Citations of BMS820FF

Surfactant-free anionic PLA nanoparticles coated with HIV-1 p24 protein induced enhanced cellular and humoral immune responses in various animal models
Ataman-Önal,Y.; Munier,S.; Ganee,A.; Terrat,C.; Durand,P.Y.; Battail,N.; Martinon,F.; Le,Grand R.; Charles,M.H.; Delair,T.; Verrier,B.

J Control Release 2006;112:175-185.
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Abstract
Microparticles and nanoparticles prepared with poly(D,L-lactide-co-glycolide) (PLGA) or poly(D,L-lactide) (PLA) polymers represent a promising method for in vivo delivery of encapsulated peptide, protein or DNA antigens. However, one major issue that limits the potential of these delivery systems is the instability or the degradation of the entrapped antigen. Charged microparticles carrying surface adsorbed antigen were developed to resolve this problem and appear more suitable for vaccine applications. We describe here new anionic PLA nanoparticles obtained by the dialysis method that are absolutely surfactant-free, which makes them more appropriate for use in humans. The potency of this delivery system as a vaccine carrier was tested in various animal models using HIV-1 p24 protein. p24-coated PLA nanoparticles (p24/PLA) induced high antibody titres (>10(6)) in mice, rabbits and macaques. Moreover, p24/PLA nanoparticles elicited strong CTL responses and a Th1-biased cytokine release (IFNgamma, IL-2) in mice. p24 protein seemed to generate a more Th1-oriented response when administered coated onto the surface of PLA nanoparticles than adjuvanted with Freund's adjuvant. Most importantly, the ability of p24/PLA particles to induce Th1 responses was also confirmed in the macaque model, since high levels of IFNgamma-producing CD4+ T cells and CD8+ T cells could be detected by the ELISPOT assay. This protein delivery system confirms the potential of charged nanoparticles in the field of vaccine development

1326

Generation of hypoallergenic DNA vaccines by forced ubiquitination: Preventive and therapeutic effects in a mouse model..
Bauer,R.; Scheiblhofer,S.; Kern,K.; Gruber,C.; Stepanoska,T.; Thalhamer,T.; Hauser-Kronberger,C.; Alinger,B.; Zoegg,T.; Gabler,M.

The Journal of Allergy and Clinical Immunology 2006;118:269-276.
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Abstract
Background Hypoallergenic immunotherapy of type I allergies aims at inducing T-cell immunity while avoiding cross-linking of pre-existing IgE. DNA-based immunotherapy depends on the recruitment of antigen-specific TH1 cells and therefore has to provide the whole repertoire of T-cell epitopes. Ubiquitination offers a general approach for the production of hypoallergenic DNA vaccines. Objective A DNA-based vaccine encoding the major birch pollen allergen Bet v 1 stably linked to ubiquitin was evaluated for its antiallergic potential in a BALB/c mouse model of allergy. Methods Plasmid DNA was applied to mice before (preventive) or after (therapeutic) sensitization with recombinant Bet v 1. In the preventive setting, mice were exposed to aerosolized allergen in addition. Cytokine production was monitored via ELISPOT and Luminex. IgG1, IgG2a, and IgE subclass antibody titers were determined by ELISA. In vitro antigen-specific cross-linking of IgE was measured in a degranulation assay. Bronchoalveolar lavages were analyzed for leukocyte subsets as well as for IFN-? and IL-5, and paraffin sections of lungs were examined for mucus production and endothelial damage. Results Prevaccination with ubiquitinated Bet v 1-stimulated TH1-biased immune responses with concomitant suppression of functional IgE, reduction of eosinophil counts in bronchoalveolar lavages, and alleviation of lung pathology, and could also suppress an ongoing IgE response in a therapeutic setting. Conclusion The data clearly demonstrate that hypoallergenic DNA vaccines encoding ubiquitin fusion constructs induce effective antiallergic immune responses. Clinical implications Ubiquitination of allergen gene vaccines eliminates the risk of IgE cross-linking, thereby meeting the safety requirements for clinical applications.

900

Anti-IL-10R antibody improves the therapeutic efficacy of targeted liposomal oligonucleotides
Brignole,C.; Marimpietri,D.; Pastorino,F.; Di,Paolo D.; Pagnan,G.; Loi,M.; Piccardi,F.; Cilli,M.; Tradori-Cappai,A.; Arrigoni,G.; Pistoia,V.; Ponzoni,M.

J Control Release 2009;› Link

Abstract
High-risk Neuroblastoma (NB) has still a poor prognosis. Liposomes targeted to NB cells and encapsulating antisense CpG-containing oligonucleotides (TL-asCpG) had increased anti-tumour efficacy in NB xenografts compared to free asCpG. Interleukin 10 (IL-10) suppresses antigen presenting cell activation contributing to tumour-mediated immune suppression. In principle, combination of TL-asCpG and antibodies against IL-10 receptor (aIL-10R) could prolong immune system activation, leading to better therapeutic results. Mice treated with TL-asCpG 4 h after human NB cell inoculation survived significantly longer than controls. An increased life span was achieved also in mice receiving TL-asCpG 24 and 72 h after NB cell challenge. The addition of aIL-10R to TL-asCpG in the 4-h protocol significantly increased the percentage of long term survivors compared to TL-asCpG only. Surviving mice treated with the combined strategy were completely cured. In contrast, long term surviving mice treated only with TL-asCpG presented lymph node infiltration with NB cells. TL-asCpG plus aIL-10R treatment was significantly superior to TL-asCpG alone also for the 24-h protocol. Ex vivo experiments demonstrated that the combined therapy evoked a stronger and more prolonged immune system activation compared to monotherapy. These results support the feasibility of a clinical trial with TL-asCpG and aIL-10R in advanced NB patients

