was assessed in 2006 through Regional Health Registry files.
At baseline MCP-1/CCL2 was increased in individuals with type 2 diabetes (P < 0.05) and showed significant correlations with biochemical risk markers of atherosclerosis. After 15 years, among the 363 subjects, there were 82 deaths due to CVD. In univariate analysis age, sex, fasting glucose and insulin, fibrinogen, glucose tolerance status, smoking habit, and MCP-1/CCL2 were associated with CVD mortality. Age, sex, fasting serum glucose, MCP-1/CCL2, and smoking habit maintained an independent association with CVD mortality in multiple regression analysis. In a subgroup of 113 subjects in whom data for C-reactive protein (CRP) were available, its level was not predictive of CVD mortality.
In middle-aged overweight/obese individuals MCP-1/CCL2 was independently associated with CVD mortality. Further studies will be necessary to establish its role as a surrogate biomarker and as a potential therapeutic target.
Diabetes care 07/2009; 32(11):2105-10. · 8.09 Impact Factor
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Valeria Sordi,
Giancarlo Bianchi,
Chiara Buracchi, Alessia Mercalli,
Federica Marchesi,
Giovanna D'Amico,
Cui-Hong Yang,
Walter Luini,
Annunciata Vecchi,
Alberto Mantovani,
Paola Allavena,
Lorenzo Piemonti
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ABSTRACT: Appropriate recruitment of dendritic cells (DC) at sites of inflammation and migration to secondary lymphoid organs is of critical importance for the initiation of Ag-specific immune responses. The proper localization of DC in selected tissues is guided primarily by the coordinated expression of chemokine receptors (CKR). Here we show that immunosuppressive drugs have divergent effects on the modulation of CKR in maturing DC.
Dexamethazone (DEX) and IL-10 inhibited human DC migration to CCL19 in vitro and mouse DC migration to lymph nodes (LN) in vivo, by impairing CCR7 expression. The calcineurin inhibitors cyclosporine A (CsA) and tacrolimus (FK506) were characterized by the inability to modulate CKR expression and migratory activity. Rapamycin (RAPA) increased DC migration to CCL19 in vitro and to LN in vivo by enhancing CCR7 expression. This effect could be mediated, in LPS-maturing DC, by the inhibition of autocrine IL-10 production. The in vivo data obtained with ex vivo RAPA treated DC were confirmed in a model of in vivo drug administration in mice, suggesting a potential clinical relevance.
These findings demonstrate that immunosuppressive agents differently modulate the CKR switch associated with maturing DC; in particular, RAPA selectively up-regulates CCR7 and enhances the migration of differentiated DC to regional LN. This study contributes to a better understanding of the role of immunosuppressive therapy on DC migration, a potentially relevant check point of immunosuppressive treatment.
Transplantation 10/2006; 82(6):826-34. · 4.00 Impact Factor
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Valeria Sordi,
Maria Luisa Malosio,
Federica Marchesi, Alessia Mercalli,
Raffaella Melzi,
Tiziana Giordano,
Nathalie Belmonte,
Giuliana Ferrari,
Biagio Eugenio Leone,
Federico Bertuzzi,
Gianpaolo Zerbini,
Paola Allavena,
Ezio Bonifacio,
Lorenzo Piemonti
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ABSTRACT: Bone marrow-derived mesenchymal stem cells (BM-MSCs) are stromal cells with the ability to proliferate and differentiate into many tissues. Although they represent powerful tools for several therapeutic settings, mechanisms regulating their migration to peripheral tissues are still unknown. Here, we report chemokine receptor expression on human BM-MSCs and their role in mediating migration to tissues. A minority of BM-MSCs (2% to 25%) expressed a restricted set of chemokine receptors (CXC receptor 4 [CXCR4], CX3C receptor 1 [CX3CR1], CXCR6, CC chemokine receptor 1 [CCR1], CCR7) and, accordingly, showed appreciable chemotactic migration in response to the chemokines CXC ligand 12 (CXCL12), CX3CL1, CXCL16, CC chemokine ligand 3 (CCL3), and CCL19. Using human pancreatic islets as an in vitro model of peripheral tissue, we showed that islet supernatants released factors able to attract BM-MSCs in vitro, and this attraction was principally mediated by CX3CL1 and CXCL12. Moreover, cells with features of BM-MSCs were detected within the pancreatic islets of mice injected with green fluorescent protein (GFP)-positive BM. A population of bona fide MSCs that also expressed CXCR4, CXCR6, CCR1, and CCR7 could be isolated from normal adult human pancreas. This study defines the chemokine receptor repertoire of human BM-MSCs that determines their migratory activity. Modulation of homing capacity may be instrumental for harnessing the therapeutic potential of BM-MSCs.
