Major role of local immune responses in antibody formation to factor IX in AAV gene transfer View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2005-10

AUTHORS

L Wang, O Cao, B Swalm, E Dobrzynski, F Mingozzi, R W Herzog

ABSTRACT

The risk of an immune response to the coagulation factor IX (F.IX) transgene product is a concern in gene therapy for the X-linked bleeding disorder hemophilia B. In order to investigate the mechanism of F.IX-specific lymphocyte activation in the context of adeno-associated viral (AAV) gene transfer to skeletal muscle, we injected AAV-2 vector expressing human F.IX (hF.IX) into outbred immune-competent mice. Systemic hF.IX levels were transiently detected in the circulation, but diminished concomitant with activation of CD4+ T and B cells. ELISPOT assays documented robust responses to hF.IX in the draining lymph nodes of injected muscle by day 14. Formation of inhibitory antibodies to hF.IX was observed over a wide range of vector doses, with increased doses causing stronger immune responses. A prolonged inflammatory reaction in muscle started at 1.5-2 months, but ultimately failed to eliminate transgene expression. By 1.5 months, hF.IX antigen re-emerged in circulation in approximately 70% of animals injected with high vector dose. Hepatic gene transfer elicited only infrequent and weaker immune responses, with higher vector doses causing a reduction in T-cell responses to hF.IX. In summary, the data document substantial influence of target tissue, local antigen presentation, and antigen levels on lymphocyte responses to F.IX. More... »

PAGES

1453

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/sj.gt.3302539

DOI

http://dx.doi.org/10.1038/sj.gt.3302539

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1042385089

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/15889137


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