2560

The Adaptor Protein CIKS/Act1 Is Essential for IL-25-Mediated Allergic Airway Inflammation
Claudio,Estefania; Sonder,Soren Ulrik; Saret,Sun; Carvalho,Gabrielle; Ramalingam,Thirumalai R.; Wynn,Thomas A.; Chariot,Alain; Garcia-Perganeda,Antonio; Leonardi,Antonio; Paun,Andrea; Chen,Amy; Ren,Nina Y.; Wang,Hongshan; Siebenlist,Ulrich

The Journal of Immunology 2009;182:1617-1630.
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Abstract
IL-17 is the signature cytokine of recently discovered Th type 17 (Th17) cells, which are prominent in defense against extracellular bacteria and fungi as well as in autoimmune diseases, such as rheumatoid arthritis and experimental autoimmune encephalomyelitis in animal models. IL-25 is a member of the IL-17 family of cytokines, but has been associated with Th2 responses instead and may negatively cross-regulate Th17/IL-17 responses. IL-25 can initiate an allergic asthma-like inflammation in the airways, which includes recruitment of eosinophils, mucus hypersecretion, Th2 cytokine production, and airways hyperreactivity. We demonstrate that these effects of IL-25 are entirely dependent on the adaptor protein CIKS (also known as Act1). Surprisingly, this adaptor is necessary to transmit IL-17 signals as well, despite the very distinct biologic responses that these two cytokines elicit. We identify CD11c+ macrophage-like lung cells as physiologic relevant targets of IL-25 in vivo

2365

Enhancement of DNA vaccine potency through linkage of antigen to filamentous bacteriophage coat protein III domain I
Cuesta,Angel M.; Suarez,Eduardo; Larsen,Martin; Jensen,Kim Bak; Sanz,Laura; Compte,Marta; Kristensen,Peter; varez-Vallina,Luis

Immunology 2006;117:502-506.
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Abstract
Summary Although DNA-based cancer vaccines have been successfully tested in mouse models, a major drawback of cancer vaccination still remains, namely that tumour antigens are weak and fail to generate a vigorous immune response in tumour-bearing patients. Genetic technology offers strategies for promoting immune pathways by adding immune-activating genes to the tumour antigen sequence. In this work, we converted a model non-immunogenic antigen into a vaccine by fusing it to domain I of the filamentous bacteriophage coat protein III gene. Vaccination with a DNA construct encoding the domain I fusion generated antigen-specific T helper 1-type cellular immune responses. These results demonstrate that the incorporation of protein III into a DNA vaccine formulation can modulate the gene-mediated immune response and may thus provide a strategy for improving its therapeutic effect

1352

Congenic Analysis of the NKT Cell Control Gene Nkt2 Implicates the Peroxisomal Protein Pxmp4
Fletcher,Julie M.; Jordan,Margaret A.; Snelgrove,Sarah L.; Slattery,Robyn M.; Dufour,Francois D.; Kyparissoudis,Konstantinos; Besra,Gurdyal S.; Godfrey,Dale I.; Baxter,Alan G.

The Journal of Immunology 2008;181:3400-3412.
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Abstract
Type 1 NKT cells play a critical role in controlling the strength and character of adaptive and innate immune responses. We have previously reported deficiencies in the numbers and function of NKT cells in the NOD mouse strain, which is a well-validated model of type 1 diabetes and systemic lupus erythematosus. Genetic control of thymic NKT cell numbers was mapped to two linkage regions: Nkt1 on distal chromosome 1 and Nkt2 on chromosome 2. Herein, we report the production and characterization of a NOD.Nkrp1b.Nkt2bb congenic mouse strain, which has increased thymic and peripheral NKT cells, a decreased incidence of type 1 diabetes, and enhanced cytokine responses in vivo and increased proliferative responses in vitro following challenge with {alpha}-galactosylceramide. The 19 highly differentially expressed candidate genes within the congenic region identified by microarray expression analyses included Pxmp4. This gene encodes a peroxisome-associated integral membrane protein whose only known binding partner is Pex19, an intracellular chaperone and component of the peroxisomal membrane insertion machinery encoded by a candidate for the NKT cell control gene Nkt1. These findings raise the possibility that peroxisomes play a role in modulating glycolipid availability for CD1d presentation, thereby influencing NKT cell function

2304

Differential Clearance and Immune Responses to Tick Cell vs. Macrophage Culture-Derived Ehrlichia chaffeensis in Mice
Ganta,Roman R.; Cheng,Chuanmin; Miller,Elizabeth C.; McGuire,Bridget L.; Peddireddi,Lalitha; Sirigireddy,Kamesh R.; Chapes,Stephen K.

