Effect of a Novel Immunosuppressant, FK 506, on Autoimmune Glomerulonephritis in Brown Norway Rats

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Mercuric-chloride (HgCl2) induces a lymphoproliferative disorder and autoimmune glomerulonephritis in Brown Norway rats. The effects of a new immunosuppressant FK 506 on this model of glomerulonephritis were studied. Brown Norway rats were treated with HgCl2 according to a standard protocol (HgCl2 1 mg/kg s.c. 3 times/ week). Rats developed proteinuria at day 7, which reached a plateau level at day 14. On day 14, renal histology showed prominent mesangial cellular proliferation and the expansion of mesangial matrix. Electron microscopic study showed the effacement of visceral epithelial foot processes and the microvillous transformation of the visceral epithelium. Immunofluorescence study showed a strong linear staining for IgG and the adhesion molecule ICAM-1 in all glomeruli. Coadministration of FK 506 (1 mg/kg s.c. daily) prevented the appearance of proteinuria at day 14 (621.4 ± 30.5 vs. 2.2 ± 2.7 mg/day) and the morphological lesions. These findings suggest that FK 506 could be useful for the therapy of certain types of human glomerulonephritis.

Related collections

Most cited references 2

Record: found
Abstract: found
Article: not found

A receptor for the immunosuppressant FK506 is a cis-trans peptidyl-prolyl isomerase.

Kathleen Harding, A Galat, Rebecca Schreiber … (1989)

The structurally novel macrolide FK506 (refs 1,2) has recently been demonstrated to have potent immunosuppressive activity at concentrations several hundredfold lower than cyclosporin A (CsA). Cyclosporin A, a cyclic peptide, has found widespread clinical use in the prevention of graft rejection following bone marrow and organ transplantation. The mechanisms of immunosuppression mediated by FK506 and CsA appear to be remarkably similar, suggesting that these unrelated structures act on a common receptor or on similar molecular targets, perhaps the CsA receptor, cyclophilin, which has recently been shown by Fischer et al. and Takahashi et al. to have cis-trans peptidyl-prolyl isomerase activity. We have prepared an FK506 affinity matrix and purified a binding protein for FK506 from bovine thymus and from human spleen. This FK506-binding protein (FKBP) has a relative molecular mass (Mr) of approximately 14,000(14K), a pI of 8.8-8.9, and does not cross-react with antisera against cyclophilin. The first 40 N-terminal residues of the bovine and 16 residues of the human FKBP were determined; the 16-residue fragments are identical to each other and unrelated to any known sequences. This protein catalyses the cis-trans isomerization of the proline amide in a tetrapeptide substrate and FK506 inhibits the action of this new isomerase. The FKBP and cyclophilin appear to be members of an emerging class of novel proteins that regulate T cell activation and other metabolic processes, perhaps by the recognition (and possibly the isomerization) of proline-containing epitopes in target proteins.

0 comments Cited 140 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Susceptibility to mercuric chloride-induced glomerulonephritis is age-dependent: study of the role of IFN-gamma.

P H van der Meide, R Groenestein, M de Labie … (1995)

The repeated administration of low-dose HgCl2 to brown Norway (BN) rats induces an autoimmune syndrome which is characterized by polyclonal B cell activation, high-level synthesis of IgE and IgG1, and massive proteinuria. Data have been presented suggesting that during disease development there is a preferential expansion of CD4+ T cells belonging to the TH2 subset. In the present study it was found that aged BN rats are far less susceptible to the immunopathological effects of HgCl2 compared to their younger counterparts. Whereas rats at 10 weeks of age develop high-level proteinuria upon three repeated injections with HgCl2, animals at 18 to 24 months of age do not release urinary protein under these conditions and develop low-level proteinuria with a delayed onset after five repeated injections with HgCl2. FACScan analysis of splenocytes from old and young rats revealed a defined increase in the frequency of CD45RB(RC)+/CD4+ T cells in the splenocyte population of older rats, suggesting an age-related shift to a more TH1-like phenotype. Moreover, splenocytes of aged rats generated a threefold higher number of IFN-gamma-producing cells than those of young rats upon polyclonal activation in vitro. The administration of neutralizing anti-rat IFN-gamma mono- and/or polyclonal antibodies to aged BN rats just prior to HgCl2 exposure significantly augmented IgE and IgG1 serum levels and exerted a small but significant stimulatory effect on proteinuria in the initial stage but not in the more advanced stages of the renal disease. When antibodies were given 7 days after the beginning of HgCl2 exposure no stimulatory effect on both IgE/IgG1 levels and proteinuria was observed. The data indicate that splenic T cells of aged BN rats possess a higher capacity to release IFN-gamma than those of young rats and that this cytokine functions to downregulate IgG1 and IgE synthesis in HgCl2-exposed BN rats. The findings further suggest that IFN-gamma plays a regulatory role in the development of glomerulonephritis.

0 comments Cited 3 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (publisher-id): NEF

Journal ID (nlm-ta): Nephron

Journal ID (doi): 10.1159/issn.1660-8151

Title: Nephron

Publisher: S. Karger AG

ISSN (Print): 1660-8151

ISSN (Electronic): 2235-3186

Publication date Subscription-year: 1999

Publication date (Print): 1999

Publication date (Electronic): 10 February 1999

Volume: 81

Issue: 2

Pages: 215-220

Affiliations

^aFifth Department of Internal Medicine, Hyogo College of Medicine, Hyogo, ^bSchool of Allied Health Sciences, Faculty of Medicine, Osaka University, Osaka, and ^cFirst Department of Medicine, Osaka University, Osaka, Japan

Article

Publisher ID: 45279 Other ID: Nephron 1999;81:215–220

DOI: 10.1159/000045279

PubMed ID: 9933758

SO-VID: 23043171-bac6-41a8-bfba-7bd565e96bca

License:

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Call for Papers: Green Renal Replacement Therapy: Caring for the Environment

Submit here before July 31, 2024

Effect of a Novel Immunosuppressant, FK 506, on Autoimmune Glomerulonephritis in Brown Norway Rats

Read this article at

Abstract

Related collections

Karger: Nephrology

Most cited references 2

A receptor for the immunosuppressant FK506 is a cis-trans peptidyl-prolyl isomerase.

Susceptibility to mercuric chloride-induced glomerulonephritis is age-dependent: study of the role of IFN-gamma.

Author and article information

Journal

Affiliations

Article

History

Page count

Categories

Comments

Comment on this article

Similar content 454

Most referenced authors 17