Blood 08/2005; 106(2):419-27. · 9.90 Impact Factor
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ABSTRACT: There are a large number of stable pancreatic ductal carcinoma cell lines (PDCL) that are used by researchers worldwide. Detailed data about their differentiation status and genetic alterations are present in the literature, but a systematic correlation with cell biological behavior is often lacking. PDCL ( n=12) were clustered by source of tumor cell (ascites, primary tumor, metastasis), and the data of functional cell biology were correlated with the reported structural and genetic profiles. Major histocompatibility complex expression, chemosensitivity and aneuploidia appeared to be related to the source of PDCL, and proliferative capacity appeared to be related to the grade of differentiation. No correlation between genetic/structural features of PDCL and biological behavior was found. All the cell lines appeared generally insensitive to in vitro treatment with 5-fluorouracil and showed variable degrees of susceptibility to gemcitabine, raltitrexed and oxaliplatin. All the PDCL showed resistance to Fas-mediated apoptosis but were significantly sensitive to the pro-apoptotic effect of inflammatory cytokines [interleukin (IL)-1beta, tumor necrosis factor (TNF)alpha and interferon gamma]. PDCL were characterized for the secretion of several factors relevant to the tumor-immune cross talk. Vascular endothelial growth factor, CCL2, CCL5 and transforming growth factor beta were the factors most frequently released; less frequent was the secretion of CXCL8, CCL22, IL-6 and sporadically CXCL12, IL-10 and hepatocyte growth factor. The cytokines IL-1beta and TNFalpha were always undetectable. In conclusion, a clear correlation between structural/genetic features and function could not be detected, suggesting the weakness of a "morphological" classification for the in vitro studies of pancreatic cancer.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 10/2004; 445(3):236-47. · 2.49 Impact Factor
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Paolo Monti,
Biagio Eugenio Leone,
Alessandro Zerbi,
Gianpaolo Balzano,
Silvia Cainarca,
Valeria Sordi,
Marina Pontillo, Alessia Mercalli,
Valerio Di Carlo,
Paola Allavena,
Lorenzo Piemonti
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ABSTRACT: Dendritic cells (DC) initiate immunity by the activation of naive T cells and control immunity through their ability to induce unresponsiveness of lymphocytes by mechanisms that include deletion and induction of regulatory cells. An inadequate presentation to T cells by tumor-induced "regulatory" DC, among several mechanisms, can explain tolerance to tumor-associated Ags. In this study, we show that tumor-derived mucin profoundly affects the cytokine repertoire of monocyte-derived DC and switch them into IL-10(high)IL-12(low) regulatory APCs with a limited capacity to trigger protective Th1 responses. In fact, DC cocultured with pancreatic tumor cell lines in a Transwell system did not reach full maturation, had low immunostimulatory functions, did not produce IL-12, and released high levels of IL-10. The involvement of known tumor-derived immune-suppressive factors (e.g., vascular endothelial growth factor, TGF-beta, IL-6, and IL-10) was considered and excluded. We provide evidence that tumor-derived MUC1 mucins are responsible for the impaired DC maturation and function. DC obtained in the presence of tumor microenvironment preferentially polarized IL-4(+) response. Moreover, T cells primed by these regulatory DC became anergic and behaved as suppressor/regulatory cells. These findings identify mucin secretion as a novel mechanism of tumor escape from immune surveillance and provide the basis for the generation of potentially tolerogenic DC.
