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Class II (class + ii)
Kinds of Class II Terms modified by Class II Selected AbstractsImmune-privileged embryonic Swiss mouse STO and STO cell-derived progenitor cells: major histocompatibility complex and cell differentiation antigen expression patterns resemble those of human embryonic stem cell linesIMMUNOLOGY, Issue 1 2006Katherine S. Koch Summary Embryonic mouse STO (S, SIM; T, 6-thioguanine resistant; O, ouabain resistant) and 3(8)21-enhanced green fluorescent protein (EGFP) cell lines exhibit long-term survival and hepatic progenitor cell behaviour after xenogeneic engraftment in non-immunosuppressed inbred rats, and were previously designated major histocompatibility complex (MHC) class I- and class II-negative lines. To determine the molecular basis for undetectable MHC determinants, the expression and haplotype of H-2K, H-2D, H-2L and I-A proteins were reassessed by reverse transcriptase,polymerase chain reaction (RT-PCR), cDNA sequencing, RNA hybridization, immunoblotting, quantitative RT-PCR (QPCR), immunocytochemistry and flow cytometry. To detect cell differentiation (CD) surface antigens characteristic of stem cells, apoptotic regulation or adaptive immunity that might facilitate progenitor cell status or immune privilege, flow cytometry was also used to screen untreated and cytokine [interferon (IFN)-,]-treated cultures. Despite prior PCR genotyping analyses suggestive of H-2q haplotypes in STO, 3(8)21-EGFP and parental 3(8)21 cells, all three lines expressed H-2K cDNA sequences identical to those of d-haplotype BALB/c mice, as well as constitutive and cytokine-inducible H-2Kd determinants. In contrast, apart from H-2Ld[LOW] display in 3(8)21 cells, H-2Dd, H-2Ld and I-Ad determinants were undetectable. All three lines expressed constitutive and cytokine-inducible CD34; however, except for inducible CD117[LOW] expression in 3(8)21 cells, no expression of CD45, CD117, CD62L, CD80, CD86, CD90·1 or CD95L/CD178 was observed. Constitutive and cytokine-inducible CD95[LOW] expression was detected in STO and 3(8)21 cells, but not in 3(8)21-EGFP cells. MHC (class I+[LOW]/class II,) and CD (CD34+/CD80,/CD86,/CD95L,) expression patterns in STO and STO cell-derived progenitor cells resemble patterns reported for human embryonic stem cell lines. Whether these patterns reflect associations with mechanisms that are regulatory of immune privilege or functional tissue-specific plasticity is unknown. [source] Prognostic significance of soluble interleukin-2 receptor levels in patients with dilated cardiomyopathyEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 6 2003C. J. Limas Abstract Background Activation of T lymphocytes is thought to mediate myocardial dysfunction in dilated cardiomyopathy (CMP), probably through cytotoxic cytokines, but its value as a prognostic factor has not been evaluated. Methods For 2 years we prospectively followed 76 patients (65 males, 11 females, age 49 ± 7 years) with CMP and New York Heart Association(NYHA) Class II,III heart failure; left ventricular (LV) function was assessed echocardiographically. Thirty-three patients (28 males, five females, age 52 ± 6 years) with ischaemic heart disease (IHD) and similar NYHA and LV function characteristics were used as controls. Serum sIL-2R levels, peripheral blood lymphocyte proliferation (basal, + concanavalin A) and HLA-DQB1 genotyping was carried out in all patients. Results The CMP patients had increased sIL-2R levels (1259 ± 130 pg mL,1) compared with the IHD patients (703 ± 80 pg mL,1, P < 0·01, only 3 > 800 pg mL,1). In the CMP patients, there was a significant (r = +0·45, P= 0·04) correlation between sIL-2R and the LV end-diastolic diameter but not with the LV ejection fraction or NYHA Class. During the 24-month follow up, 17 of the CMP patients had an adverse clinical course (death, need for cardiac transplantation, or worsening heart failure). Of these, 14 (75%) had elevated (, 800 pg mL,1) sIL-2R levels (Group I) compared with only five (6%) with a stable clinical course (Group II). Neither [3H] thymidine incorporation into the peripheral blood lymphocytes nor the excess of HLA-DQB1-30 histidine homozygotes in the Group I patients (38% vs. 17%, P < 0·05) could predict the clinical outcome. Conclusion Increased sIL-2R levels in CMP patients are an independent predictor of a more aggressive clinical course. [source] MHC Class II and HIV pathogenesis: lots of data, few conclusionsEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 11 2001M. C. I. Lipman No abstract is available for this article. [source] Interactions between major histocompatibility complex class II surface expression and HIV: implications for pathogenesisEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 11 2001W. Kamp Although it has been almost 20 years since the first cases of acquired immunodeficiency syndrome (AIDS) were documented, the pathogenesis is still not completely understood. Interactions between major histocompatibility complex (MHC) Class I and human immunodeficiency virus (HIV), resulting in down-regulation of MHC-I surface expression, have been reported to contribute to pathogenesis by suppressing the host's immune response. Interactions between MHC Class II and HIV have also been described, but it is unclear how these contribute to the pathogenesis. MHC-II surface expression on HIV-infected monocytes and monocytic cell lines has been described to be increased as well as decreased when compared to uninfected control monocytes. HIV-specific mechanisms appear to down-regulate MHC-II expression on blood monocytes during HIV-1 infection, whereas host mechanisms up-regulate MHC-II expression in response to infection of blood monocytes as well as brain macrophages. A balance between these two may determine MHC-II expression levels in individual patients. Altogether, HIV seems to be able to benefit from both low and high levels of MHC-II surface expression. The first results in reduced immune surveillance of the host, allowing the virus to replicate faster; the second increases infectivity of the virus as a result of higher MHC-II density on macrophages and virion particles. [source] Chewing efficiency of pre-orthognathic surgery patients: selection and breakage of food particlesEUROPEAN JOURNAL OF ORAL SCIENCES, Issue 5 2001Willem Van Den Braber Comminution of food is the composite result of selection and breakage. Selection