Therapy with TLR7 agonists induces lymphopenia: correlating pharmacology to mechanism in a mouse model.
J Clin Immunol
; 32(5): 1082-92, 2012 Oct.
Article
em En
| MEDLINE
| ID: mdl-22476912
ABSTRACT
BACKGROUND AND OBJECTIVE:
Synthetic TLR7 agonists have been proposed as oral replacements for interferonα (IFNα) therapy in the treatment of hepatitis C virus infection. However, adverse effects, such as lymphopenia and cardiovascular irregularities, have been observed in the clinical following treatment with TLR7 agonists. We wished to understand and characterise the relationship between TLR7 agonism and adverse effects.METHODS:
We compared responses to two prototypic TLR7 agonists (Resiquimod R-848; and PF-04878691) in a mouse model and compared the responses to treatment with IFNα. We measured clinically relevant adverse effects such as lymphopenia and cardiovascular irregularities and related them to plasma drug levels and clinically relevant efficacy biomarkers such as the pro-inflammatory cytokine IP-10, 2'5'OAS and TLR7 receptor expression.RESULTS:
By 2 h post dose all agents had induced a dose-dependent transient lymphopenia. IFNα increased heart rate immediately following dosing, persisting for 5 h, whilst PF-04878691 induced significant reductions in blood pressure. Lymphopenia co-incided with maximum plasma drug levels, raised levels of IP-10 and the auto-induction of TLR7 expression in the blood and lymph nodes. Peak levels of 2'5'OAS occurred at 24 h post-dose and only at doses which also induced lymphopenia.CONCLUSIONS:
We conclude that systemic delivery of TLR7 agonists or IFNα induces similar exaggerated pharmacology, consistent with there being a narrow therapeutic window between efficacy and safety. This clinically validated mouse model will help to investigate whether more potent agonists or optimised dosing schedules, will be successful strategies for targeting TLR7 in patients.
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Base de dados:
MEDLINE
Assunto principal:
Sulfonamidas
/
Receptor 7 Toll-Like
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Aminoquinolinas
/
Hipotensão
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Imidazóis
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Linfopenia
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article