Infection and Immunity 2006;75:135-145.
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Abstract
Human monocytic ehrlichiosis is caused by the tick transmitted rickettsia, Ehrlichia chaffeensis. We recently reported that E. chaffeensis grown in tick cells expresses different proteins than the bacteria grown in macrophages. Therefore, we tested the hypothesis that immune responses against E. chaffeensis would be different if mice are challenged with bacteria grown in macrophages or tick cells. We assessed the E. chaffeensis clearance from the peritoneum, spleen, and liver by C57BL/6J mice using a TaqMan-based real time RT-PCR assay. Macrophage-grown E. chaffeensis was cleared in two weeks from the peritoneum, whereas the pathogen from tick cells persisted for nine additional days and included three relapses of increasing bacterial load separated by three-day intervals. Tick cell-grown bacteria also persisted in the liver and spleen with higher bacterial loads compared to macrophage-grown bacteria and fluctuated over a period of 35 days. Three-day periodic cycles were detected in T-cell CD62L:CD44 ratios in the spleen and bone marrow in response to infections with both tick cell- and macrophage-grown bacteria and were accompanied by similar periodic cycles of spleen cell cytokine secretions, and nitric oxide and IL-6 by peritoneal macrophages. The E. chaffeensis-specific IgG response was considerably higher and steadily increased in mice infected with the tick cell-derived E. chaffeensis compared to DH82-grown bacteria. In addition, antigens detected by the immunoglobulins were significantly different between mice infected with the E. chaffeensis originating from tick cell or macrophage. The differences in the immune response to tick cell-grown bacteria compared to macrophage -grown bacteria reflected a delay in the shift of gene expression from tick cell-specific Omp 14 gene to macrophage-specific Omp 19 gene. These data suggest that the host response to E. chaffeensis depends on the source of the bacteria and that this experimental model requires the most natural inoculum possible to allow for a realistic understanding of host resistance

713

Targeting of the transcription factor STAT4 by antisense phosphorothioate oligonucleotides suppresses collagen-induced arthritis
Hildner,K.M.; Schirmacher,P.; Atreya,I.; Dittmayer,M.; Bartsch,B.; Galle,P.R.; Wirtz,S.; Neurath,M.F.

J Immunol 2007;178:3427-3436.
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Abstract
The transcription factor STAT4 mediates signals of various proinflammatory cytokines, such as IL-12, IL-15, and IL-23, that initiate and stabilize Th1 cytokine production. Although Th1 cytokine production has been suggested to play a major pathogenic role in rheumatoid arthritis, the role of STAT4 in this disease is poorly understood. In this study, we demonstrate a key functional role of STAT4 in murine collagen-induced arthritis (CIA). In initial studies we found that STAT4 expression is strongly induced in CD4(+) T cells and to a lesser extent in CD11b(+) APCs during CIA. To analyze the role of STAT4 for arthritis manifestation, we next investigated the outcome of interfering with STAT4 gene expression in CIA by using STAT4-deficient mice. Interestingly, STAT4-deficient mice developed significantly less severe arthritis than wild-type control mice and the T cells from such mice produced less IL-6, TNF, and IL-17. In addition, the targeting of STAT4 expression by a specific antisense phosphorothioate oligonucleotide directed at the translation start site suppressed STAT4 levels and signs of CIA even when applied during the onset of disease manifestation. These data suggest a key regulatory role of STAT4 in the pathogenesis and manifestation of murine collagen-induced arthritis. Furthermore, the targeting of STAT4 emerges as a novel approach to therapy for chronic arthritis

1319

RORgamma expressing Th17 cells drive chronic intestinal inflammation via redundant effects of IL-17A and IL-17F
Leppkes,Moritz; Becker,Christoph; Ivanov,Ivaylo I.; Hirth,Sebastian; Wirtz,Stefan; Neufert,Clemens; Pouly,Sandrine; Murphy,Andrew J.; Valenzuela,David M.; Yancopoulos,George D.; Becher,Burkhard; Littman,Dan R.; Neurath,Markus F.

Gastroenterology 2009;136:257-267.
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Abstract
Background and AimsIL-17-producing CD4+ T-helper cells (Th17) contribute to chronic autoimmune inflammation in the brain, and levels of Th17-derived cytokines increase in patients with colitis, suggesting a role in pathogenesis. We analyzed the roles of Th17 cells and the transcription factor retinoic acid receptor-related organ receptor (ROR)?, which regulates Th17 differentiation, in chronic intestinal inflammation.MethodsUsing an adoptive transfer model of colitis, we compared the colitogenic potential of wild-type, interleukin-17A (IL-17A)-, IL-17F-, IL-22-, and ROR?-deficient CD4+CD25- T cells in RAG1-null mice.ResultsAdoptive transfer of IL-17A-, IL-17F-, or IL-22-deficient T lymphocytes into RAG1-null mice caused severe colitis that was indistinguishable from that caused by wild-type cells. In contrast, transfer of ROR?-null T cells failed to increase mucosal IL-17 cytokine levels and did not induce colitis. Treatment with IL-17A was able to restore colitis after transfer of ROR?-null T cells, indicating a crucial role for Th17 cells in pathogenesis. Treatment of RAG1 mice that received IL-17F-null (but not wild-type) T cells with a neutralizing anti-IL-17A antibody significantly suppressed disease, indicating redundant biological effects of IL-17A and IL-17F.ConclusionsWe have identified a crucial role of ROR?-expressing Th17 cells in chronic intestinal inflammation. ROR? controls IL-17A and IL-17F production, and these cytokines have a redundant but highly pathogenic role in gut inflammation. Reagents that target ROR? or a combination of anti-IL-17A and anti-IL-17F might be developed as therapeutics for chronic colitis.

