Immunopharmacology of CpG Oligodeoxynucleotides and Ribavirin

Vollmer, Jörg; Rankin, Robert; Hartmann, Hanna; Jurk, Marion; Samulowitz, Ulrike; Wader, Tanja; Janosch, Andrea; Schetter, Christian; Krieg, Arthur Μ.

doi:10.1128/aac.48.6.2314-2317.2004

Cited by 27 publications

(18 citation statements)

References 13 publications

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“…The exact mechanism by which ribavirin contributes to anti-HCV activity is not fully understood, and may involve both immune-modulating and direct antiviral actions. 33,34 However, at in vitro concentrations up to approximately 200 mol/L (severalfold higher than plasma concentrations achieved in patients), ribavirin lacks the TLR7-activating properties of isatoribine, 14,35 and so the mechanism of anti-HCV activity by isatoribine is likely distinct from that of ribavirin.…”

Section: Discussionmentioning

confidence: 99%

Isatoribine, an agonist of TLR7, reduces plasma virus concentration in chronic hepatitis C infection

et al. 2005

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Immune-based therapy is the mainstay treatment for chronic hepatitis C virus (HCV) infection but causes multiple side effects and achieves durable viral clearance in only approximately 50% of patients. Most new investigational anti-HCV compounds are direct-acting antivirals for which durability of response and risk of viral mutations and resistance are not yet known. Therefore, continuing discovery and development of new immune-based treatments is desirable. Toll-like receptors (TLRs) are pathogen recognition receptors that initiate the innate immune response. The responsiveness of HCV or other ongoing chronic systemic infections to treatment with a selective TLR agonist has not been reported. Isatoribine is a selective agonist of TLR7. In a proof-of-concept study, we found that once-daily 7-day treatment with intravenous isatoribine 800 mg caused a significant (P ‫؍‬ .001) reduction of plasma HCV RNA (mean, ؊0.76; range, ؊2.85 to ؉0.21 log 10 units) in otherwise untreated patients (n ‫؍‬ 12) who were chronically infected with HCV. Viral load reduction occurred in patients infected with genotype 1 as well as non-genotype 1 HCV. The reduction of viral load was correlated with induction of markers of a heightened immune antiviral state, including 2-, 5-oligoadenylate synthetase levels in whole blood. This treatment was well tolerated, with a low frequency of mild to moderate adverse events. In conclusion, systemic administration of the selective TLR7 agonist isatoribine resulted in dose-dependent changes in immunologic biomarkers and a statistically significant antiviral effect with relatively few and mild side effects. ( C hronic infection with hepatitis C virus (HCV) is a major cause of morbidity and mortality, affecting 170 million persons worldwide. 1,2 Although chronic HCV infection is largely asymptomatic, persistent infection over many years significantly increases the risk of cirrhosis, hepatocellular carcinoma, and end-stage liver disease. [1][2][3][4] The current standard-of-care treatment for HCV infection is immune based, consisting of an injectable interferon-alpha product (a type 1 cytokine) in combination with the orally administered nucleoside analog ribavirin. 1,5,6 This treatment can durably clear HCV from approximately 50% of treated patients but has multiple side effects that often result in early abandonment of treatment. Thus, a need remains for novel anti-HCV therapies to improve response rates and reduce adverse effects.A variety of investigational anti-HCV compounds are approaching or undergoing clinical studies. 7 Aside from modified versions of interferon-alpha and ribavirin, most investigational compounds are direct-acting antivirals that bind to virally encoded targets. Whether durable virological responses can be achieved with direct-acting anti-HCV agents is unknown. Moreover, the high rate and low fidelity of HCV replication may lead to rapid emergence of resistance to direct-acting antivirals. 8,9 In light of these uncertainties, continuing to explore immune stimulation as an appro...

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Section: Discussionmentioning

confidence: 99%

Isatoribine, an agonist of TLR7, reduces plasma virus concentration in chronic hepatitis C infection

et al. 2005

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“…4,5 However, one should be aware that acyclic nucleotide analogs may be able to express several other putative mechanisms of action, including that of an immunoregulator. [6][7][8][9][10] From these preliminary observations, a change from one nucleotide analog to another may be risky. It still remains speculative whether overlapping regi- Fig.…”

Section: Reactivation Of Viral Replication After Replacement Of Tenofmentioning

confidence: 99%

“…To date, 26 VOD patients treated with TIPS, have survived, 20% of the total [2][3][4][5][6][7][8][9][10][11] (Table 1). All but 2 (with previous liver transplantation) underwent BMT.…”

Section: Tips For Veno-occlusive Disease: Is the Contraindication Real?mentioning

confidence: 99%

Reactivation of viral replication after replacement of tenofovir by adefovir

Bömmel¹,

Berg²

2005

Hepatology

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“…Over a dozen TLRs have been identified, each with a defined ligand and unique expression patterns within and outside the immune system, especially on DCs, macrophages, and monocytes, where they serve to bridge innate and adaptive immunity (3). While TLRs were initially thought to be pattern recognition receptors for the exclusive sensing of microbial components, recent studies show that endogenous nucleic acid-immunoglobulin complexes circulating in lupus patients potently activate immune cells through nucleic acid-sensing TLRs and FcRs (4)(5)(6)(7)(8)(9)(10)(11)(12)(13) and hence may play a role in the development of autoimmunity.…”

Section: Introductionmentioning

confidence: 99%

Effective posttransplant antitumor immunity is associated with TLR-stimulating nucleic acid–immunoglobulin complexes in humans

Lin¹,

Zhang²,

Cai³

et al. 2011

J. Clin. Invest.

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Donor lymphocyte infusion (DLI), whereby donor mononuclear cells are infused into patients, is one of the few effective immunotherapeutic strategies that generate long-lasting tumor remissions. We previously demonstrated that chronic myelogenous leukemia (CML) patients treated with DLI develop high-titer plasma antibodies specific for CML-associated antigens, the majority of which have been reported to bind nucleic acids These observations led us to predict that circulating antibody-antigen complexes in DLI-responsive patients carry nucleic acids that can engage innate immune sensors. Consistent with this, we report here that post-DLI plasma from 5 CML patients that responded to DLI treatment induced massive upregulation of MIP-1α, IP-10, and IFN-α in normal blood mononuclear cells. Importantly, this was not observed with plasma obtained before DLI and from DLI nonresponders and imatinib-treated patients. This endogenous immunostimulatory activity required nucleic acid and protein for its adjuvant effect and activated antigen-presenting cells through the RNA and DNA sensors TLR8 and TLR9. Presence of the immunoglobulin Fc receptor CD32 enhanced cellular responses, suggesting that immunoglobulins associate with this activity. Finally, a TLR-induced expression signature was detectable in post-DLI but not pre-DLI blood, consistent with an active circulating TLR8/9-stimulating factor. We have therefore demonstrated that effective tumor immunity correlates with the presence of endogenous nucleic acid-immunoglobulin complexes in patient plasma, thus providing a putative mechanism for the induction of potent antigen-specific immunity against malignant cells.

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Immunopharmacology of CpG Oligodeoxynucleotides and Ribavirin

Cited by 27 publications

References 13 publications

Isatoribine, an agonist of TLR7, reduces plasma virus concentration in chronic hepatitis C infection

Isatoribine, an agonist of TLR7, reduces plasma virus concentration in chronic hepatitis C infection

Reactivation of viral replication after replacement of tenofovir by adefovir

Effective posttransplant antitumor immunity is associated with TLR-stimulating nucleic acid–immunoglobulin complexes in humans

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