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41.
42.
Annett Ostmann Hans-Joachim Paust Ulf Panzer Claudia Wegscheid Sonja Kapffer Samuel Huber Richard A. Flavell Annette Erhardt Gisa Tiegs 《Journal of the American Society of Nephrology : JASN》2013,24(6):930-942
Regulatory T cells (Tregs) exert their immunosuppressive activity through several immunoregulatory mechanisms, including the production of anti-inflammatory cytokines such as IL-10. Although several studies suggest a role for Tregs in modulating crescentic GN, the underlying mechanisms are not well understood. Here, using IL-10 reporter mice, we detected IL-10–producing Foxp3+ T cells in the kidney, blood, and secondary lymphoid tissue in a mouse model of crescentic GN. Specific inactivation of Il10 in Foxp3+ Tregs eliminated the ability of these cells to suppress renal and systemic production of IFNγ and IL-17; these IL-10–deficient Tregs lost their capacity to attenuate renal tissue injury. These data highlight the suppressive functions of Tregs in crescentic GN and suggest the importance of Treg-derived IL-10 in ameliorating disease severity and in modulating both the Th1 and most notably Th17 immune response.The discovery of CD4+CD25+Foxp3+ regulatory T cells (Tregs) in the 1990s and their indispensable role in (self) tolerance and autoimmunity marked the beginning of a new era in immunology.1 Since then, different suppressive mechanisms mediated by various Treg cell subsets were identified,2,3 particularly in well studied models of autoimmune diseases such as Crohn''s disease,4 multiple sclerosis,5 or rheumatoid arthritis.6,7 Until now, only limited numbers of studies have assessed the function of regulatory T cells in crescentic GN. Adoptive cell transfer experiments in mice showed the beneficial role of exogenous wild-type (wt) CD4+CD25+ Tregs in attenuation of crescentic GN,8 whereas CCR6- and CCR7-deficient CD4+CD25+ Tregs failed to protect mice against GN.9,10 Recently, our own published data revealed the importance of endogenous Foxp3+ Tregs in suppressing the Th1 immune response and consequently ameliorating the disease severity in the T cell–dependent GN model of nephrotoxic nephritis (NTN).11 Concurrently, Ooi and coworkers confirmed the relevance of endogenous Foxp3+ Tregs in an accelerated model of experimental crescentic GN.12
However, the mechanisms of Treg cell-mediated suppression in crescentic GN are still unclear. One important player might be the anti-inflammatory cytokine IL-10, which is known to be released by Tregs in order to suppress immune responses and therefore might protect against autoimmunity.13 Indeed, endogenous IL-10 regulates the Th1 immune response in an accelerated model of experimental crescentic GN, as kidney damage is aggravated in IL-10–deficient mice.14 However, the source of protective IL-10 still needs to be clarified. Because IL-10 detection and tracking in vivo is difficult, most findings are based on studies with IL-10−/− mice.Therefore, to study the cell-specific function of IL-10, we used a double-knockin reporter mouse model (Foxp3-IRES-mRFP (FIR) x IL-10 ires gfp-enhanced reporter [tiger]), which enables detection of the well-defined and simultaneous expression of IL-10 (green fluorescent protein [GFP]) and Foxp3 (monomeric red fluorescent protein [mRFP]). Indeed, we detected a distinct population of renal mRFP+(Foxp3+) Tregs expressing GFP (IL-10) upon induction of NTN. Thus, to investigate the role of Treg cell-derived IL-10 in NTN, we first adoptively transferred CD4+CD25+ Tregs from wt or IL-10−/− mice into wt mice subsequently challenged with nephrotoxic sheep serum. Adoptively transferred wt Tregs attenuated the course of NTN, whereas IL-10−/− Tregs did not. Furthermore, to analyze the role of endogenous IL-10 produced by Tregs, we generated Foxp3YFP-Cre x Il10flox/flox mice, in which IL-10 is selectively inactivated in Foxp3+ Tregs.15 Indeed, lack of Treg-derived IL-10 resulted in an aggravated course of NTN. In summary, we demonstrated a crucial role of Treg cell-derived IL-10 in regulating the Th1 and most notably the Th17 immune response in NTN. Hence, this study contributes to the understanding of the suppressive mechanisms of Tregs in crescentic GN and will have biologic implications for designing therapeutic approaches. 相似文献
43.