1942

p47phox Deficiency Induces Macrophage Dysfunction Resulting in Progressive Crystalline Macrophage Pneumonia
Liu,Qi; Cheng,Lily I.; Yi,Liang; Zhu,Nannan; Wood,Adam; Changpriroa,Cattlena May; Ward,Jerrold M.; Jackson,Sharon H.

American Journal of Pathology 2009;174:153-163.
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Abstract
Nicotinamide dinucleotide phosphate oxidase-deficient (p47phox-/-) mice are a model of human chronic granulomatous disease; these mice are prone to develop systemic infections and inflammatory diseases. The use of antibiotic (Bactrim) prophylaxis in a specific pathogen-free environment, however, impedes infection in the majority of p47phox-/- mice. We examined infection-free p47phox-/- mice between 1 and 14 months of age and found that they developed proliferative macrophage lesions containing Ym1/Ym2 protein and crystals in lung, bone marrow, lymph nodes, and spleen. Here, we show that the lung lesions progressed from single macrophages with intracellular Ym1/Ym2 protein crystals to severe diffuse crystalline macrophage pneumonia without histological evidence of either granulation tissue or pulmonary fibrosis. Ym1/Ym2 is a chitinase-like secretory protein that is transiently induced in alternatively activated macrophages during T-helper (Th)2-biased pathogenesis and during chemical and traumatic inflammation. Bronchoalveolar lavage from p47phox-/- mice contained significantly higher levels of Th-1 (interferon-{gamma}), Th-2 (interleukin-4), and Th-17 (interleukin-17)-associated cytokines than wild-type mice, as well as copious amounts of interleukin-12, indicating that Ym1-secreting p47phox-/- macrophages are also integrated into classically activated macrophage responses. These results suggest that p47phox-/- macrophages are extremely pliable, due in part to an intrinsic dysfunction of macrophage activation pathways that allows for distinct classical or alternative activation phenotypes

2384

IL-10 Controls Ultraviolet-Induced Carcinogenesis in Mice
Loser,Karin; Apelt,Jenny; Voskort,Maik; Mohaupt,Mariette; Balkow,Sandra; Schwarz,Thomas; Grabbe,Stephan; Beissert,Stefan

The Journal of Immunology 2007;179:365-371.
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Abstract
UV radiation-induced immunosuppression contributes significantly to the development of UV-induced skin cancer by inhibiting protective immune responses. IL-10 has been shown to be a key mediator of UV-induced immunosuppression. To investigate the role of IL-10 during photocarcinogenesis, groups of IL-10+/+, IL-10+/-, and IL-10-/- mice were chronically irradiated with UV. IL-10+/+ and IL-10+/- mice developed skin cancer to similar extents, whereas IL-10-/- mice were protected against the induction of skin malignancies by UV. Because UV is able to induce regulatory T cells, which play a role in the suppression of protective immunity, UV-induced regulatory T cell function was analyzed. Splenic regulatory T cells from UV-irradiated IL-10-/- mice were unable to confer immunosuppression upon transfer into naive recipients. UV-induced CD4+CD25+ T cells from IL-10-/- mice showed impaired suppressor function when cocultured with conventional CD4+CD25- T cells. CD4+CD25- T cells from IL-10-/- mice produced increased amounts of IFN-{gamma} and enhanced numbers of CD4+TIM-3+ T cells were detectable within UV-induced tumors in IL-10-/- mice, suggesting strong Th1-drived immunity. Mice treated with CD8+ T cells from UV-irradiated IL-10-/- mice rejected a UV tumor challenge significantly faster, and augmented numbers of granzyme A+ cells were detected within injected UV tumors in IL-10-/- animals, suggesting marked antitumoral CTL responses. Together, these findings indicate that IL-10 is critically involved in antitumoral immunity during photocarcinogenesis. Moreover, these results point out the crucial role of Th1 responses and UV-induced regulatory T cell function in the protection against UV-induced tumor development

831

Murine mast cells secrete a unique profile of cytokines and prostaglandins in response to distinct TLR2 ligands
Mrabet-Dahbi,S.; Metz,M.; Dudeck,A.; Zuberbier,T.; Maurer,M.