is characterised by the chance that a food particle will at least be damaged by the teeth during chewing. For any size, this chance equals the ratio between the weight of damaged or broken particles and that of all initial particles. The breakage process refers to fracturing of selected particles. The aim was to examine whether a reduced chewing performance of pre-orthognathic surgery patients is due to an impairment of selection, breakage or both. Eight cubes of 8.0 mm of the silicone-rubber Optosil® were used as a test food to determine chewing efficiency for 12 patients (skeletal Angle Class II and dental Angle Class II, subdivision 1) and 12 controls (class I molar relation). Selection and breakage were determined in one-chew experiments using various particle sizes. Chewing efficiency was significantly lower for the patients than for the controls. The selection chance was significantly smaller for the patients, in particular for smaller (,4.8 mm) particles. The degree of breakage was lower for the patients, in particular for medium-sized particles of 4.8 mm. These findings suggest that the reduced chewing performance of pre-orthognathic surgery patients is due to an impairment of both selection and breakage. [source] Provision of Atraumatic Restorative Treatment (ART) restorations to Chinese pre-school children , a 30-month evaluationINTERNATIONAL JOURNAL OF PAEDIATRIC DENTISTRY, Issue 1 2001E.C.M. Summary.Objectives. The objectives of this study were: to provide restorations using the ART approach to pre-school children in Southern China in a kindergarten environ-ment, using a high-strength glass-ionomer restorative material; to assess the accept-ability of this approach and to evaluate on a longitudinal basis the restorations placed. Sample and methods. A total of 170 ART restorations were placed in 95 children, aged 5·1 ± 0·7 years, by seven final-year dental students using standard ART procedures and hand instruments. The restorations were evaluated every six months thereafter by two calibrated independent examiners using explorers and mouth-mirrors. Results. 93% of the children reported that they did not feel pain during treatment and 86% were willing to receive ART restorations again. The cumulative 12- and 30-month survival rates of Class I restorations were 91% and 79%, respectively. The corresponding figures for Class V restorations were 79% and 70%, while those for Class II restorations were 75% and 51%. The failure rates of Class III and IV restor-ations were high with more than half of them scored as missing within the first year. Conclusions. The ART approach was shown to be acceptable to Chinese pre-school children for providing restorative dental care outside the traditional clinical setting. The success rates were high for Class I and V restorations in primary teeth, modest for Class II, and low for Class III and IV restorations. [source] Multicenter, Prospective, Randomized Safety and Efficacy Study of a New Atrial-Based Managed Ventricular Pacing Mode (MVP) in Dual Chamber ICDsJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 8 2005MICHAEL O. SWEENEY M.D. Background: Ventricular desynchronization caused by right ventricular pacing may impair ventricular function and increase risk of heart failure (CHF), atrial fibrillation (AF), and death. Conventional DDD/R mode often results in high cumulative percentage ventricular pacing (Cum%VP). We hypothesized that a new managed ventricular pacing mode (MVP) would safely provide AAI/R pacing with ventricular monitoring and DDD/R during AV block (AVB) and reduce Cum%VP compared to DDD/R. Methods: MVP RAMware was downloaded in 181 patients with Marquis DR ICDs. Patients were initially randomized to either MVP or DDD/R for 1 month, then crossed over to the opposite mode for 1 month. ICD diagnostics were analyzed for cumulative percentage atrial pacing (Cum%AP), Cum%VP, and duration of DDD/R pacing for spontaneous AVB. Results: Baseline characteristics included age 66 ± 12 years, EF 36 ± 14%, and NYHA Class II,III 36%. Baseline PR interval was 190 ± 53 msec and programmed AV intervals (DDD/R) were 216 ± 50 (paced)/189 ± 53 (sensed) msec. Mean Cum%VP was significantly lower in MVP versus DDD/R (4.1 ± 16.3 vs 73.8 ± 32.5, P < 0.0001). The median absolute and relative reductions in Cum%VP during MVP were 85.0 and 99.9, respectively. Mean Cum%AP was not different between MVP versus DDD/R (48.7 ± 38.5 vs 47.3 ± 38.4, P = 0.83). During MVP overall time spent in AAI/R was 89.6% (intrinsic conduction), DDD/R 6.7% (intermittent AVB), and DDI/R 3.7% (AF). No adverse events were attributed to MVP. Conclusions: MVP safely achieves functional atrial pacing by limiting ventricular pacing to periods of intermittent AVB and AF in ICD patients, significantly reducing Cum%VP compared to DDD/R. MVP is a universal pacing mode that adapts to AVB and AF, providing both atrial pacing and ventricular pacing support when needed. [source] Biowaiver monographs for immediate release solid oral dosage forms: Amitriptyline hydrochloride,JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 5 2006R.H. Manzo Abstract Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing amitriptyline hydrochloride are reviewed. Its therapeutic uses, its pharmacokinetic properties, the possibility of excipient interactions and reported BE/bioavailability (BA) problems are also taken into consideration. Literature data indicates that amitriptyline hydrochloride is a highly permeable active pharmaceutical ingredient (API). Data on the solubility according to the current Biopharmaceutics Classification System (BCS) were not fully available and consequently amitriptyline hydrochloride could not be definitively assigned to either BCS Class I or BCS Class II. But all evidence taken together, a biowaiver can currently be recommended provided that IR tablets are formulated with excipients used in existing approved products and that the dissolution meets the criteria defined in the Guidances. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 95:966,973, 2006 [source] Differing Expansion Contributions of Three Investment Materials Used for Casting TitaniumJOURNAL OF PROSTHODONTICS, Issue 5 2009Danny Low BDS, MScDent, MScMed Abstract Purpose: This laboratory study aimed at investigating the effect of setting expansion (SE), which could enlarge a wax pattern by concurrent exothermic reaction. Materials and Methods: Two phosphate-bonded investment materials (Rematitan Plus, T-invest C & B) and alumina-magnesia-based investment material (Titavest CB) were subjected to setting temperature and SE measurements (n = 10). Full-crown wax patterns were prepared from metal dies having the same design. Crown castings (n = 6) were made using a one-chamber high-pressure casting machine. Commercially pure titanium ingot (Japanese Industrial Standard Class II) was used for each casting. Dimensional accuracy of the cast crowns was expressed by marginal discrepancy for a pair of wax pattern and casting prepared from the same die. All results were then subjected to regression analysis. Results: Rematitan Plus gave the highest setting temperature (about 70°C) and the highest SE (1.16 ± 0.01%) almost concurrently. The result was that Rematitan Plus produced oversized crowns from the lowest thermal expansion (TE) value (0.53 ± 0.05%) reducing the linear correlation to 0.80 (p < 0.05). No significant linear relationship was found between SE of investment material and crown-casting accuracy. Conclusions: The almost concurrent occurrence of high SE and high setting temperature generation in Rematitan Plus enlarged the wax pattern and effectively supplemented its low TE to produce oversized crowns. Despite this adverse effect, the correlation between TE and crown accuracy was still high. It is generally expected that the TE values given by manufacturers predict crown accuracy, when uniform TE, small SE, and minimum heat generation during setting are assured. [source] Expression of MHC Class II, CD70, CD80, CD86 and pro-inflammatory cytokines is differentially regulated in oral epithelial cells following bacterial challengeMOLECULAR ORAL MICROBIOLOGY, Issue 6 2003D. C. Han Oral epithelium may play a regulatory role in local immune responses when interacting with bacteria. The present study was undertaken to investigate the effects of selected bacterial pathogens found in periodontal and endodontic infections on oral epithelial cells. Expression of cell surface molecules (major histocompatibility complex (MHC) Class II, CD54, CD70, CD80 and CD86) and secretion of inflammatory cytokines (interleukin (IL)-1,, IL-6, and tumor necrosis factor (TNF)-,) in response to selected bacterial challenge were examined on an immortalized oral epithelial cell line, HOK-18A and a skin epithelial cell line, HaCaT. Actinomyces viscosus, Actinomyces israelii, Fusobacterium nucleatum lipopolysaccharide (LPS) or primary human periradicular exudate from a granuloma were co-cultured with epithelial cells for 4 or 24 h. Subsequently, cell surface expression of MHC Class II, CD54, CD70, CD80 and CD86, along with pro-inflammatory cytokine levels were determined using flow cytometry, ELISA and RT-PCR. Results indicated that the selected oral bacteria have greater effects on oral versus skin epithelial cells. F. nucleatum increased MHC Class II and CD54 (ICAM-1) cell surface expression on HOK-18A and HaCaT cells. A. israelii also had enhancing effects on the expression of CD54 and MHC Class II. A. israelii and LPS induced a 2.8-fold (P < 0.001) and 4.4-fold (P < 0.005) TNF-, secretion, respectively, while F. nucleatum and LPS induced a 10-fold (P < 0.0004) and 6-fold (P < 0.01) IL-1, secretion, respectively by HOK-18A. Interestingly, CD70, CD80, and CD86 were generally decreased upon bacteria and LPS challenge on HOK-18A. The effects of increased MHC Class II and decreased CD70 were also evident with challenge of human periradicular exudate on HOK-18A. The implications of the study are unique in that oral epithelial cells may play both activating and inhibitory roles in the host immune response towards infection by oral bacteria. We introduce a concept of ,dormancy' where the differential expression of key cell surface antigens on oral epithelial cells may keep the recruited immune effector cells in a state of unresponsiveness, thus contributing to the long term quiescent period observed in many periodontal and endodontic lesions. [source] Determinants of Mortality in Patients Undergoing Cardiac Resynchronization Therapy: Baseline Clinical, Echocardiographic, and Angioscintigraphic Evaluation Prior to ResynchronizationPACING AND CLINICAL ELECTROPHYSIOLOGY, Issue 12 2005ANTONIO DE SISTI Background: In dilated cardiomyopathy (DCM) patients (pts) with cardiac resynchronization therapy (CRT) for ventricular dyssynchrony, long-term predictors of mortality and morbidity remain poorly investigated. Method and Results: We reviewed data of 102 pts, 68 ± 10 years, NYHA Class II,IV (14 Class II, 67 Class III, 21 Class IV), who benefited from CRT (69 CRT, 33 CRT-ICD). Fifty-two patients had an ischemic DCM, 36 a previously implanted conventional PM/ICD, 29 a permanent atrial fibrillation, and 19 needed dobutamine in the month preceding implant. QRS duration was 187 ± 35 ms, left ventricular end-diastolic diameter 72 ± 10 mm, mitral regurgitation severity 1.9 ± 0.8, echographic aorto-pulmonary electromechanical delay 61.5 ± 25 ms and septo-lateral left intraventricular delay 86 ± 56 ms, pulmonary artery pressure (PAP) 43 ± 11 mmHg, angioscintigraphic left ventricular ejection fraction (EF) 20 ± 9%, and right ventricular EF 30.5 ± 14%. Over a mean follow-up of 23 ± 20 months, 26 pts died (18 heart failures (HFs), 1 arrhythmic storm, 7 noncardiac deaths). Positive univariate predictors of death from any cause were NYHA Class IV (P < 0.001), and need for dobutamine the month preceding CRT (P < 0.008), while use of ,-blocking agents (P < 0.08) and left ventricular EF (P < 0.09) were negative ones. NYHA Class IV was the only independent predictor at multivariate analysis (P < 0.01). Survival at 24 months was 85% in Class II, 80% in Class III, and 37% in Class IV (II vs III, P = ns; III vs IV, P < 0.001). When using a composite endpoint of death from any cause and unplanned rehospitalization for a major cardiovascular event, there were 48 events (14 HF deaths, 3 noncardiac deaths, 26 HF rehospitalizations, 2 paroxysmal atrial fibrillation, 2 sustained ventricular tachycardia, 1 nonfatal pulmonary embolism). Predictors of death from any cause/unplanned rehospitalization for a major cardiovascular event in the follow-up were NYHA Class IV (P < 0.001), need for dobutamine during the month preceding CRT (P < 0.002), and PAP (<0.02). NYHA Class IV was the only independent predictor at multivariate analysis (P < 0.05). Event-free