Michael Untch Bernd Gerber Nadia Harbeck Christian Jackisch Norbert Marschner Volker M?bus Gunter von Minckwitz Sibylle Loibl Matthias W. Beckmann Jens-Uwe Blohmer Serban-Dan Costa Thomas Decker Ingo Diel Thomas Dimpfl Wolfgang Eiermann Tanja Fehm Klaus Friese Fritz J?nicke Wolfgang Janni Walter Jonat Marion Kiechle Uwe K?hler Hans-Joachim Lück Nicolai Maass Kurt Possinger Achim Rody Anton Scharl Andreas Schneeweiss Christoph Thomssen Diethelm Wallwiener Anja Welt 《Breast care (Basel, Switzerland)》2013,8(3):221-229
Zusammenfassung
Alle zwei Jahre findet in St. Gallen (Schweiz) die internationale Konsensuskonferenz zur Behandlung des primären Mammakarzinoms statt. Da sich das internationale Panel in St. Gallen aus Experten unterschiedlicher Länder zusammensetzt, spiegelt der Konsensus ein internationales Meinungsbild wider. Vor diesem Hintergrund erscheint es aus deutscher Sicht sinnvoll, die Abstimmungsergebnisse für den Therapiealltag in Deutschland zu konkretisieren. Eine deutsche Arbeitsgruppe mit acht Brustkrebsexperten, von denen zwei Mitglieder des internationalen St. Gallen-Panels sind, hat daher die Abstimmungsergebnisse der St. Gallen-Konsensuskonferenz (2013) für den Klinikalltag in Deutschland kommentiert. Inhaltliche Schwerpunkte der diesjährigen St. Gallen-Konferenz waren operative Fragestellungen der Brust und der Axilla, strahlentherapeutische und systemische Therapieoptionen sowie die klinische Relevanz der Tumorbiologie. Intensiv diskutiert wurde der klinische Einsatz von Multigen-Assays, inkl. ihrer Bedeutung für die individuelle Therapieentscheidung. 相似文献44.
45.
Teuber Ziwen Nussbeck Fridtjof W. Wild Elke 《Child psychiatry and human development》2022,53(2):403-403
Child Psychiatry & Human Development - A correction to this paper has been published: https://doi.org/10.1007/s10578-021-01198-3 相似文献
46.
Kuhla B Boeck K Schmidt A Ogunlade V Arendt T Münch G Lüth HJ 《Neurobiology of aging》2007,28(1):29-41
The reaction of lysine and arginine residues of proteins with 1,2-dicarbonyl compounds result in the formation of advanced glycation end products (AGEs). Accumulation of AGEs is a characteristic feature of the aging brain and contributes to the development of neurodegenerative diseases such as Alzheimer's disease (AD). Therefore, it is of particular interest to study the cellular defense mechanisms against AGE formation and particularly the detoxification of their precursors. AGE precursor compounds such as methylglyoxal and glyoxal were cellulary detoxified by the glyoxalase system, consisting of glyoxalases I and II. Glyoxalase I levels are diminished in old aged brains but elevated in AD brains. However, it is still unknown how glyoxalase I level of AD brains changes in a disease and in an age-dependent manner. Therefore, we investigated the AD stage- and the age-dependent levels of glyoxalase I in the Brodmann area 22 of AD brains (n=25) and healthy controls (n=10). Our results obtained from RT-PCR reveal reducing glyoxalase I RNA levels with advancing stage of AD and with increasing age. Western Blot analysis indicates that in comparison to healthy controls, glyoxalase I protein amounts are 1.5-fold increased in early AD subjects and continuously decrease in middle and late stages of AD. The glyoxalase I protein amounts of AD patients also decrease with age. Results obtained from glyoxalase I activity measurement show 1.05-1.2-fold diminished levels in AD brains compared to healthy controls and no significant decrease neither with the stage of AD nor with age. The immunohistochemical investigations demonstrate an elevated number of glyoxalase I stained neurons in brains of early and middle but not in late AD subjects compared to age-matched healthy controls. In addition, the stage-dependent immunohistochemical investigation demonstrates that with reduced glyoxalase I staining AGE deposits prevail, specifically in late stage of AD. In conclusion, the decrease of glyoxalase I expression with increasing AD stage might be one reason for methylglyoxal-induced neuronal impairment, apoptosis, and AGE formation in plaques and tangles. 相似文献
47.
Heller F Lindenmeyer MT Cohen CD Brandt U Draganovici D Fischereder M Kretzler M Anders HJ Sitter T Mosberger I Kerjaschki D Regele H Schlöndorff D Segerer S 《The American journal of pathology》2007,170(2):457-468
Local B-cell infiltrates play a role in tissue fibrosis, neolymphangiogenesis, and renal allograft survival. We sought to characterize the B-cell infiltrates, factors involved in B-cell recruitment, and lymphangiogenesis in renal interstitial injury (ie, acute and chronic interstitial nephritis and chronic IgA nephropathy). CD20-positive B cells formed a prominent part of the interstitial infiltrating cells. Together with CD3-positive T cells, the CD20-positive B cells formed larger nodular structures. CD10-positive pre-B cells were rare, and the majority were mature CD27-positive B cells. Proliferating B cells were detected within nodular infiltrates. The level of mRNA expression of the chemokine CXCL13 was increased and correlated with CD20 mRNA in the tubulointerstitial space. CXCL13 protein was predominantly found at sites of nodular infiltrates, in association with CXCR5-positive B cells. Furthermore, sites of chronic interstitial inflammation were associated with a high number of lymphatic vessels. B-cell infiltrates form a prominent part of the interstitial infiltrates both in primary interstitial lesions and in IgA nephropathy. CXCR5-positive B cells might be recruited via the chemokine CXCL13 and seem to contribute to the formation of intrarenal lymphoid follicle-like structures. These might represent an intrarenal immune system. 相似文献
48.
