Immunoglobulin Subclasses in Patients with Neutralizing and Nonneutralizing Antibodies Against IFN-β1b

Deisenhammer, Florian; Reindl, Markus; Berger, Thomas

doi:10.1089/107999001750133195

Cited by 35 publications

(31 citation statements)

References 20 publications

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“…We have shown the presence of both IgG1 and IgG4-ADA contributing to the IFNβ-specific ADA profile. Earlier studies have shown a predominance of IgG4-ADA against IFNβ1a preparations [12] and, IgG2 and IgG4-ADA to IFNβ1b preparation [11]. These observations are similar to the immunogenic responses against glatiramer acetate (GA) treatment in RRMS which has shown predominance of IgG4-ADA [17,18].…”

Section: Discussionsupporting

confidence: 69%

Immunoglobulin G1 and immunoglobulin G4 antibodies in multiple sclerosis patients treated with IFNβ interact with the endogenous cytokine and activate complement

Sethu

Govindappa

Quinn

et al. 2013

Clinical Immunology

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A subset of patients with relapsing-remitting multiple sclerosis (RRMS) on therapy with interferon beta (IFNβ) develop neutralising anti-drug antibodies (ADA) resulting in reduced, or loss of, therapeutic efficacy. The aims were to characterise the relative contributions of anti-IFNβ antibody isotypes to drug neutralising activity, ability of these antibodies to cross-react with endogenous IFNβ, to form immune complexes and activate complement. IFNβ-specific ADA were measured in plasma from RRMS patients treated with IFNβ1a (Rebif®). Neutralisation of endogenous and therapeutic IFNβ by ADA was determined by IFNβ bioassay. IFNβ-ADA profile was predominantly comprised of IgG1 and IgG4 antibody isotypes. The contribution of IgG4-ADA towards neutralising activity was found to be minimal. Neutralising IFNβ-ADA blocks endogenous IFNβ activity. ADA interaction with therapeutic IFNβ results in immune complex formation and complement activation. In summary, IgG1 and IgG4 IFNβ-ADA have the ability to neutralise therapeutic and endogenous protein and to activate complement.

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Section: Discussionsupporting

confidence: 69%

Immunoglobulin G1 and immunoglobulin G4 antibodies in multiple sclerosis patients treated with IFNβ interact with the endogenous cytokine and activate complement

Sethu

Govindappa

Quinn

et al. 2013

Clinical Immunology

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“…9 The neutralizing antibody in multiple sclerosis (MS) patients is enriched for the IgG4 isotype, and neutralizing IgG antibodies as a whole are found at higher titers than in patients with the non-neutralizing antibody. 10 The development of IgG class antibodies has been shown to correlate with the development of an antigen-specific response by CD4 þ T cells. [11][12][13][14] To investigate the basis for the development of NAbs, the sequence of human IFN-b-1b was examined for the presence of CD4 þ T-cell epitope regions using a previously established systematic in vitro method.…”

Section: Introductionmentioning

confidence: 99%

The HLA-DR2 haplotype is associated with an increased proliferative response to the immunodominant CD4+ T-cell epitope in human interferon-β

Stickler¹,

Valdes

Gebel³

et al. 2004

Genes Immun

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Human CD4 þ T-cell epitopes were identified in interferon-beta (IFN-b)-1b. A prominent peptide epitope region was found that induced a proliferative response in 16% of all donors tested. Responses corresponded to the presence of the HLA-DR2 haplotype. Responsive donors expressing the HLA-DQ6 allele showed an increased level of proliferation to the epitope as compared to peptide-responsive HLA-DQ6 negative donors. A similar result was found for HLA-DR15-expressing donors. PBMC from donors expressing HLA-DR15 were more likely to proliferate in response to IFN-b in a whole-protein in vitro assay than donors who did not carry this haplotype. It is striking that the common DQ6 allele HLA-DQB1*0602 is found in linkage disequilibrium with HLA-DRB1*1501, and this combination defines the HLA genotype associated with the development of multiple sclerosis. The HLA association between a response to IFN-b and MS might explain the prevalence of neutralizing antibody development, and may underlie the etiology of the disease.

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“…BAb detection with RIPA technique is simple, inexpensive, and easy to standardize in different routine laboratories, but with the limit that 125 I IFN-should be used within 7 days to avoid radiolysis or proteolysis [110]. It should be reminded that RIPA measures antibodies of IgG class [95,102] without subtype distinction, while antibodies that reduce the biological activity of IFNare primarily of IgG2 and IgG4 isotypes [113]. RIPA results correlate significantly more with changes in lesion burden detected by MRI than NAb titres, but no NAb-positive sample is negative in RIPA [105].…”

Section: Methodological Approaches To Quantify Anti-ifn-antibodiesmentioning

confidence: 99%

Interferon-Beta Therapy Monitoring in Multiple Sclerosis Patients

Sottini

Capra²,

Serana³

et al. 2009

EMIDDT

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Interferon-beta (IFN-beta) therapy has a central place in the management of multiple sclerosis (MS). The three recombinant IFN-beta preparations currently available have shown benefit on activity measures (relapses and active lesions apparent on magnetic resonance imaging), while therapy advantages on progression measures (disability and total lesion burden) are less consistent. Moreover, IFN-beta is effective only in a percentage of patients, since in many of them neutralizing anti-IFN-beta antibodies develop after 6-18 months of treatment, leading to loss of drug bioactivity. Comparative data across studies made with different IFN-beta preparations suggest that the optimal choice of IFN-beta subtype, preparation and dose regimen are important determinants of efficacy. Because IFN-beta actions depend on the activation of IFN-inducible genes, in addition to the direct quantification of anti-IFN-beta antibodies, several other methods for the measure of IFN-beta biologic activity have been recently developed. Among these, the determination of the IFN-beta-inducible gene product Myxovirus protein A (MxA) has proven to be the most reliable one. Another still open point is the role of the differential expression of IFN-beta receptor (IFNAR) components, since IFNAR2 subunit can be synthesized in three isoforms: functional, truncated non-functional and soluble. While this and other important issues require further studies, this article reviews and discusses the importance, potential and limits of the methods currently available to monitor IFN-beta therapy in MS patients.

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Immunoglobulin Subclasses in Patients with Neutralizing and Nonneutralizing Antibodies Against IFN-β1b

Cited by 35 publications

References 20 publications

Immunoglobulin G1 and immunoglobulin G4 antibodies in multiple sclerosis patients treated with IFNβ interact with the endogenous cytokine and activate complement

Immunoglobulin G1 and immunoglobulin G4 antibodies in multiple sclerosis patients treated with IFNβ interact with the endogenous cytokine and activate complement

The HLA-DR2 haplotype is associated with an increased proliferative response to the immunodominant CD4+ T-cell epitope in human interferon-β

Interferon-Beta Therapy Monitoring in Multiple Sclerosis Patients

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