期刊
THROMBOSIS AND HAEMOSTASIS
卷 85, 期 1, 页码 125-133出版社
GEORG THIEME VERLAG KG
DOI: 10.1055/s-0037-1612915
关键词
factor VIII; inhibitors; T cells; immune response
资金
- NHLBI NIH HHS [HL46215, HL61922] Funding Source: Medline
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL061922, R01HL046215] Funding Source: NIH RePORTER
Mice genetically deficient in factor VIII (fVIII) are a model of hemophilia A. As a first step to reproduce in this mouse model what occurs over time in hemophilia A patients treated with human fVIII (hfVIII), we have investigated the time course and the characteristics of their immune response to hfVIII, after multiple intravenous injections. Anti-hfVIII antibodies appeared after four to five injections. They were IgG1 and to a lesser extent 1gG2, indicating that they were induced by both Th2 and Th1 cells. Inhibitors appeared after six injections. CD4(+) enriched splenocytes, from hfVIII-treated mice proliferated in response to fVIII and secreted IL-10: in a few mice they secreted also IFN-gamma and in one mouse IL-4, but never IL-2. A hfVIII-specific T cell line derived from hfVIII-treated mice secreted both IL-4 and LFN-gamma, suggesting that it included both Th1 and Th2 cells. CD4+ enriched splenocytes of hfVIII-treated mice recognized all hfVIII domains. Thus, hemophilic mice develop an immune response to hfVIII administered intravenously similar to that of hemophilia A patients. Their anti-hfVIII antibodies can be inhibitors and belong to IgG subclasses homologous to those of inhibitors in hemophilic patients; their anti-hfVIII CD4(+) cells recognize a complex repertoire and both Th1 and Th2 cytokines, and especially IL-10, may drive the antibody synthesis.
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