Exp.Dermatol. 2009;18:437-444.
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Abstract
Mast cells (MCs) are important effector cells in host defense against bacteria. In the course of a bacterial infection, MCs can be activated by various mechanisms, i.e. bacterial toxins, endogenously produced infection-associated peptides or via complement receptors, fimbrial adhesion molecules and toll-like receptors (TLRs). While some of these mechanisms are well established, the effects of TLR2 ligand-driven MC activation are far less understood. Here, we show that murine mature connective tissue-type MCs, but not immature bone marrow-derived cultured mast cells, express significant amounts of full length TLR2 on their surface. Activation by various TLR2 ligands only induces the selective release of cytokines in peritoneum-derived cultured mast cells (PCMCs) with preferential secretion of pro-inflammatory cytokines (IL-6 > IL-17 > IFN-gamma TNF > IL-1 > GM-CSF) upon stimulation with lipoteichoic acid (LTA). This response is much lower in PCMCs stimulated with the TLR2/6 agonist macrophage-activating lipopeptide-2 (MALP-2), which most prominently triggers the release of the immunomodulatory cytokine IL-10. Furthermore, only LTA but not MALP-2 induces prostaglandin D2 secretion which is again restricted to the mature MC phenotype. These findings suggest that TLR2 ligand-mediated activation of mature MCs, i.e. tissue-residing cells, which most likely occurs during infection, can selectively raise a potent inflammatory or anti-inflammatory response, depending on TLRs which are engaged

2720

Cutting Edge: Th1 Cells Facilitate the Entry of Th17 Cells to the Central Nervous System during Experimental Autoimmune Encephalomyelitis
O'Connor,Richard A.; Prendergast,Catriona T.; Sabatos,Catherine A.; Lau,Clement W.Z.; Leech,Melanie D.; Wraith,David C.; Anderton,Stephen M.

The Journal of Immunology 2008;181:3750-3754.
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Abstract
It has recently been proposed that experimental autoimmune encephalomyelitis, once considered the classical Th1 disease, is predominantly Th17 driven. In this study we show that myelin-reactive Th1 preparations devoid of contaminating IL-17+ cells are highly pathogenic. In contrast, Th17 preparations lacking IFN-{gamma}+ cells do not cause disease. Our key observation is that only Th1 cells can access the noninflamed CNS. Once Th1 cells establish the experimental autoimmune encephalomyelitis lesion, Th17 cells appear in the CNS. These data shed important new light on the ability of Th1 vs Th17 cells to access inflamed vs normal tissue. Because the IL-17-triggered release of chemokines by stromal cells could attract many other immune cells, allowing Th17 cells to access the tissues only under conditions of inflammation may be a key process limiting (auto)immune pathology. This has major implications for the design of therapeutic interventions, many of which are now aiming at Th17 rather than Th1 cells

2410

Patterns of interstitial inflammation during the evolution of renal injury in experimental aristolochic acid nephropathy
Pozdzik,A.A.; Salmon,I.J.; Husson,C.P.; Decaestecker,C.; Rogier,E.; Bourgeade,M.F.; schodt-Lanckman,M.M.; Vanherweghem,J.L.; Nortier,J.L.

Nephrol.Dial.Transplant 2008;23:2480-2491.
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Abstract
BACKGROUND: Interstitial inflammation is a prominent feature associated with the severity of renal injury and progressive kidney failure. We utilized an animal model of aristolochic acid (AA)-induced nephropathy (AAN) to assess patterns of infiltration and inflammation during the evolution of tubulointerstitial damage and to relate them to the development of fibrosis. METHODS: Male Wistar rats receiving sc daily AA or vehicle were sacrificed between Days 1 and 35. Infiltrating mononuclear cells were characterized by immunohistochemistry. The kidney infiltrating T lymphocytes were phenotyped by flow cytometry. Urinary levels of Th-1/ Th-2 cytokines, of monocyte chemoattractant protein-1 and of active transforming growth factor-beta (TGF-beta) were measured. Tissue expression of phosphorylated smad 2/3 protein was used to examine the TGF-beta signalling pathway. RESULTS: In AA rats, monocytes/macrophages and T lymphocytes predominantly infiltrated areas of necrotic proximal tubular cells. The coexpressions of ED1 and/or Ki-67/MHCII by infiltrating cells reflected monocyte/macrophage proliferation and their activation, respectively. The accumulation of cytotoxic T lymphocytes was attested by severe signs of CD8+ cell tubulitis. The CD8/E-cadherin costaining confirmed intrarenal homing of CD8+CD103+ cells. Urinary levels of proinflammatory cytokines and of active TGF-beta significantly increased at Days 10 and 35. An early and persistent nuclear overexpression of phosphorylated smad 2/3 protein was detected in tubular and interstitial compartments. CONCLUSION: An early and massive interstitial inflammation characterized by activated monocytes/macrophages and cytotoxic CD8+CD103+ T lymphocytes is demonstrated for the first time during the progression of experimental AAN. The involvement in an interstitial fibrosis onset of active TGF-beta is highly suggested, at least via the psmad 2/3 intracellular signalling pathway

1315

Coexpression of TGF-{beta}1 and IL-10 Enables Regulatory T Cells to Completely Suppress Airway Hyperreactivity
Presser,Katrin; Schwinge,Dorothee; Wegmann,Michael; Huber,Samuel; Schmitt,Steffen; Quaas,Alexander; Maxeiner,Joachim H.; Finotto,Susetta; Lohse,Ansgar W.; Blessing,Manfred; Schramm,Christoph

