Interferon Inhibitory Activity in Patients With Multiple Sclerosis

Chadha, Kailash C.; Weinstock‐Guttman, Bianca; Zivadinov, Robert; Bhasi, Kavitha; Muhitch, Jason B.; Feichter, Joan; Tamaño‐Blanco, Miriam; Abdelrahman, Nadir; Ambrus, Julian L.; Munschauer, Frederick E.; Ramanathan, Murali

doi:10.1001/archneur.63.11.1579

Cited by 17 publications

(15 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, our studies directly show that increased levels of sIFNAR2a do not decrease IFN-mediated responses; in fact, the opposite occurs, and IFN activity is amplified. Indeed, our data support other studies in which the lack of response to IFN therapy did not correlate with high sIFNAR2a levels observed in patient serum (28)(29)(30)(31)64). Therefore, the SolOX mouse line is a valuable new model with which to study the impact of pathological levels of endogenous sIFNAR2a on exogenously administered type I IFNs.…”

Section: Comparison With Ifnar1supporting

confidence: 89%

Soluble IFN Receptor Potentiates In Vivo Type I IFN Signaling and Exacerbates TLR4-Mediated Septic Shock

Samarajiwa

Mangan

Hardy

et al. 2014

The Journal of Immunology

View full text Add to dashboard Cite

Circulating levels of a soluble type I IFNR are elevated in diseases, such as chronic inflammation, infections, and cancer, but whether it functions as an antagonist, agonist, or transporter is unknown. In this study, we elucidate the in vivo importance of the soluble type I IFNAR, soluble (s)IFNAR2a, which is generated by alternative splicing of the Ifnar2 gene. A transgenic mouse model was established to mimic the 10–15-fold elevated expression of sIFNAR2a observed in some human diseases. We generated transgenic mouse lines, designated SolOX, in which the transgene mRNA and protein-expression patterns mirrored the expression patterns of the endogenous gene. SolOX were demonstrated to be more susceptible to LPS-mediated septic shock, a disease model in which type I IFN plays a crucial role. This effect was independent of “classical” proinflammatory cytokines, such as TNF-α and IL-6, whose levels were unchanged. Because the increased levels of sIFNAR2a did not affect the kinetics of the increased interferonemia, this soluble receptor does not potentiate its ligand signaling by improving IFN pharmacokinetics. Mechanistically, increased levels of sIFNAR2a are likely to facilitate IFN signaling, as demonstrated in spleen cells overexpressing sIFNAR2a, which displayed quicker, higher, and more sustained activation of STAT1 and STAT3. Thus, the soluble IFNR is an important agonist of endogenous IFN actions in pathophysiological processes and also is likely to modulate the therapeutic efficacy of clinically administered IFNs.

show abstract

Section: Comparison With Ifnar1supporting

confidence: 89%

Soluble IFN Receptor Potentiates In Vivo Type I IFN Signaling and Exacerbates TLR4-Mediated Septic Shock

Samarajiwa

Mangan

Hardy

et al. 2014

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…The substantial delay of Ϸ7 days in the mean onset of EAE in TNF-␣-deficient mice is also reproducible (8). We were unable to find any reference to previous studies of EAE in IFN-␣␤-R KO mice, which is surprising with respect to the fact that individuals with MS are treated with IFN-␤ (23,24). Notably, in this regard we found that these mice develop EAE more rapidly and with increased incidence and severity than their congenic counterparts, supporting the notion that there is an IFN-␣␤-driven mechanism that protects against the pathogenesis of CNS inflammation.…”

Section: Discussionmentioning

confidence: 69%

Loss of blood–brain barrier integrity in the spinal cord is common to experimental allergic encephalomyelitis in knockout mouse models

Fabis¹,

Scott²,

Kean³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Experimental allergic encephalomyelitis (EAE) is an inflammatory demyelinating disease of the CNS that is used to model certain parameters of multiple sclerosis. To establish the relative contributions of T cell reactivity, the loss of blood-brain barrier (BBB) integrity, CNS inflammation, and lesion formation toward the pathogenesis of EAE, we assessed the incidence of EAE and these parameters in mice lacking NF-B, TNF-␣, IFN-␣␤ receptors, IFN-␥ receptors, and inducible nitric oxide synthase. Although increased myelin oligodendrocyte glycoprotein-specific T cell reactivity was generally associated with a more rapid onset or increased disease severity, the loss of BBB integrity and cell accumulation in spinal cord tissues was invariably associated with the development of neurological disease signs. Histological and real-time RT-PCR analyses revealed differences in the nature of immune/inflammatory cell accumulation in the spinal cord tissues of the different mouse strains. On the other hand, disease severity during the acute phase of EAE directly correlated with the extent of BBB permeability. Thus, the loss of BBB integrity seems to be a requisite event in the development of EAE and can occur in the absence of important inflammatory mediators.gene knockout mice ͉ multiple sclerosis

show abstract

“…Using traditional assays these patients will be NAb-positive, but BAb-negative [Gilli et al 2006a]. Interestingly, sIFNAR levels were higher in NAb-negative MS patients compared with controls [Chadha et al 2006].…”

Section: Ifn-b Immunogenicitymentioning

confidence: 99%

Review: Neutralizing antibodies against interferon-beta

Sørensen

2008

Ther Adv Neurol Disord

View full text Add to dashboard Cite

The development of neutralizing antibodies (NAbs) is a major problem in multiple sclerosis (MS) patients treated with interferon-beta (IFN-). Whereas binding antibodies (BAbs) can be demonstrated in the vast majority of patients, only a smaller proportion of patients develop NAbs. The principle in NAb in vitro assays is the utilization of cultured cell lines that are responsive to IFN-. The cytopathic effect (CPE) assay measures the capacity of NAbs to neutralize IFN-'s protective effect on cells challenged with virus and the MxA induction assay measures the ability of NAbs to reduce the IFN--induced expression of MxA, either at the mRNA or the protein level. A titer of !20 neutralizing units/ml traditionally defines NAb positivity. NAbs in high titers completely abrogate the in vivo response to IFN-, whereas the effect of low and intermediate titers is unpredictable. As clinically important NAbs appear only after 9-18 months IFN-therapy, short-term studies of two years or less are unsuitable for evaluation of clinical NAb effects. All long-term trials of three years or more concordantly show evidence of a detrimental effect of NAbs on relapses, disease activity on MRI, or on disease progression. Persistent high titers of NAbs indicate an abrogation of the biological response and, hence, absence of therapeutic efficacy, and this observation should lead to a change of therapy. As low and medium titers are ambiguous treatment decisions in patients with low NAb titres should be guided by determination of in vivo mRNA MxA induction and clinical disease activity.

show abstract

Interferon Inhibitory Activity in Patients With Multiple Sclerosis

Cited by 17 publications

References 22 publications

Soluble IFN Receptor Potentiates In Vivo Type I IFN Signaling and Exacerbates TLR4-Mediated Septic Shock

Soluble IFN Receptor Potentiates In Vivo Type I IFN Signaling and Exacerbates TLR4-Mediated Septic Shock

Loss of blood–brain barrier integrity in the spinal cord is common to experimental allergic encephalomyelitis in knockout mouse models

Review: Neutralizing antibodies against interferon-beta

Contact Info

Product

Resources

About