Effects of vitamin D3 and cyclosporin A on HgCl2-induced autoimmunity in Brown Norway rats

BACKGROUND.: Mercuric chloride (HgCl₂ induces a lymphoproliferative disorderand autoimmune glomerulonephritis in Brown Norway (BN) rats.This syndrome is the consequence of T cell-dependent polyclonalB cell activation and autoantibody production. We have previouslyshown that HgCl₂-induced autoimmune perturbations can be preventedin BN rats by the administration of cyclosporin A (CsA). Themost potent vitamin D₃ metabolite 1,25(OH)₂ D₃ (Vit D₃) sharescertain immunomodulatory properties with CsA. We therefore choseto compare the effects of Vit D₃ to those of CsA in BN ratstreated with HgCl₂ in order to establish whether Vit D₃ eitheralone or in combination with CsA can attenuate an autoimmunesyndrome in vivo. METHODS.: BN rats were treated with HgCl₂ according to a standard protocol.Subgroups of rats were also given CsA alone, Vit D₃ or syntheticanalogues of Vit D₃ alone, or combinations of both agents. Differentdoses and routes of administration were compared. The followingmarkers of disease activity were evaluated: mortality, peakproteinuria, serum IgE concentrations, and renal immunoglobulindeposition. RESULTS.: Disease activity was markedly attenuated in all rats treatedwith CsA alone. Vit D₃ and certain of its synthetic analoguesadministered alone also tempered the autoimmune process, butto a lesser extent than did CsA. The effect of CsA alone wasso potent, that no additive or synergistic effects could bedemonstrated when CsA was administered in combination with VitD₃. CONCLUSIONS.: Despite similar described immunomodulatory effects in vitro,CsA is clearly more effective than Vit D₃ in preventing HgCl₂autoimmune disease in BN rats. This suggests that there is adifference in the cellular targets of these two agents in vivo,and/or a difference in the potency with which HgCl2-triggeredimmune activation is suppressed.     

Invariant and noninvariant natural killer T cells exert opposite regulatory functions on the immune response during murine schistosomiasis

CD1d-restricted natural killer T (NKT) cells represent a heterogeneous population of innate memory immune cells expressing both NK and T-cell markers distributed into two major subsets, i.e., invariant NKT (iNKT) cells, which express exclusively an invariant T-cell receptor (TCR) alpha chain (Valpha14Jalpha18 in mice), and non-iNKT cells, which express more diverse TCRs. NKT cells quickly produce Th1- and/or Th2-type cytokines following stimulation with glycolipid antigen (Ag) and, through this property, play potent immunoregulatory roles in autoimmune diseases, cancer, and infection. No study has addressed the role of NKT cells in metazoan parasite infections so far. We show that during murine schistosomiasis, the apparent frequency of both iNKT cells and non-iNKT cells decreased in the spleen as early as 3 weeks postinfection (p.i.) and that both populations expressed a greater amount of the activation marker CD69 at 6 weeks p.i., suggesting an activated phenotype. Two different NKT-cell-deficient mouse models, namely, TCR Jalpha18-/- (exclusively deficient in iNKT cells) and CD1d-/- (deficient in both iNKT and non-iNKT cells) mice, were used to explore the implication of these subsets in infection. We show that whereas both iNKT and non-iNKT cells do not have a major impact on the immune response during the early phase (1 and 4 weeks) of infection, they exert important, although opposite, effects on the immune response during the acute phase of the disease (7 and 12 weeks), after schistosome egg production. Indeed, iNKT cells contribute to Th1 cell differentiation whereas non-iNKT cells might be mostly implicated in Th2 cell differentiation in response to parasite Ag. Our findings suggest, for the first time, that helminths activate both iNKT and non-iNKT cells in vivo, enabling them to differentially influence the Th1/Th2 balance of the immune response.     

Plasma Exchange in a Rat Model of Autoimmune Glomerulonephritis

Using an original technique permitting repeated plasma exchangein the rat, we have tested this therapeutic approach in animalsactively immunised with horseradish peroxidase, and in ratswith HgCl₂-induced autoimmune glomerulonephritis. Plasma exchangeeffectively removes circulating JgG anti-horseradish peroxidaseantibodies from the sera of immunised rats. When applied tothe model of HgCl₂ antiglomerular basement membrane glomerulonephritisin Brown-Norway rats, this technique is also remarkably effective.In these rats, proteinuria is abolished during the plasma exchangetreatment period and no circulating antiglomerular basementmembrane antibodies can be detected. These antibodies are, however,found in the ultrafiltrates of exchanged rats. Serum IgE, characteristicallyelevated in HgCl₂-treated rats, is also markedly diminishedin exchanged rats. Control rats treated with infusions of freshfrozen plasma or with heparin alone did not show any improvementin disease severity. These results suggest that plasma exchangealone can attenuate antiglomerular basement membrane nephritisin HgCl₂-treated rats. This observation may be of relevancefor the treatment of human antiglomerular-basement membrane-mediatedglomerulonephritis.     