The Journal of Immunology 07/2004; 172(12):7341-9. · 5.79 Impact Factor
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ABSTRACT: Leptin and tumor necrosis factor (TNF)-alpha are associated with insulin resistance and cardiovascular disease. In vitro studies suggested that these effects may be mediated via overproduction of monocyte chemoattracting protein (MCP)-1/CCL2, which is a chemokine involved in the pathogenesis of atherosclerosis.
In this study, fasting plasma leptin, soluble TNF-alpha receptor 2 (TNF-alpha-R2), and MCP-1/CCL2 concentrations were measured in 207 middle-aged women (age 61 +/- 12 years, BMI 30.1 +/- 6.6 kg/m(2)), including 53 patients with type 2 diabetes, 42 with impaired glucose tolerance, and 112 with normal glucose tolerance, to assess cross-sectionally their relationship with markers of atherosclerosis and, longitudinally over 7 years, whether their circulating levels were associated with cardiovascular disease (CVD) mortality.
At baseline, leptin and TNF-alpha-R2 were not different among groups; meanwhile, MCP-1/CCL2 was increased in type 2 diabetes (P < 0.05). All showed significant associations with biochemical risk markers of atherosclerosis. In a univariate analysis, age, fasting insulin, leptin, and MCP-1/CCL2 were associated with CVD mortality at 7 years. When a multivariate analysis was performed, only age, leptin, and insulin retained an independent association with CVD mortality, with leptin showing a protective effect (hazard ratio 0.88; P < 0.02).
In middle-aged women, MCP-1/CCL2, leptin, and TNF-alpha-R2 were all related to biochemical risk markers of atherosclerosis. MCP-1/CCL2 concentration was the only one to be increased in type 2 diabetes with respect to nondiabetic women and the only one to be associated with increased risk of CVD mortality after a 7-year follow-up period in the univariate analysis. In the multivariate analysis, neither MCP-1/CCL2 nor TNF-alpha-R2 was associated with CVD mortality, and inspection of the data showed that leptin, in both the univariate and multivariate analysis, was associated with a protective effect.
Diabetes Care 10/2003; 26(10):2883-9. · 8.09 Impact Factor
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ABSTRACT: Rapamycin is a recently introduced immunosuppressive agent. Its effect on lymphocytes has been extensively studied. Whether it can also modulate dendritic cell (DC) function is unknown.
The effect of rapamycin on differentiation, antigen uptake, and the immunostimulatory capacity of human DC was examined. DC were derived from monocytes upon culture with interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor in the presence or absence of rapamycin (0.1-100 ng/mL). Surface phenotype and antigen uptake capacity of DC were assessed by flow cytometry. Immunostimulatory capacity was measured by mixed lymphocyte culture.
Rapamycin reduced DC recovery and increased DC apoptosis. DC differentiated in the presence of rapamycin (rapa-DC) had increased expression of CD1a, CD1b, and CD1c and decreased expression of MHC I, MHC II, CD80, CD86, and CD40. Antigen uptake receptor expression (mannose receptor, CD32, CD91, CD46) was decreased, and receptor-mediated endocytosis of fluorescein isothiocyanate-dextran was markedly impaired in rapa-DC, as were fluid phase endocytosis of Lucipher Yellow and phagocytic activity of bacteria and dead or apoptotic cells. CD40 ligand-induced production of both IL-12 and IL-10 was reduced in rapa-DC, and allogeneic T lymphocyte responses were moderately impaired when rapa-DC were used as stimulator cells. Neither cyclosporine nor FK506 affected DC function. However, the effects of rapamycin on DC could be completely inhibited by a 10-fold excess of FK506 but not by up to 100-fold excess of cyclosporine.
Rapamycin has a unique and profound inhibitory effect on DC function, which seems to be at least in part mediated by the FKBP immunophilins.
Transplantation 02/2003; 75(1):137-45. · 4.00 Impact Factor
