September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Anterior Chamber Associated Immune Deviation (ACAID) as an inhibitory mechanism for anti-transgene cellular immune responses to systemic gene transfer
Author Affiliations & Notes
  • Quentin Khebizi
    Genethon/INSERM UMR_S951, Evry, France
    University of Evry Val d'Essonne, Evry, France
  • Sabrina Donnou-Triffault
    Genethon/INSERM UMR_S951, Evry, France
    University of Evry Val d'Essonne, Evry, France
  • Julie Vendomèle
    Genethon/INSERM UMR_S951, Evry, France
    University of Evry Val d'Essonne, Evry, France
  • Mirella Mormin
    Genethon/INSERM UMR_S951, Evry, France
  • Catherine Poinsignon
    Genethon/INSERM UMR_S951, Evry, France
    University of Evry Val d'Essonne, Evry, France
  • Séverine Ciré
    Genethon/INSERM UMR_S951, Evry, France
  • Anne Galy
    Genethon/INSERM UMR_S951, Evry, France
  • Sylvain Fisson
    Genethon/INSERM UMR_S951, Evry, France
    University of Evry Val d'Essonne, Evry, France
  • Footnotes
    Commercial Relationships   Quentin Khebizi, None; Sabrina Donnou-Triffault, None; Julie Vendomèle, None; Mirella Mormin, None; Catherine Poinsignon, None; Séverine Ciré, None; Anne Galy, None; Sylvain Fisson, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 5867. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to Subscribers Only
      Sign In or Create an Account ×
    • Get Citation

      Quentin Khebizi, Sabrina Donnou-Triffault, Julie Vendomèle, Mirella Mormin, Catherine Poinsignon, Séverine Ciré, Anne Galy, Sylvain Fisson; Anterior Chamber Associated Immune Deviation (ACAID) as an inhibitory mechanism for anti-transgene cellular immune responses to systemic gene transfer. Invest. Ophthalmol. Vis. Sci. 2016;57(12):5867.

      Download citation file:


      © ARVO (1962-2015); The Authors (2016-present)

      ×
  • Supplements
Abstract

Purpose : In vivo gene therapy using viral vectors, such as Adeno-Associated Virus (AAV), represents a promising approach to treat some genetic disorders. However, immune responses directed against capsid or transgene product can limit the success of this therapeutic strategy. We propose here a novel basic approach to overcome this issue exploiting the immunological properties of the eye. Indeed, Anterior Chamber-Associated Immune Deviation (ACAID) is an antigen specific peripheral immunomodulatory mechanism triggered when an antigen is introduced into the aqueous humor of a mammalian eye. The hypothesis tested here aims to induce an ACAID mechanism leading to an inhibition of the transgene-specific cellular immune response which occurs following an intravenous infusion of an AAV coding for a specific transgene.

Methods : We set up an experimental model of ACAID consisting in an intracameral injection of soluble peptides (DBY and UTY) from the HY male antigen into wild type female C57Bl/6 mice (H-2b background). Seven days later, an intravenous injection of a recombinant AAV2/8 vector (rAAV2/8-GFP-HY) was performed, leading to the expression of the fusion GFP-HY transgene. Cellular immune response was measured on splenocytes at different time points by IFNγ ELISpot and cytokine titration, and the cytotoxic immune response against transgene expressing cells was monitored by an in vivo cytotoxicity assay.

Results : Anterior chamber injection of HY peptides, compared to PBS control, led to a reduction (up to 80%) of the number of IFNγ producing T-cells. In addition, cytokine secretion assay showed an impairment of the Th1 cytokine profile in ACAID condition, with a 8 and 2 fold reduction in the secretion of IFNγ and TNFα, respectively. Moreover, results of the in vivo cytotoxicity assay suggested that HY-expressing cells can survive in ACAID-induced mice.

Conclusions : In conclusion, lymphocyte polarization impairment and inhibition of cellular cytotoxic immune responses against transgene expressing cells, indicate that ACAID seems to be a powerful inhibitory mechanism in the context of systemic gene transfer. This new basic approach exploiting the ocular immune privilege could open opportunities to regulate immune responses in the context of gene therapy.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×