proportion at 24 months was 70% in Class II, 64% in Class III, and 37% in Class IV (II vs III, P = ns; III vs IV, P < 0.01). When considering determinants of mortality only in NYHA Class IV patients, no variable was significantly correlated to mortality. Need for dobutamine during the last month preceding CRT did not add an adjunctive mortality risk. Conclusion: Baseline NYHA Class IV at implantation appears as the most important determinant of a poor clinical outcome in terms of both mortality and morbidity. No predictive criteria seem available for NYHA Class IV patients, in order to discriminate who will die after CRT and who will not. NYHA Class IV strongly influences the clinical outcome, suggesting that, in future studies planned on mortality and rehospitalization as major endpoints, baseline NYHA Class IV should be separately taken into account. [source] Anti-CD28 Antibody-Induced Kidney Allograft Tolerance Related to Tryptophan Degradation and TCR, Class II, B7+ Regulatory CellsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 10 2005Fabienne Haspot B7/CTLA-4 interactions negatively regulate T-cell responses and are necessary for transplant tolerance induction. Tolerance induction may therefore be facilitated by selectively inhibiting the B7/CD28 pathway without blocking that of B7/CTLA-4. In this study, we selectively inhibited CD28/B7 interactions using a monoclonal antibody modulating CD28 in a rat model of acute kidney graft rejection. A short-term treatment abrogated both acute and chronic rejection. Tolerant recipients presented few alloantibodies against donor MHC class II molecules, whereas untreated rejecting controls developed anti-MHC class I and II alloantibodies. PBMC from tolerant animals were unable to proliferate against donor cells but could proliferate against third-party cells. The depletion of B7+, non-T cells fully restored this reactivity whereas purified T cells were fully reactive. Also, NK cells depletion restored PBMC reactivity in 60% of tolerant recipients. Conversely, NK cells from tolerant recipients dose-dependently inhibited alloreactivity. PBMC anti-donor reactivity could be partially restored in vitro by blocking indoleamine-2,3-dioxygenase (IDO) and iNOS. In vivo, pharmacologic inhibition of these enzymes led to the rejection of the otherwise tolerated transplants. This study demonstrates that an initial selective blockade of CD28 generates B7+ non-T regulatory cells and a kidney transplant tolerance sustained by the activity of IDO and iNOS. [source] Molecular cloning, chromosomal localization and expression pattern of porcine ADP-ribosylation factor(Arf) gene familyANIMAL SCIENCE JOURNAL, Issue 4 2010Rongrong ZHANG ABSTRACT Adenosine diphosphate-ribosylation factors (Arfs) are a family of guanosine triphosphate-binding proteins involved in fundamental biological processes including secretion, endocytosis, phagocytosis, cytokinesis, cell adhesion and tumor cell invasion. We report here the molecular cloning, chromosome localization and expression analysis of porcine Arf1,6, of which Arf1,3 (Class I) have >93% similarity to each other and encode nearly similar proteins with 181 amino acids in length. Arf4 and Arf5 (Class II) are 78,81% homologous to Class I Arfs and both encode a protein of 180 amino acids, Arf6 (Class III) shows 64,68% homology to the other Arfs and encodes 175 amino acids. With radiation hybrid mapping, porcine Arf1,6 are assigned to chromosomes 14q21-q22, 12p14, 5p12-q11, 13q21.1, 18q24, 1q21-q27, respectively. Moreover, real-time quantitative RT-PCR assays show that porcine Arf1-6 are ubiquitous in all tissues examined, with the highest levels in the kidney and stomach and the lowest in muscle and the heart. This is the first report of molecular characterization of the Arf gene family in pigs. [source] An analysis of variability in the manufacturing of dexosomes: Implications for development of an autologous therapy,BIOTECHNOLOGY & BIOENGINEERING, Issue 2 2005Sanjay Patel Abstract Dexosomes are nanometer-size vesicles released by dendritic-cells, possessing much of the cellular machinery required to stimulate an immune response (i.e. MHC Class I and II). The ability of patient-derived dexosomes loaded with tumor antigens to elicit anti-tumor activity is currently being evaluated in clinical trials. Unlike conventional biologics, where variability between lots of product arises mostly from the manufacturing process, an autologous product has inherent variability in the starting material due to heterogeneity in the human population. In an effort to assess the variability arising from the dexosome manufacturing process versus the human starting material, 144 dexosome preparations from normal donors (111) and cancer patients (33) from two Phase I clinical trials were analyzed. A large variability in the quantity of dexosomes (measured as the number of MHC Class II molecules) produced between individual lots was observed (,>,50-fold). An analysis of intra-lot variability shows that the manufacturing process introduces relatively little of this variability. To identify the source(s) of variability arising from the human starting material, distributions of the key parameters involved in dexosome production were established, and a model created. Computer simulations using this model were performed, and compared to the actual data observed. The main conclusion from these simulations is that the number of cells collected per individual and the productivity of these cells of are the principal sources of variability in the production of Class II. The approach described here can be extended to other autologous therapies in general to evaluate control of manufacturing processes. Moreover, this analysis of process variability is directly applicable to production at a commercial scale, since the large scale manufacture of autologous products entails an exact process replication rather than scale-up in volume, as is the case with traditional drugs or biologics. © 2005 Wiley Periodicals, Inc. [source] MHC Gene Related Effects on Microglia and Macrophages in Experimental Autoimmune Encephalomyelitis Determine the Extent of Axonal InjuryBRAIN PATHOLOGY, Issue 3 2002Maria K. Storch Myelin-oligodendrocyte-glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) in rats is a chronic inflammatory demyelinating disease of the central nervous system (CNS) strongly mimicking multiple sclerosis (MS). We