The Journal of Immunology 2008;181:7751-7758.
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Abstract
In allergic airway disease, Treg may play an important role in the modulation of airway hyperreactivity (AHR) and inflammation. We therefore investigated the therapeutic potential of Treg in an Ag-dependent murine asthma model. We here describe that AHR can be completely suppressed by adoptive transfer of Treg overexpressing active TGF-{beta}1. Using mice with impaired TGF-{beta} signaling in T cells, we could demonstrate that TGF-{beta} signaling in recipient effector T cells or transferred Treg themselves is not required for the protective effects on AHR. However, the expression of IL-10 by Treg was found to be essential for the suppression of AHR, since Treg overexpressing active TGF-{beta}1 but deficient in IL-10 lacked protective effects. Airway inflammation could not be significantly suppressed by wild-type or transgenic Treg. In conclusion, modulation of cytokine expression by Treg may have therapeutic potential for the treatment of AHR in asthma. The mechanisms of the effects of Treg on airway inflammation require further clarification

2528

The B Subunit of Escherichia coli Heat-Labile Enterotoxin Inhibits Th1 but Not Th17 Cell Responses in Established Experimental Autoimmune Uveoretinitis
Raveney,Ben J.E.; Richards,Claire; Aknin,Marie Laure; Copland,David A.; Burton,Bronwen R.; Kerr,Emma; Nicholson,Lindsay B.; Williams,Neil A.; Dick,Andrew D.

Investigative Ophthalmology & Visual Science 2008;49:4008-4017.
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Abstract
PURPOSE. To investigate the efficacy of the B subunit of Escherichia coli heat-labile enterotoxin (EtxB) in the treatment of ocular autoimmune disease. Murine experimental autoimmune uveoretinitis (EAU) is an animal model of autoimmune posterior uveitis initiated by retinal antigen-specific Th1 and Th17 CD4+ T cells, which activate myeloid cells, inducing retinal damage. EtxB is a potent immune modulator that ameliorates other Th1-mediated autoimmune diseases, enhancing regulatory T-cell activity. METHODS. EAU was induced in B10.RIII mice by immunization with peptide hIRBP161-180. Disease severity was measured by clinical and histologic assessment, and functional responses of macrophages (M{phi}s) and T cells were assessed, both in vivo and in cocultures in vitro. EtxB was administered intranasally daily for 4 days, starting either 3 days before or 3 days after EAU induction. RESULTS. Preimmunization treatment with EtxB protected mice from EAU, limiting both the number and the activation status of retinal infiltrating immune cells. Treatment after EAU induction did not alter the disease course, despite suppression of IFN-{gamma}. Although EtxB treatment of in vitro cocultures of T cells and M{phi}s increased IL-10 production, EtxB treatment in vivo increased the proportion and number of IL-17-producing CD4+ cells infiltrating the eye. CONCLUSIONS. EtxB preimmunization protects mice from EAU induction by inhibiting Th1 responses, but the resultant reduction in IFN-{gamma} responses by EtxB does not effect infiltration or structural damage in established EAU, where Th17 responses predominate. These data highlight the critical importance of the dynamics of T-cell phenotype and infiltration during EAU when considering immunomodulatory therapy

2314

Priming but not boosting with plasmid DNA encoding mycolyl-transferase Ag85A from Mycobacterium tuberculosis increases the survival time of Mycobacterium bovis BCG vaccinated mice against low dose intravenous challenge with M. tuberculosis H37Rv.
Romano M,D'Souza S,Adnet PY,Laali R,Jurion F,Palfliet K,Huygen K.

Vaccine 2006;24:4640-4643.
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Abstract
DNA vaccination is a potent means for inducing strong CD4+ (Th1) and particularly CD8+ mediated immune responses and protective immunity against tuberculosis infection in mice. Here we have analyzed the potential of a DNA vaccine encoding the immunodominant mycolyl-transferase Ag85A for increasing the efficacy of the current tuberculosis vaccine Mycobacterium bovis Bacille Calmette-Guérin (BCG) in three long-term survival experiments. BALB/c mice were vaccinated with BCG either following DNA priming or prior to DNA boosting. Ag85A specific CD4+ and CD8+ mediated IFN-gamma responses were increased in mice primed with DNA prior to BCG, and in BCG vaccinated mice subsequently boosted with DNA. In the latter immunization protocol, antigenic stimulation also induced significant levels of IL-17. Mice were monitored for cachexia and survival following a low dose intravenous challenge with M. tuberculosis H37Rv. Priming with Ag85A but not control DNA increased significantly the protective efficacy of the BCG vaccine as indicated by reduced cachexia and prolonged survival time: 32 weeks versus 23 weeks in one experiment and 33 weeks versus 26 weeks in another experiment (MST in control, TB infected mice: 17 weeks in both experiments). On the other hand, boosting of BCG by subsequent Ag85A DNA in saline or vaxfectin--or recombinant 85A protein or MVA-85A for that matter--did not augment the efficacy of BCG (MST 19-21 weeks in all vaccinated groups versus 11 weeks in control, TB infected mice). Our results demonstrate that Ag85A DNA priming can increase efficacy of BCG and that boosting protocols of BCG may possibly be hampered by the induction of Th(IL-17) cells.

