Treatment with type 1 interferons (IFN-alpha and IFN-beta).
|IFN-alpha, -beta and -gamma have been used for treatment of many diseases. For example, recombinant IFN-beta is the first-line treatment for relapsing-remitting MS and several large randomized trials have shown that IFN-beta reduces the frequency and severity of clinical relapses, slows the progression of permanent disability, and suppresses the lesion load on magnetic resonance imaging (MRI).
Like many other proteins, all IFN species are potentially immunogenic, especially those produced by recombinant gene technologies. The reported frequencies and titers of anti-IFN antibodies (Ab) vary considerably depending upon diseases, IFN preparations and administration, and the types of assays being used (1-9). However, Ab-mediated decrease in bioactivity of IFN (ADB), a condition in which the clinical effect of continued injection of IFN is minimized or abrogated, is increasingly being recognized (10).
There is an obvious need for clinically useful, inexpensive and standardized screening assays for in vivo anti-IFN activities, but attempts in this direction have failed. A major reason for this is the inconvenience and high cost of carrying out elaborate antiviral neutralisation assays in the clinical setting, and the fact that some of these assays have not been validated with regard to clinical relevance and therefore may provide little useful information to the clinician.
Indeed, several years of use of such assays have contributed to the conception of, and distinction between, 'non-neutralising binding antibodies' (BAb) and 'neutralising antibodies' (NAb) occurring in patients receiving IFN therapies (11, 12); and this issue has been complicated further by the frequent use of BAb assays that may give false positive results; see Assay for binding antibodies (BAb) to cytokines.
1. Antonelli G, Currenti M, Turriziani O, Dianzani F. neutralising antibodies to interferon-a: Relative frequency in patients treated with different interferon preparations. J Infect Dis 1991;163:882-5.
2. The IFN-beta Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. neutralising antibodies during treatment of multiple sclerosis with interferon b-1b: experience during the first three years. Neurology 1996;47:889-94.
3. Files JG, Gray JL, Do LT, Foley WP, Gabe JD, Nestaas E, Pungor E, Jr. A novel sensitive and selective bioassay for human type I interferons. J Interferon Cytokine Res 1998;18:1019-24.
4. Pungor E, Jr., Files JG, Gabe JD, Do LT, Foley WP, Gray JL, Nelson JW, Nestaas E, Taylor JL, Grossberg SE. A novel bioassay for the determination of neutralising antibodies to IFN-beta1b. J Interferon Cytokine Res 1998;18:1025-30.
5. Antonelli G, Simeoni E, Bagnato F, Pozzilli C, Turriziani O, Tesoro R, Di Marco P, Gasperini C, Fieschi C, Dianzani F. Further study on the specificity and incidence of neutralising antibodies to interferon (IFN) in relapsing remitting multiple sclerosis patients treated with IFN beta-1a or IFN beta-1b. J Neurol Sci 1999;168:131-6.
6. Brickelmaier M, Hochman PS, Baciu R, Chao B, Cuervo JH, Whitty A. ELISA methods for the analysis of antibody responses induced in multiple sclerosis patients treated with recombinant interferon-beta. J Immunol Methods 1999;227:121-35.
7. Ross C, Clemmesen KM, Svenson M, Sorensen PS, Koch-Henriksen N, Skovgaard GL, Bendtzen K. Immunogenicity of interferon-b in multiple sclerosis patients: influence of preparation, dosage, dose frequency, and route of administration. Danish Multiple Sclerosis Study Group. Ann Neurology 2000;48:706-12.
8. Pachner AR. Measurement of antibodies to interferon beta in patients with multiple sclerosis. Arch Neurol 2001;58:1299-300.
9. Bertolotto A, Malucchi S, Sala A, Orefice G, Carrieri PB, Capobianco M, Milano E, Melis F, Giordana MT. Differential effects of three interferon betas on neutralising antibodies in patients with multiple sclerosis: a follow up study in an independent laboratory. J Neurol Neurosurg Psychiatry 2002;73:148-53.
10. Bertolotto A, Gilli F, Sala A, Capobianco M, Malucchi S, Milano E, Melis F, Marnetto F, Lindberg RL, Bottero R, Di Sapio A, Giordana MT. Persistent neutralising antibodies abolish the interferon beta bioavailability in MS patients. Neurology 2003;60:634-9.
11. Kivisäkk P, Alm GV, Fredrikson S, Link H. neutralising and binding anti-interferon-b (IFN-b) antibodies. A comparison between IFN-beta-1a and IFN-beta-1b treatment in multiple sclerosis. Eur J Neurol 2000;7:27-34.
12. Scagnolari C, Bellomi F, Turriziani O, Bagnato F, Tomassini V, Lavolpe V, Ruggieri M, Bruschi F, Meucci G, Dicuonzo G, Antonelli G. neutralising and binding antibodies to IFN-beta: relative frequency in relapsing-remitting multiple sclerosis patients treated with different IFN-beta preparations. J Interferon Cytokine Res 2002;22:207-13.