determined the involvement of macrophages and microglia in the lesions of MOG-EAE in relation to different major histocompatibility complex (MHC, RT1 in rat) haplotypes. We used intra-RT1 recombinant rat strains with recombinations between the RT1a and RT1u haplotypes on the disease permissive LEW non-MHC genome. Activated microglia and macrophages were identified morphologically and by expression of ED1 and allograft inhibitory factor-1 (AIF-1), and differentiated by their morphological phenotype. White matter lesions contained more macrophages and less microglia compared to grey matter lesions. Similarly active lesions were mainly infiltrated by macrophages, while microglia were abundant in inactive demyelinated plaques. In addition, we found a highly significant genetic association between a macrophage or microglia dominated lesional phenotype, which was independent from location and activity of the lesions. This was not only the case in demyelinating plaques of chronic EAE, but also in purely inflammatory lesions of acute passive transfer EAE. Rat strains with an u-haplotype in both the Class II and the telomeric non-classical Class I region revealed inflammatory and demyelinating lesions, which were dominated by activated microglia. The a-haplotype in any of these regions was associated with macrophage dominated lesions. A comparison of lesions, exactly matched for stages of demyelinating activity in these different rat strains, showed that in spite of a similar extent of demyelination, axonal injury was significantly less in microglia compared to macrophage dominated lesions. Thus, our studies document a genetic influence of the MHC-region on the relative contribution of macrophages versus microglia in the pathogenesis of EAE. [source] Testicular carcinoma and HLA Class II genesCANCER, Issue 9 2002Dirk J. A. Sonneveld M.D., Ph.D. Abstract BACKGROUND The association with histocompatibility antigens (HLA), in particular Class II genes (DQB1, DRB1), has recently been suggested to be one of the genetic factors involved in testicular germ cell tumor (TGCT) development. The current study, which uses genotyping of microsatellite markers, was designed to replicate previous associations. METHODS In 151 patients, along with controls comprising parents or spouses, the HLA region (particularly Class II) on chromosome 6p21 was genotyped for a set of 15 closely linked microsatellite markers. RESULTS In both patients and controls, strong linkage disequilibrium was observed in the genotyped region, indicating that similar haplotypes are likely to be identical by descent. However, association analysis and the transmission disequilibrium test did not show significant results. Haplotype sharing statistics, a haplotype method that derives extra information from phase and single marker tests, did not show differences in haplotype sharing between patients and controls. CONCLUSION The current genotyping study did not confirm the previously reported association between HLA Class II genes and TGCT. As the HLA alleles for which associations were reported are also prevalent in the Dutch populations, these associations are likely to be nonexistent or much weaker than previously reported. Cancer 2002;95:1857,63. © 2002 American Cancer Society. DOI 10.1002/cncr.10903 [source] Generation of cytotoxic T cell responses directed to human leucocyte antigen Class I restricted epitopes from the Aspergillus f16 allergenCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 1 2005G. Ramadan Summary Invasive aspergillosis (IA) is a major cause of infection-related mortality in patients with haematological malignancies, especially in recipients of haematopoietic stem cell transplants. We have prepared overlapping pentadecapeptides (11-aa overlap with previous peptide) spanning the entire 427-aa coding region of the Aspergillus allergen, Asp f16 shown previously in mice to induce Th1-type cell responses in vivo and in humans to induce proliferative and cytotoxic CD4+ T cell responses. Mature dendritic cells (DC) pulsed with a complete pool of peptides were used to generate T cell lines. Two lines from HLA-B*3501+ donors were found to be strongly cytotoxic to autologous Asp f16-peptide pool- and Aspergillus culture extract-pulsed targets after 4,5 weekly primings. Cytotoxic T lymphocyte (CTL) culture supernatant killed Aspergillus conidia, and cells directly killed Aspergillus hyphae. Cytotoxic activity and interferon (IFN)-, production were mediated exclusively by CD8+ T cells in response to pool-pulsed targets. Interleukin (IL)-4 production was not detected. CTL activity was restricted by HLA-B*3501 and based on peptide prediction programmes was most probably directed to YFKYTAAAL (YFK), LPLCSAQTW (LPL) and GTRFPQTPM (GTR) in one donor, while only LPL was recognized by CTL from the second donor. Pool-pulsed B*3503+ BLCL but not B*3502+ or B*3508+ BLCL presented peptide to donor no. 1. B*3503+ BLCL presented YFK and to a lesser extent GTR, but not peptide LPL. Our data show that in addition to our previously identified Class II restricted peptide response, DC pulsed with a pentadecapeptide pool from Asp f16 are capable of inducing polyclonal, HLA-Class I-restricted, Aspergillus -specific T cells that may be capable of conferring immunity to IA. [source] The Atrial Fibrillation Paradox of Heart FailureCONGESTIVE HEART FAILURE, Issue 1 2010Rhidian J. Shelton MRCP Congest Heart Fail. 2010;16:3,9. ©2009 Wiley Periodicals, Inc. The prevalence of atrial fibrillation (AF) in patients with heart failure (HF) is high, but longitudinal studies suggest that the incidence of AF is relatively low. The authors investigated this paradox prospectively in an epidemiologically representative population of patients with HF and persistent AF. In all, 891 consecutive patients with HF [mean age, 70±10 years; 70% male; left ventricular ejection fraction, 32%±9%] were enrolled. The prevalence of persistent AF at baseline was 22%. The incidence of persistent AF at 1 year was 26 per 1000 person-years, ranging from 15 in New York Heart Association class I/II to 44 in class III/IV. AF occurred either at the same time or prior to HF in 76% of patients and following HF in 24%. A risk score was developed to predict the occurrence of persistent AF. The annual risk of persistent AF developing was 0.5% (0%,1.3%) for those in the low-risk group compared with 15% (3.4%,26.6%) in the high-risk group. Despite