Ninichuk V Khandoga AG Segerer S Loetscher P Schlapbach A Revesz L Feifel R Khandoga A Krombach F Nelson PJ Schlöndorff D Anders HJ 《The American journal of pathology》2007,170(4):1267-1276
Diabetic nephropathy is associated with interstitial macrophage infiltrates, but their contribution to disease progression is unclear. We addressed this question by blockade of chemokine receptor (CCR)1 because CCR1 mediates the macrophage recruitment to the renal interstitium. In fact, when CCR1 was blocked with BL5923, a novel orally available CCR1 antagonist, the interstitial recruitment of ex vivo labeled macrophages was markedly decreased in uninephrectomized male db/db mice with advanced diabetic nephropathy. Likewise, BL5923 (60 mg/kg, twice a day) orally administered from months 5 to 6 of life reduced the numbers of interstitial macrophages in uninephrectomized db/db mice. This was associated with reduced numbers of Ki-67 proliferating tubular epithelial and interstitial cells, tubular atrophy, and interstitial fibrosis in uninephrectomized db/db mice. Glomerular pathology and proteinuria were not affected by the CCR1 antagonist. BL5923 reduced renal mRNA expression of Ccl2, Ccr1, Ccr2, Ccr5, transforming growth factor-beta1, and collagen I-alpha1 when compared with untreated uninephrectomized male db/db mice of the same age. Thus, we identified a previously unrecognized role for interstitial macrophages for tubulointerstitial injury, loss of peritubular microvasculature, interstitial inflammation, and fibrosis in type 2 diabetic db/db mice. These data identify oral treatment with the CCR1 antagonist BL5923 as a potential therapy for late-stage diabetic nephropathy. 相似文献
49.
Gunnar Plehn Julia Vormbrock Christian Zühlke Martin Christ Christian Perings Stefan Perings Hans-Joachim Trappe und Axel Meissner 《Medizinische Klinik》2007,102(9):707-713
BACKGROUND AND PURPOSE: Cardiac performance can be characterized in terms of the relative duration of systole and diastole. In pediatric patients with dilated cardiomyopathy (DCM), a disproportionate shortening of left ventricular diastole was observed. The present study was intended to reproduce these findings in an adult patient group and to evaluate exercise-related changes of both time intervals. PATIENTS AND METHODS: Exercise radionuclide angiography was used in 61 patients with DCM NYHA (New York Heart Association) stage II-III. The phases of the cardiac cycle were derived from a radionuclide time-activity curve with high temporal resolution. The control group consisted of 26 patients referred for ventricular function assessment with radionuclide angiography before cardiotoxic cancer treatment. RESULTS: When the duration of systole was expressed as the product of systolic time and heart rate, DCM patients exhibited a significant increase in left ventricular systolic time at rest (23.9 vs. 21.5 s/min; p = 0.006) and during peak exercise (29.2 vs. 26.7 s/min; p = 0.01). The prolongation of left ventricular systole at peak exercise was evident, although the peak heart rate was significantly lower in the patient group than in the control group (118 vs. 127/min; p = 0.04). In DCM patients the diastolic time loss per beat was further quantified using a regression equation obtained from the healthy control group. A significant shortening of left ventricular diastolic time was confirmed during peak exercise. Furthermore, a progressive loss in diastolic time per beat from rest to peak exercise was noted. CONCLUSION: Cardiac cycle abnormalities of patients with DCM are characterized by a prolongation of left ventricular systole and an abnormal shortening of left ventricular diastole. The systolic-diastolic mismatch is accentuated during exercise and has the potential to impair the cardiac reserve in these patients by restricting ventricular filling and perfusion. 相似文献
50.
Malte A. Kluger Michael Luig Claudia Wegscheid Boeren Goerke Hans-Joachim Paust Silke R. Brix Isabell Yan Hans-Willi Mittrücker Beate Hagl Ellen D. Renner Gisa Tiegs Thorsten Wiech Rolf A.K. Stahl Ulf Panzer Oliver M. Steinmetz 《Journal of the American Society of Nephrology : JASN》2014,25(6):1291-1302