1308

CD86 Has Sustained Costimulatory Effects on CD8 T Cells
Thomas,Ian J.; Petrich de Marquesini,Liliana G.; Ravanan,Rommel; Smith,Richard M.; Guerder,Sylvie; Flavell,Richard A.; Wraith,David C.; Wen,Li; Wong,F.Susan

The Journal of Immunology 2007;179:5936-5946.
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Abstract
CD80 and CD86 both costimulate T cell activation. Their individual effects in vivo are difficult to study as they are coordinately up-regulated on APCs. We have studied mice expressing rat insulin promoter (RIP)-CD80 and RIP-CD86 on the NOD and NOD.scid genetic background to generate in vivo models, using diabetes as a readout for cytotoxic T cell activation. Accelerated spontaneous diabetes onset was observed in NOD-RIP-CD80 mice and the transfer of diabetes from 6-wk-old NOD mice to NOD.scid-RIP-CD80 mice was greater compared with NOD-RIP-CD86 and NOD.scid-RIP-CD86 mice, respectively. However, the secondary in vivo response was maintained if T cells were activated through CD86 costimulation compared with CD80. This was demonstrated by greater ability to cause recurrent diabetes in NOD-RIP-CD86 diabetic mice transplanted with 6-wk-old NOD islets and adoptively transferred diabetes from diabetic NOD-RIP-CD86 mice to NOD.scid mice. In vitro, CD80 costimulation enhanced cytotoxicity, proliferation, and cytokine secretion in activated CD8 T cells compared with CD86 costimulation. We demonstrated increased CTLA-4 and programmed death-1 inhibitory molecule expression following costimulation by both CD80 and CD86 (CD80 > CD86). Furthermore, T cells stimulated by CD80 were more susceptible to inhibition by CD4+CD25+ T cells. Overall, while CD86 does not stimulate an initial response as strongly as CD80, there is greater sustained activity that is seen even in the absence of continued costimulation. These functions have implications for the engineered use of costimulatory molecules in altering immune responses in a therapeutic setting

2555

Toll-like receptor 4 mediates maladaptive left ventricular remodeling and impairs cardiac function after myocardial infarction
Timmers L,Sluijter JP,van Keulen JK,Hoefer IE,Nederhoff MG,Goumans MJ,Doevendans PA,van Echteld CJ,Joles JA,Quax PH,Piek JJ,Pasterkamp G,de Kleijn DP.

Circ Res. 2008;102:257-264.
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Abstract
Left ventricular (LV) remodeling leads to congestive heart failure and is a main determinant of morbidity and mortality following myocardial infarction. Therapeutic options to prevent LV remodeling are limited, which necessitates the exploration of alternative therapeutic targets. Toll-like receptors (TLRs) serve as pattern recognition receptors within the innate immune system. Activation of TLR4 results in an inflammatory response and is involved in extracellular matrix degradation, both key processes of LV remodeling following myocardial infarction. To establish the role of TLR4 in postinfarct LV remodeling, myocardial infarction was induced in wild-type BALB/c mice and TLR4-defective C3H-Tlr4(LPS-d) mice. Without affecting infarct size, TLR4 defectiveness reduced the extent of LV remodeling (end-diastolic volume: 103.7+/-6.8 microL versus 128.5+/-5.7 microL; P<0.01) and preserved systolic function (ejection fraction: 28.2+/-3.1% versus 16.6+/-1.3%; P<0.01), as assessed by MRI. In the noninfarcted area, interstitial fibrosis, and myocardial hypertrophy were reduced in C3H-Tlr4(LPS-d) mice. In the infarcted area, however, collagen density was increased, which was accompanied by fewer macrophages, reduced inflammation regulating cytokine expression levels (interleukin [IL]-1alpha, IL-2, IL-4, IL-5, IL-6, IL-10, IL-17, tumor necrosis factor-alpha, interferon-gamma, granulocyte/macrophage colony-stimulating factor), and reduced matrix metalloproteinase-2 (4684+/-515 versus 7573+/-611; P=0.002) and matrix metalloproteinase-9 activity (76.0+/-14.3 versus 168.0+/-36.2; P=0.027). These data provide direct evidence for a causal role of TLR4 in postinfarct maladaptive LV remodeling, probably via inflammatory cytokine production and matrix degradation. TLR4 may therefore constitute a novel target in the treatment of ischemic heart failure.

1289

Targeted Deletion of Nuclear Factor {kappa}B p50 Enhances Cardiac Remodeling and Dysfunction Following Myocardial Infarction
Timmers,Leo; van Keulen,J.Karlijn; Hoefer,Imo E.; Meijs,Matthijs F.L.; van Middelaar,Ben; den Ouden,Krista; van Echteld,Cees J.A.; Pasterkamp,Gerard; de Kleijn,Dominique P.V.

Circulation Research 2009;104:699-706.
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Abstract
Myocardial infarction is commonly complicated by left ventricular remodeling, a process that leads to cardiac dilatation, congestive heart failure and death. The innate immune system plays a pivotal role in the remodeling process via nuclear factor (NF)-{kappa}B activation. The NF-{kappa}B transcription factor family includes several subunits (p50, p52, p65, c-Rel, and Rel B) that respond to myocardial ischemia. The function of NF-{kappa}B p50, however, is controversial in this process. To clarify the role of NF-{kappa}B p50 in postinfarct left ventricular remodeling, myocardial infarction was induced in wild-type 129Bl6 mice and NF-{kappa}B p50-deficient mice. Without affecting infarct size, deletion of NF-{kappa}B p50 markedly increased the extent of expansive remodeling (end-diastolic volume: 176{+/-}13 {micro}L versus 107{+/-}11 {micro}L; P=0.003) and aggravated systolic dysfunction (left ventricular ejection fraction: 16.1{+/-}1.5% versus 24.7{+/-}3.7%; P=0.029) in a 28-day time period. Interstitial fibrosis and hypertrophy in the noninfarcted myocardium was increased in NF-{kappa}B p50 knockout mice. In the infarct area, a lower collagen density was observed, which was accompanied by an increased number of macrophages, higher gelatinase activity and increased inflammatory cytokine expression. In conclusion, targeted deletion of NF-{kappa}B p50 results in enhanced cardiac remodeling and functional deterioration following myocardial infarction by increasing matrix remodeling and inflammation