a high prevalence of persistent AF in patients with HF, the incidence of persistent AF is relatively low. This is predominantly due to AF coinciding with or preceding the development of HF. The annual risk of persistent AF developing can be estimated from clinical variables. [source] Baseline Characteristics of Patients Randomized in the Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) StudyCONGESTIVE HEART FAILURE, Issue 2 2008Cecilia Linde MD The Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) study is a randomized controlled trial currently assessing the safety and efficacy of cardiac resynchronization therapy in patients with asymptomatic left ventricular (LV) dysfunction with previous symptoms of mild heart failure. This paper describes the baseline characteristics of randomized patients; 610 patients with New York Heart Association (NYHA) class II (82.3%) heart failure or asymptomatic (NYHA class I) LV dysfunction with previous symptoms (17.7%) were randomized in 73 centers. The mean age was 62.5±11.0 years, the mean LV ejection fraction was 26.7%±7.0%, and the mean LV end-diastolic diameter was 66.9±8.9 mm. A total of 97% of patients were taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and 95.1% were taking ,-blockers, which were at the target dose in 35.1% of patients. Compared with previous randomized cardiac resynchronization therapy trials, REVERSE patients are on better pharmacologic treatment, are younger, and have a narrower QRS width despite similar LV dysfunction. [source] Activation of receptors negatively coupled to adenylate cyclase is required for induction of long-term synaptic depression at Schaffer collateral-CA1 synapsesDEVELOPMENTAL NEUROBIOLOGY, Issue 3 2006Linda A. Santschi Abstract Chemical LTD (CLTD) of synaptic transmission is triggered by simultaneously increasing presynaptic [cGMP] while inhibiting PKA. Here, we supply evidence that class II, but not III, metabotropic glutamate receptors (mGluRs), and A1 adenosine receptors, both negatively coupled to adenylate cyclase, play physiologic roles in providing PKA inhibition necessary to promote the induction of LTD at Schaffer collateral-CA1 synapses in hippocampal slices. Simultaneous activation of group II mGluRs with the selective agonist (2S,2,R,3,R)-2-(2,,3,-dicarboxy-cyclopropyl) glycine (DCGIV; 5 ,M), while raising [cGMP] with the type V phosphodiesterase inhibitor, zaprinast (20 ,M), resulted in a long-lasting depression of synaptic strength. When zaprinast (20 ,M) was combined with a cell-permeant PKA inhibitor H-89 (10 ,M), the need for mGluR IIs was bypassed. DCGIV, when combined with a "submaximal" low frequency stimulation (1 Hz/400 s), produced a saturating LTD. The mGluR II selective antagonist, (2S)-alpha-ethylglutamic acid (EGLU; 5 ,M), blocked induction of LTD by prolonged low frequency stimulation (1 Hz/900 s). In contrast, the mGluR III selective receptor blocker, (RS)-a-Cyclopropyl-[3- 3H]-4-phosphonophenylglycine (CPPG; 10 ,M), did not impair LTD. The selective adenosine A1 receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 100 nM), also blocked induction of LTD, while the adenosine A1 receptor agonist N6 -cyclohexyl adenosine (CHA; 50 nM) significantly enhanced the magnitude of LTD induced by submaximal LFS and, when paired with zaprinast (20 ,M), was sufficient to elicit CLTD. Inhibition of PKA with H-89 rescued the expression of LTD in the presence of either EGLU or DPCPX, confirming the hypothesis that both group II mGluRs and A1 adenosine receptors enhance the induction of LTD by inhibiting adenylate cyclase and reducing PKA activity. © 2005 Wiley Periodicals, Inc. J Neurobiol, 2006 [source] Association between Endothelial Function and Chronotropic Incompetence in Subjects with Chronic Heart Failure Receiving Optimal Medical TherapyECHOCARDIOGRAPHY, Issue 3 2010M.D., Timothy J. Vittorio M.S. Objective: Impairment of flow-mediated, endothelium-dependent vasodilatation (FMD) of the brachial artery identifies peripheral endothelial dysfunction in subjects with chronic congestive heart failure (CHF) and is associated with increased morbidity and mortality. To further elucidate the interaction of peripheral and central mechanisms in the syndrome of CHF, we examined the association between endothelial function and chronotropic incompetence, an emerging prognostic marker in CHF. Methods: Thirty subjects with stable New York Heart Association (NYHA) functional class II,III CHF were studied. A vascular ultrasound study was performed to measure brachial artery FMD. The percentage of age-adjusted maximal predicted heart rate (MPHR) reached during cardiopulmonary exercise tolerance testing (CPETT) was used to assess the degree of chronotropic competence. All patients received ACE inhibitors and ,-adrenoceptor blockers. Results: Brachial artery FMD averaged 1.3 ± 2.4% and age-adjusted % MPHR 74.1 ± 11.7%. FMD correlated with % MPHR among all patients (r = 0.60, P = 0.01). FMD and resting heart rate (RHR) did not significantly correlate (r = 0.13, P = 0.55). Conclusions: FMD, a measure of peripheral endothelial dysfunction, and % MPHR, a central determinant of cardiac output, are moderately correlated in heart failure patients receiving optimal medical therapy. Whether a cause-effect relationship underlies this association remains to be investigated. (Echocardiography 2010;27:294-299) [source] Simultaneous analysis of multiple PCR amplicons enhances capillary SSCP discrimination of MHC allelesELECTROPHORESIS, Issue 8 2010Miguel Alcaide Abstract Major histocompatibility complex (MHC) genotyping still remains one of the most challenging issues for evolutionary ecologists. To date, none of the proposed methods have proven to be perfect, and all provide both important pros and cons. Although denaturing capillary electrophoresis has become a popular alternative, allele identification commonly relies upon conformational polymorphisms of two single-stranded DNA molecules at the most. Using the MHC class II (, chain, exon 2) of the black kite (Aves: Accipitridae) as our model system, we show that the simultaneous analysis of overlapping PCR amplicons from the same target region substantially enhances allele discrimination. To cover this aim, we designed a multiplex PCR capable to generate four differentially sized and labeled amplicons from the same allele. Informative peaks to assist allele calling then fourfold those generated by