Biomedical subjects

B Ryffel

Publications and source records attributed to B Ryffel.

167 records · Page 10Linked to original sources

PubMedDate not supplied

Nephrotoxicity of immunosuppressants in rats: comparison of macrolides with cyclosporin.

The nephrotoxic potential of the macrolide immunosuppressants, FK506 and rapamycin, was compared with that of cyclosporin (CsA) in male Wistar rats. FK506 induced a reduction of creatinine clearance, hypomagnesemia and hyperuricemia as previously described for CsA. In contrast, equidosed rapamycin did not alter the glomerular filtration rate. FK506 caused proximal tubular epithelial changes consisting of atrophy, vacuolization, inclusion bodies, microcalcification and focal mononuclear interstitial infiltrate as described for CsA. The most striking alteration was hypertrophy of the juxtaglomerular apparatus (JGA). The percentage of renin-containing JGA and the extent of renin immunoreactivity along afferent vessels were significantly increased in FK506- and CsA-treated rats. By contrast, no renal morphologic lesions were found in rapamycin-treated animals. Renal cortical extracts contained abundant cyclophilin and FK506-binding protein (FKBP), the main intracytoplasmic receptors for CsA and FK506, respectively. Furthermore, we demonstrated that receptor bound CsA and FK506, but not rapamycin, formed complexes with the phosphatase calcineurin, as shown previously for lymphocytes. Thus, it is hypothesized that both the immunosuppressive and toxic effects of FK506 and CsA, but not of rapamycin, are mediated through an immunophilin-drug-calcineurin complex. The renal substrate of calcineurin, which mediates renal vasoconstriction is yet to be identified.

Amino Acid Isomerases↗

PubMedDate not supplied

Lipopolysaccharide-induced glomerulonephritis develops in the absence of interferon-gamma signaling.

IFN gamma is a costimulator of macrophage activation and it plays an important role as a proinflammatory cytokine by upregulation of adhesion molecules and MHC antigens. In this study we tested the role of IFN gamma in a model of endotoxin-induced glomerulonephritis. A systemic lupus-like disease was induced by injection of 50 micrograms bacterial LPS twice a week for 4 weeks in wild-type and in IFN gamma receptor-deficient (IFN gamma R-/-) mice. The renal cortex was examined by immunofluorescence and by light microscopy. LPS treatment induced an increase in serum levels of IgG and anti-dsDNA antibodies. A mild glomerulonephritis was characterized morphologically, but proteinuria was not observed. The main histological features of glomerulonephritis were an increase in ICAM-1 expression, deposition of immune complexes and of complement in the glomeruli, increased mesangial matrix and mesangial hypercellularity. The number of intraglomerular leukocytes, detected by MHC class-II and LFA-1 expression increased roughly 4-fold. All those alterations took place in a similar manner in wild-type and in IFN gamma R-/-mice. Therefore it is concluded that IFN gamma does not play an important role in the development of endotoxic glomerulonephritis.

Animals↗

PubMedDate not supplied

Tumor necrosis factor receptor-1 signaling is required for differentiation of follicular dendritic cells, germinal center formation, and full antibody responses.

Using mice double deficient for tumor necrosis factor and lymphotoxin alpha (TNF/LT alpha-/-) we have demonstrated that TNF and/or LT alpha are important for morphogenesis of secondary lymphoid organs and for T-cell-dependent antibody responses. In the present study we attempted to identify the receptors involved in those functions of TNF and LT alpha. Spleen morphology and antibody responses were investigated in wild-type, TNFR1-/-, TNFR2-/-, and TNF/LT alpha-/- mice immunized with SRBC. TNF/LT alpha-/- mice, which have a complete disruption of the TNF/LT alpha signaling system including the lymphotoxin beta (LT beta) receptor pathway, displayed an abnormal splenic microarchitecture and isotype switch did not take place. TNFR1-/- and TNFR2-/- mice displayed a normal splenic morphology and mounted an IgM and IgG antibody response to SRBC. However, the IgG production in TNFR1-/- mice was abnormal, with titers leveling off after 6 days following primary immunization, and with a minimal response to a second antigen challenge. Immunofluorescence analysis of spleen sections revealed in this strain a lack of follicular dendritic cell (FDC) network and of germinal centers. In conclusion, while normal splenic microarchitecture and isotype switch might require the LT beta receptor, differentiation of the FDC network, development of germinal centers, a sustained IgG response, and probably the development of memory cells depend on signaling via TNFR1.

Animals↗

PubMedDate not supplied

Contribution of TNF/TNF receptor and of Fas ligand to toxicity in murine models of endotoxemia and bacterial peritonitis.

Fas/Fas ligand and TNF/TNF receptors are involved in apoptosis. Whether both systems are involved in septic shock has not been determined so far. We investigated the role of TNF/TNFR and Fas/Fas ligand in models of endotoxemia and of speticemia in mice. Upon LPS challenge, TNF and TNFR p55 were involved in the process inducing lethality. FasL did not contribute to enhance lethality, as evidenced in gld mice, lacing FasL. Following an intraperitoneal injection of live E. coli, TNF and TNFR p55 were necessary to combat infection. Disruption of either gene was associated with enhanced lethality and failure to clear the bacteria. No effect observed in gld mice in this peritonitis model. Thus, these observations confirmed the pathogenic role of TNF/TNFR in endotoxemia and its beneficial role in local bacterial infections. In addition the data ruled out a major role for Fas/FasL in septic shock in mice.

Animals↗

PubMedDate not supplied

Crescentic glomerulonephritis in interferon-gamma receptor deficient mice.

Activation of macrophages by T cells is considered an initiating event in glomerular crescent formation. Since interferon-gamma (INF gamma) is a key mediator in T-cell-mediated activation of macrophages, we decided to test its role in a model of crescentic glomerulonephritis. An anti-glomerular basement membrane (GBM) serum was injected intravenously in presensitized wild-type or IFN gamma receptor deficient (IFN gamma(R)-/-) mice. Glomerulonephritis with glomerular crescents and tubulointerstitial inflammation developed in both strains, even though most evaluated morphological parameters and proteinuria indicated a less severe pathology in the mutant mice compared to the wild type. Thus, IFN gamma is not essential either for glomerular crescent formation or for tubulointerstitial involvement in anti-GBM glomerulonephritis in mice. In conclusion, the role of macrophages in this model might have been overestimated, or other cytokines may compensate for deficient IFN gamma signaling in the activation of macrophages.

Animals↗