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Nonredundant roles of IL-10 and TGF-? in suppression of immune responses to hepatic AAV-factor IX gene transfer.


ABSTRACT: Hepatic gene transfer using adeno-associated viral (AAV) vectors has been shown to efficiently induce immunological tolerance to a variety of proteins. Regulatory T-cells (Treg) induced by this route suppress humoral and cellular immune responses against the transgene product. In this study, we examined the roles of immune suppressive cytokines interleukin-10 (IL-10) and transforming growth factor-? (TGF-?) in the development of tolerance to human coagulation factor IX (hF.IX). Interestingly, IL-10 deficient C57BL/6 mice receiving gene transfer remained tolerant to hF.IX and generated Treg that suppressed anti-hF.IX formation. Effects of TGF-? blockade were also minor in this strain. In contrast, in C3H/HeJ mice, a strain known to have stronger T-cell responses against hF.IX, IL-10 was specifically required for the suppression of CD8(+) T-cell infiltration of the liver. Furthermore, TGF-? was critical for tipping the balance toward an regulatory immune response. TGF-? was required for CD4(+)CD25(+)FoxP3(+) Treg induction, which was necessary for suppression of effector CD4(+) and CD8(+) T-cell responses as well as antibody formation. These results demonstrate the crucial, nonredundant roles of IL-10 and TGF-? in prevention of immune responses against AAV-F.IX-transduced hepatocytes.

SUBMITTER: Hoffman BE 

PROVIDER: S-EPMC3129563 | biostudies-other | 2011 Jul

REPOSITORIES: biostudies-other

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Nonredundant roles of IL-10 and TGF-β in suppression of immune responses to hepatic AAV-factor IX gene transfer.

Hoffman Brad E BE   Martino Ashley T AT   Sack Brandon K BK   Cao Ou O   Liao Gongxian G   Terhorst Cox C   Herzog Roland W RW  

Molecular therapy : the journal of the American Society of Gene Therapy 20110308 7


Hepatic gene transfer using adeno-associated viral (AAV) vectors has been shown to efficiently induce immunological tolerance to a variety of proteins. Regulatory T-cells (Treg) induced by this route suppress humoral and cellular immune responses against the transgene product. In this study, we examined the roles of immune suppressive cytokines interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) in the development of tolerance to human coagulation factor IX (hF.IX). Interestingly, IL  ...[more]

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