the analysis of single PCR amplicons. Our approach proved successful to differentiate all the alleles (N=13) isolated from eight unrelated birds at a single optimal run temperature and electrophoretic conditions. In particular, we emphasize that this approach may constitute a straightforward and cost-effective alternative for the genotyping of single or duplicated MHC genes displaying low to moderate sets of divergent alleles. [source] Comprehensive analysis of cooperative gene mutations between class I and class II in de novo acute myeloid leukemiaEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 2 2009Yuichi Ishikawa Abstract Acute myeloid leukemia (AML) has been thought to be the consequence of two broad complementation classes of mutations: class I and class II. However, overlap-mutations between them or within the same class and the position of TP53 mutation are not fully analyzed. We comprehensively analyzed the FLT3, cKIT, N-RAS, C/EBPA, AML1, MLL, NPM1, and TP53 mutations in 144 newly diagnosed de novo AML. We found 103 of 165 identified mutations were overlapped with other mutations, and most overlap-mutations consisted of class I and class II mutations. Although overlap-mutations within the same class were found in seven patients, five of them additionally had the other class mutation. These results suggest that most overlap-mutations within the same class might be the consequence of acquiring an additional mutation after the completion both of class I and class II mutations. However, mutated genes overlapped with the same class were limited in N-RAS, TP53, MLL -PTD, and NPM1, suggesting the possibility that these irregular overlap-mutations might cooperatively participate in the development of AML. Notably, TP53 mutation was overlapped with both class I and class II mutations, and associated with morphologic multilineage dysplasia and complex karyotype. The genotype consisting of complex karyotype and TP53 mutation was an unfavorable prognostic factor in entire AML patients, indicating this genotype generates a disease entity in de novo AML. These results collectively suggest that TP53 mutation might be a functionally distinguishable class of mutation. [source] Pulmonary stromal cells induce the generation of regulatory DC attenuating T-cell-mediated lung inflammationEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2008Qian Li Abstract The tissue microenvironment may affect the development and function of immune cells such as DC. Whether and how the pulmonary stromal microenvironment can affect the development and function of lung DC need to be investigated. Regulatory DC (DCreg) can regulate T-cell response. We wondered whether such regulatory DC exist in the lung and what is the effect of the pulmonary stromal microenvironment on the generation of DCreg. Here we demonstrate that murine pulmonary stromal cells can drive immature DC, which are regarded as being widely distributed in the lung, to proliferate and differentiate into a distinct subset of DCreg, which express high levels of CD11b but low levels of MHC class II (I-A), CD11c, secrete high amounts of IL-10, NO and prostaglandin E2 (PGE2) and suppress T-cell proliferation. The natural counterpart of DCreg in the lung with similar phenotype and regulatory function has been identified. Pulmonary stroma-derived TGF-, is responsible for the differentiation of immature DC to DCreg, and DCreg-derived PGE2 contributes to their suppression of T-cell proliferation. Moreover, DCreg can induce the generation of CD4+CD25+Foxp3+ Treg. Importantly, infusion with DCreg attenuates T-cell-mediated eosinophilic airway inflammation in vivo. Therefore, the pulmonary microenvironment may drive the generation of DCreg, thus contributing to the maintenance of immune homoeostasis and the control of inflammation in the lung. [source] Increased TLR responses in dendritic cells lacking the ITAM-containing adapters DAP12 and FcR,EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 1 2008Ching-Liang Chu Dr. Abstract The inhibitory effect of DAP12 on macrophages has been revealed by examining myeloid cells from DAP12-deficient mice. In this report, we demonstrate that both DAP12 and the Fc,RI,-chain (FcR,) are required for negative regulation of TLR responses in bone marrow-derived dendritic cells (DC). Loss of both DAP12 and FcR, enhanced the pro-inflammatory cytokine production and maturation of DC after TLR stimulation, resulting in a greater percentage of DC that produced IL-12 p40, TNF, and IL-6, and expressed high levels of MHC class II, CD80, and CD86. Whereas DC lacking only DAP12 showed some increased TLR responses, those lacking only FcR, had a greater enhancement of maturation and cytokine production, though to a lesser extent than DC lacking both DAP12 and FcR,. Additionally, antigen-specific T cell proliferation was enhanced by DAP12,/,FcR,,/, DC relative to wild-type DC after maturation. Similar to DAP12,/,FcR,,/, DC, Syk-deficient DC also had increased inflammatory cytokine production, maturation, and antigen presentation. These results confirm the inhibitory effect of immunoreceptor tyrosine-based activation motif (ITAM) signaling in myeloid cells and show that DC and macrophages differ in their dependence on the ITAM-containing adapters DAP12 and FcR, for negative regulation of TLR signaling. [source] Notch signaling is activated by TLR stimulation and regulates macrophage functionsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 1 2008Tanapat Palaga Dr. Abstract Notch signaling is a well-conserved pathway involved in cell fate decisions, proliferation and apoptosis. We report on the involvement of Notch signaling in regulating gene expression in activated macrophages. Toll-like receptors (TLR) agonists such as bacterial lipopeptide, polyI:C, lipopolysaccharide and unmethylated CpG DNA all induced up-regulation of Notch1 in primary and macrophage-like cell lines. Notch1 up-regulation was dependent on the MyD88 pathway when stimulated through TLR2, but not TLR4. Activated Notch1 and expression of the Notch target genes, Hes1 and Deltex, were detected in activated macrophages, suggesting that Notch signaling was activated upon stimulation. Inhibiting processing of Notch receptor by ,-secretase using a ,-secretase inhibitor (GSI), the expression of Notch1 was down-regulated to basal levels. This treatment significantly modulated expression of TNF-,, IL-6, and IL-10. In