Retention in edema of the upper limb]

Treatment of lymphedema of the upper limb by the now classical elastocompression technique of Van Der Mollen, provides a reduction time that is followed by retention. The latter is selected and adapted in keeping with clinical elements and is definitive. It is necessary to provide both psychological assistance and to check on proper local tolerance. The elastic arm band assures under these conditions a satisfactory correction of "swollen arm".     

TMC647055, a Potent Nonnucleoside Hepatitis C Virus NS5B Polymerase Inhibitor with Cross-Genotypic Coverage

Hepatitis C virus (HCV) infection is a major global health burden and is associated with an increased risk of liver cirrhosis and hepatocellular carcinoma. There remains an unmet medical need for efficacious and safe direct antivirals with complementary modes of action for combination in treatment regimens to deliver a high cure rate with a short duration of treatment for HCV patients. Here we report the in vitro inhibitory activity, mode of action, binding kinetics, and resistance profile of TMC647055, a novel and potent nonnucleoside inhibitor of the HCV NS5B RNA-dependent RNA polymerase. In vitro combination studies with an HCV NS3/4A protease inhibitor demonstrated potent suppression of HCV RNA replication, confirming the potential for combination of these two classes in the treatment of chronic HCV infection. TMC647055 is a potent nonnucleoside NS5B polymerase inhibitor of HCV replication with a promising in vitro biochemical, kinetic, and virological profile that is currently undergoing clinical evaluation.     

Rat monoclonal antibodies. III. A simple method for facilitation of hybridoma cell growth in vivo

Hybridoma cells that did not grow when injected subcutaneously or intraperitoneally in histocompatible or Rnu/Rnu rats were injected intravenously into histocompatible recipients. Eight of the 9 cell lines injected in this way grew in several organs of the recipient 3-7 weeks later. Hybridoma cells proliferated mainly in the liver. When the liver homogenate of these animals was injected intraperitoneally into histocompatible recipients, hybridoma cells grew readily giving rise to ascites containing the expected monoclonal antibody for 6 of the 9 cell lines.     

Zirconia: Established facts and perspectives for a biomaterial in dental implantology

Currently, zirconia is widely used in biomedical area as a material for prosthetic devices because of its good mechanical and chemical properties. Largely employed in clinical area for total hip replacement, zirconia ceramics (ZrO(2)) are becoming a prevalent biomaterial in dentistry and dental implantology. Although titanium is used in dental implantology currently, there is a trend to develop new ceramic-based implants as an alternative to monolithic titanium. This article reviews the evolution and development of zirconia through data published between 1963 and January 2008 in English language. Articles were identified via a MEDLINE search using the following keywords: zirconia, zirconia/biocompatibility, zirconia/osseointegration, zirconia/periointegration, zirconia/review, and zirconia/bacterial adhesion or colonization. This review of the literature aims at highlighting and discussing zirconia properties in biological systems for their future use in dental implantology. In conclusion, zirconia with its interesting microstructural properties has been confirmed to be a material of choice for the "new generation" of implants, thanks to its biocompatibility, osseoconductivity, tendency to reduce plaque accumulation, and interaction with soft tissues, which leads to periointegration. However, scientific studies are promptly needed to fulfill gaps like long-term clinical evaluations of "all zirconia implants," currently leading to propose an alternative use of "hybrid systems" (i.e., titanium screw with zirconia collar) and also bacterial colonization of zirconia. Moreover, there is a permanent need for consistent information about topography and chemistry of zirconia allowing easier cross-product comparisons of clinical devices.     

T-cell responsiveness towards various synthetic peptides of the P28 antigen in rat and mouse models during Schistosoma mansoni infection.

It has recently been demonstrated that the Schistosoma mansoni P28 antigen can induce a strong protective immunity after direct immunization in various experimental models. T lymphocytes from Fischer rats immunized with the recombinant P28 antigen were cultured in vitro in the presence of seven synthetic peptides derived from the amino acid sequence of the P28. The most significant and reproducible proliferation was obtained with the 24-43 and 115-131 synthetic peptides. In order to analyze whether these located determinants were also exposed to the host's immune system during the natural S. mansoni infection or after immunization with crude antigenic extracts of various development stages of the parasite, the T-cell responsiveness of infected or immunized Fischer rats and BALB/c mice was tested towards these synthetic peptides. The results showed that, in both permissive (mouse) and non-permissive (rat) hosts, 24-43 and 115-131 synthetic peptides are recognized during the course of infection and that there is a dynamic variation of this recognition. These peptides are also recognized by T cells educated against crude antigenic extracts of different developmental stages of the parasite which contained the native form of the P28 molecule. Taken together, the results indicated that these synthetic peptides derived from the recombinant P28 antigen can activate T lymphocytes educated against the native P28 molecule during the development and maturation of the parasite in their hosts. Therefore, they might be useful for the construction of synthetic vaccines against schistosomiasis.