2516

Inactivation of JNK1 enhances innate IL-10 production and dampens autoimmune inflammation in the brain
Tran,Elise H.; Azuma,Yasu Taka; Chen,Manchuan; Weston,Claire; Davis,Roger J.; Flavell,Richard A.

Proceedings of the National Academy of Sciences U.S.A. 2006;103:13451-13456.
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Abstract
Environmental insults such as microbial pathogens can contribute to the activation of autoreactive T cells, leading to inflammation of target organs and, ultimately, autoimmune disease. Various infections have been linked to multiple sclerosis and its animal counterpart, autoimmune encephalomyelitis. The molecular process by which innate immunity triggers autoreactivity is not currently understood. By using a mouse model of multiple sclerosis, we found that the genetic loss of the MAPK, c-Jun N-terminal kinase 1 (JNK1), enhances IL-10 production, rendering innate myeloid cells unresponsive to certain microbes and less capable of generating IL-17-producing, encephalitogenic T cells. Moreover, JNK1-deficient central nervous system myeloid cells are unable to respond to effector T cell inflammatory cytokines, preventing further progression to neuroinflammation. Thus, we have identified the JNK1 signal transduction pathway in myeloid cells to be a critical component of a regulatory circuit mediating inflammatory responses in autoimmune disease. Our findings provide further insights into the pivotal MAPK-regulated network of innate and adaptive cytokines in the progression to autoimmunity

104

The transcription factor NFATc2 controls IL-6-dependent T cell activation in experimental colitis
Weigmann,Benno; Lehr,Hans A.; Yancopoulos,George; Valenzuela,David; Murphy,Andrew; Stevens,Sean; Schmidt,Jan; Galle,Peter R.; Rose-John,Stefan; Neurath,Markus F.

Journal of Experimental Medicine 2008;205:2099-2110.
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Abstract
The nuclear factor of activated T cells (NFAT) family of transcription factors controls calcium signaling in T lymphocytes. In this study, we have identified a crucial regulatory role of the transcription factor NFATc2 in T cell-dependent experimental colitis. Similar to ulcerative colitis in humans, the expression of NFATc2 was up-regulated in oxazolone-induced chronic intestinal inflammation. Furthermore, NFATc2 deficiency suppressed colitis induced by oxazolone administration. This finding was associated with enhanced T cell apoptosis in the lamina propria and strikingly reduced production of IL-6, -13, and -17 by mucosal T lymphocytes. Further studies using knockout mice showed that IL-6, rather than IL-23 and -17, are essential for oxazolone colitis induction. Administration of hyper-IL-6 blocked the protective effects of NFATc2 deficiency in experimental colitis, suggesting that IL-6 signal transduction plays a major pathogenic role in vivo. Finally, adoptive transfer of IL-6 and wild-type T cells demonstrated that oxazolone colitis is critically dependent on IL-6 production by T cells. Collectively, these results define a unique regulatory role for NFATc2 in colitis by controlling mucosal T cell activation in an IL-6-dependent manner. NFATc2 in T cells thus emerges as a potentially new therapeutic target for inflammatory bowel diseases

2312

Protection from lethal septic peritonitis by neutralizing the biological function of interleukin 27
Wirtz,Stefan; Tubbe,Ingrid; Galle,Peter R.; Schild,Hans J.; Birkenbach,Mark; Blumberg,Richard S.; Neurath,Markus F.

Journal of Experimental Medicine 2006;203:1875-1881.
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Abstract
The immune response to bacterial infections must be tightly controlled to guarantee pathogen elimination while preventing tissue damage by uncontrolled inflammation. Here, we demonstrate a key role of interleukin (IL)-27 in regulating this critical balance. IL-27 was rapidly induced during murine experimental peritonitis induced by cecal ligation and puncture (CLP). Furthermore, mice deficient for the EBI3 subunit of IL-27 were resistant to CLP-induced septic peritonitis as compared with wild-type controls, and this effect could be suppressed by injection of recombinant single-chain IL-27. EBI3-/- mice displayed significantly enhanced neutrophil migration and oxidative burst capacity during CLP, resulting in enhanced bacterial clearance and local control of infection. Subsequent studies demonstrated that IL-27 directly suppresses endotoxin-induced production of reactive oxygen intermediates by isolated primary granulocytes and macrophages. Finally, in vivo blockade of IL-27 function using a newly designed soluble IL-27 receptor fusion protein led to significantly increased survival after CLP as compared with control-treated mice. Collectively, these data identify IL-27 as a key negative regulator of innate immune cell function in septic peritonitis. Furthermore, in vivo blockade of IL-27 is a novel potential therapeutic target for treatment of sepsis

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