Induction of antigen-specific CD4+ T-cell anergy and deletion by in vivo viral gene transfer

Dobrzynski, Eric; Mingozzi, Federico; Liu, Yilin; Bendo, Elisabeth; Cao, Ou; Wang, Lixin; Herzog, Roland W.

doi:10.1182/blood-2004-03-0847

Cited by 123 publications

(135 citation statements)

References 66 publications

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“…22 Consistent with our published data on hF.IX, low levels of hepatic hF.IX transgene expression elicited Th1 responses, while increased expression from increased vector doses caused a shift toward Th2 or tolerance. 20 Overall, we failed to induce a robust immune response to hFIX by hepatic gene transfer in CD-1 mice, and relatively low levels of transgene expression were sufficient to downregulate immune responses.…”

Section: Weak Immune Responses or Tolerance Induction After Hepatic Gsupporting

confidence: 91%

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

et al. 2005

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Section: Weak Immune Responses or Tolerance Induction After Hepatic Gsupporting

confidence: 91%

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

et al. 2005

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“…The liver induces antigen-specific tolerance by a series of mechanisms, including clonal deletion (similar to central tolerance), as well as induction of Tregs and inhibition of memory T-cell responses, which favor peripheral tolerance (6,22,(27)(28)(29). However, the precise mechanisms underlining liver tolerance are not fully understood.…”

Section: Discussionmentioning

confidence: 99%

Liver type I regulatory T cells suppress germinal center formation in HBV-tolerant mice

Yin

Sun

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The liver plays a critical role in inducing systemic immune tolerance, for example, during limiting hypersensitivity to food allergy and in rendering acceptance of allotransplant or even hepatotropic pathogens. We investigated the unknown mechanisms of liver tolerance by using an established hepatitis B virus (HBV)-carrier mouse model, and found that these mice exhibited an antigen-specific tolerance toward peripheral HBsAg vaccination, showing unenlarged draining lymph node (DLN), lower number of germinal centers (GC), and inactivation of GC B cells and follicular T helper (Tfh) cells. Both in vivo and in vitro immune responses toward HBsAg were suppressed by mononuclear cells from HBV-carrier mice, which were CD4 + Foxp3 − type 1 regulatory T (Tr1)-like cells producing IL-10. Using recipient Rag1 −/− mice, hepatic Tr1-like cells from day 7 of HBV-persistent mice acquired the ability to inhibit anti-HBV immunity 3 d earlier than splenic Tr1-like cells, implying that hepatic Tr1-like cells were generated before those in spleen. Kupffer cell depletion or IL-10 deficiency led to impairment of Tr1-like cell generation, along with breaking HBV persistence. The purified EGFP + CD4 + T cells (containing Tr1-like cells) from HBV-carrier mice trafficked in higher numbers to DLN in recipient mice after HBsAg vaccination, and subsequently inactivated both Tfh cells and GC B cells via secreting IL-10, resulting in impaired GC formation and anti-HB antibody production. Thus, our results indicate Tr1-like cells migrate from the liver to the DLN and inhibit peripheral anti-HBV immunity by negatively regulating GC B cells and Tfh cells.peripheral tolerance | unresponsive

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“…52 Further studies provided evidence that the induction of immune tolerance to AAVencoded therapeutic transgene products in liver is mediated by regulatory T cells. 53 Dobrzynski et al 53 demonstrated induction of antigenspecific CD4+ T-cell tolerance to a secreted transgene product (ovalbumin, ova) in ova-specific T-cell receptor transgenic mice by hepatic AAV-mediated gene transfer. Transduced mice failed to mount an immune response to the ova transgene.…”

Section: Immunity To the Encoded Transgenementioning

confidence: 99%

Immunity to adeno-associated virus vectors in animals and humans: a continued challenge

2008

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Induction of antigen-specific CD4+ T-cell anergy and deletion by in vivo viral gene transfer

Cited by 123 publications

References 66 publications

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

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

Liver type I regulatory T cells suppress germinal center formation in HBV-tolerant mice

Immunity to adeno-associated virus vectors in animals and humans: a continued challenge

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