addition, the amount of nitric oxide produced was significantly lower and the expression of MHC class II was up-regulated in GSI-treated cells. Treatment with GSI or silencing Notch1 resulted in decreased translocation of NF-,Bp50 into nucleus upon stimulation. Taken together, stimulation of macrophages through the TLR signaling cascade triggered activation of Notch signaling, which in turn regulated gene expression patterns involved in pro-inflammatory responses, through activation of NF-,B. [source] Direct role of NF-,B activation in Toll-like receptor-triggered HLA-DRA expressionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2006Keun-Wook Lee Abstract Microbial components, such as DNA containing immunostimulatory CpG motifs (CpG-DNA) and lipopolysaccharides (LPS), elicit the cell surface expression of MHC class II (MHC-II) through Toll-like receptor (TLR)/IL-1R. Here, we show that CpG-DNA and LPS induce expression of the HLA-DRA in the human B cell line, RPMI 8226. Ectopic expression of the dominant negative mutant of CIITA and RNA interference targeting the CIITA gene indicate that CIITA activation is not enough for the maximal MHC-II expression induced by CpG-DNA and LPS. Additionally, nuclear factor (NF)-,B activation is required for the CpG-DNA-activated and LPS-activated HLA-DRA expression, whereas IFN-,-induced MHC-II expression depends on CIITA rather than on NF-,B. Comprehensive mutant analyses, electrophoretic mobility shift assays and chromatin immunoprecipitation assays, reveal that the functional interaction of NF-,B with the promoter element is necessary for the TLR-mediated HLA-DRA induction by CpG-DNA and LPS. This novel mechanism provides the regulation of MHC-II gene expression with complexity and functional diversity. [source] MHC class II-independent CD25+ CD4+ CD8,,,+ ,,, T cells attenuate CD4+ T cell-induced transfer colitisEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2004Tamara Krajina Abstract CD4+ ,,, T cell populations that develop in mice deficient in MHC class II (through ,knockout' of either the A,, or the A, chain of the I-Ab molecule) comprise a major ,single-positive' (SP) CD4+ CD8, subset (60,90%) and a minor ,double-positive' (DP) CD4+ CD8,,,+ subset (10,40%). Many DP T cells found in spleen, mesenteric lymph nodes (MLN) and colonic lamina propria (cLP) express CD25, CD103 and Foxp3. Adoptive transfer of SP but not DP T cells from A,,/, or A,,/, B6 mice into congenic RAG,/, hosts induces colitis. Transfer of SP T cells repopulates the host with only SP T cells; transfer of DP T cells repopulates the host with DP and SP T cells. Anti-CD25 antibody treatment of mice transplanted with DP T cells induces severe, lethal colitis; anti-CD25 antibody treatment of mice transplanted with SP T cells further aggravates the course of severe colitis. Hence, regulatory CD25+ T cells within (or developing from) the DP T cell population of MHC class II-deficient mice control the colitogenic potential of CD25, CD4+ T cells. [source] The Toll-like receptor ligand MALP-2 stimulates dendritic cell maturation and modulates proteasome composition and activityEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2004Claudia Link Abstract A 2-kDa synthetic derivative of the macrophage-activating lipopeptide (MALP-2) from Mycoplasma fermentans is a potent inducer of monocytes/macrophages and improves the immunogenicity of antigens co-administered by systemic and mucosal routes. Dendritic cells (DC) are the most potent antigen-presenting cells, which are able to prime naive T cells in vivo. To elucidate the underlying mechanisms of MALP-2 adjuvanticity, we analyzed its activity on bone marrow-derived murine DC. In vitro stimulation of immature murine DC with MALP-2 resulted in the induction of maturation with up-regulated expression of MHC class II, costimulatory (CD80, CD86) and adhesion (CD40, CD54) molecules. MALP-2 also enhances the secretion of cytokines (IL-1,, IL-6 and IL-12), and increases DC stimulatory activity on naive and antigen-specific T cells. Further studies demonstrated that MALP-2 treatment of DC results in a dose-dependent shift from the protein pattern of proteasomes to immunoproteasomes (up-regulation of LMP2, LMP7 and MECL1), which correlates with an increased proteolytic activity. Thus, the adjuvanticity of MALP-2 can be mediated, at least in part, by the stimulation of DC maturation, which in turn leads to an improved antigen presentation. Therefore, MALP-2 is a promising molecule for the development of immune therapeutic or prophylactic interventions. [source] In vitro differentiation of lineage-negative bone marrow cells into microglia-like cellsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2010Daisuke Noto Abstract Microglia are believed to be the only resident immune cells in the CNS, originating from hematopoietic-derived myeloid cells and invading the CNS during development. However, the detailed mechanisms of differentiation and transformation of microglial cells are not fully understood. Here, we demonstrate that murine microglial cells show two morphological forms in vitro, namely, small round cells expressing CD11b, Iba1, triggering receptor expressing on myeloid cells-2 (TREM2), and weakly expressing major histocompatibility complex class II and large flat cells expressing only CD11b and Iba1. Moreover, lineage-negative bone marrow (LN) cells cultured with primary mixed glial culture cells could differentiate into only the small round microglia-like cells, despite the absence of CCR2 and Gr-1 expression. Addition of macrophage colony stimulating factor (M-CSF) to LN cell culture allowed the proliferation and expression of TREM2 in LN cells, and the addition of neutralizing anti-M-CSF antibodies suppressed the proliferation of LN cells despite the expression of TREM2. When LN cells were cultured with M-CSF, the number of small round cells in the culture was considerably low, indicating that the small round morphology of the immature cells is not maintained in the presence of only M-CSF. On the other hand, when LN cells were grown in the presence of astrocytes, the small round cells were maintained at a concentration of approximately 30% of the total population. Therefore, cell,cell contact with glial cells, especially astrocytes, may be necessary to maintain the small round shape of the immature cells expressing TREM2. [source] | |||||||||||||||||||||||||||||||||||||||||||