Differential capacity of therapeutic drugs to induce Rods/Rings structures in vitro and in vivo and generation of anti-Rods/Rings autoantibodies

Differential capacity of therapeutic drugs to induce Rods/Rings structures in vitro and in vivo and generation of anti-Rods/Rings autoantibodies

Author Keppeke, Gerson Dierley Autor UNIFESP Google Scholar
Prado, Monica Simon Autor UNIFESP Google Scholar
Nunes, Eunice Autor UNIFESP Google Scholar
Perazzio, Sandro Felix Autor UNIFESP Google Scholar
Rodrigues, Silvia Helena Autor UNIFESP Google Scholar
Ferraz, Maria Lucia Cardoso Gomes Autor UNIFESP Google Scholar
Chan, Edward K. L. Google Scholar
Andrade, Luiz Eduardo Coelho Autor UNIFESP Google Scholar
Abstract Some HCV patients using ribavirin and interferon alpha (IFN-alpha) develop anti-rods and rings (RR) autoantibodies, the main target of which is inosine monophosphate dehydrogenase (IMPDH), the rate-determining enzyme in de novo GTP biosynthesis. In vitro inhibition of IMPDH by ribavirin induces RR formation. Here we investigate whether other commonly used drugs that interfere with GTP biosynthesis can induce RR structures in vitro and vivo and elicit generation of autoantibodies. HEp-2 cells treated for 24 h with ribavirin, mycophenolic acid (MPA), azathioprine, methotrexate or acyclovir were positive for RR structures. However, adefovir, entecavir, tenofovir and lamivudine did not induce RR structures in these cells. Structures induced by ribavirin in HEp-2 cells are stable after 24 h drug-washout, while structures induced by other drugs are relatively labile, disappearing within 2 h. Looking at patients treated with these drugs, HCV patients treated with ribavirin (n = 17) showed higher average percentage of RR-positive peripheral mononuclear cells than autoimmune patients treated with RR-inducing immunosuppressant drugs (n = 21). Serum from 173 autoimmune patients who had been treated with MPA, azathioprine or methotrexate was tested for presence of anti-RR autoantibodies, and only one sample was found to be positive. Conversely, of 48 anti-RR autoantibody positive samples identified at Fleury Laboratories over 30 months, 94% were from HCV patients treated with ribavirin plus IFN-alpha. These data indicate that RR structures can be induced by a variety of drugs in vitro and in vivo, but anti-RR autoantibody production is mostly restricted to HCV patients under ribavirin + IFN-alpha treatment. (C) 2016 Elsevier Inc. All rights reserved.
xmlui.dri2xhtml.METS-1.0.item-coverage San Diego
Language English
Sponsor Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Grant number CNPq: 305064/2011-8
CNPq: 232711/2014-3
CAPES: 9028-11-0
FAPESP: 2011/12448-0
Date 2016
Published in Clinical Immunology. San Diego, v. 173, p. 149-156, 2016.
ISSN 1521-6616 (Sherpa/Romeo, impact factor)
Publisher Academic Press Inc Elsevier Science
Extent 149-156
Origin http://dx.doi.org/10.1016/j.clim.2016.10.004
Access rights Closed access
Type Article
Web of Science ID WOS:000389864200020
URI https://repositorio.unifesp.br/handle/11600/56627

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