4.6 Article

Characterization of Gene Therapy Associated Uveitis Following Intravitreal Adeno-Associated Virus Injection in Mice

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出版社

ASSOC RESEARCH VISION OPHTHALMOLOGY INC
DOI: 10.1167/iovs.62.2.41

关键词

animal model; uveitis; intravitreal injection; AAV; gene therapy; inflammation; T cell

资金

  1. Research to Prevent Blindness career development award
  2. Alcon Research Institute [K08 EY023998, R01EY030431, P30-001730]
  3. Research to Prevent Blindness
  4. Graham and Brenda Siddall Uveitis Research Fund
  5. Mark J. Daily, MD Research Fund

向作者/读者索取更多资源

The intravitreal injection of AAV in mice results in mild clinically evident inflammation that tends to resolve spontaneously. However, the total number of intraocular CD45+ cells, particularly T cells, remains elevated. Both innate and adaptive immune cells respond to intravitreal AAV regardless of prior immune status, but the adaptive response is delayed in AAV naive eyes.
PURPOSE. To characterize the intraocular immune cell infiltrate induced by intravitreal adeno-associated virus (AAV) gene therapy. METHODS. AAV vectors carrying plasmids expressing green fluorescent protein under the control of PR2.1 were injected intravitreally into AAV naive and AAV primed C57B1/6 mice. Clinical inflammation was assessed using optical coherence tomography. Intraocular immune cell populations were identified and quantified by flow cytometry on days 1, 7, and 29 after intravitreal injection and compared with sham and fellow eye controls. RESULTS. Optical coherence tomography inflammation score and total CD45+ cell number were significantly higher in AAV injected eyes compared to uninjected fellow eye and sham injected controls. Clinically apparent inflammation (vitritis on optical coherence tomography) and cellular inflammation (CD45+ cell number) was significantly increased in AAV injected eyes and peaked around day 7. Vitritis resolved by day 29, but cellular inflammation persisted through day 29. On day 1, neutrophils and activated monocytes were the dominant cell populations in all AAV injected eyes. On day 7, eyes of AAV exposed animals had significantly more dendritic cells and T cells than eyes of AAV naive animals. By day 29, CD8- T cells were the dominant CD45+ cell population in AAV injected eyes. CONCLUSIONS. Intravitreal AAV injection in mice generates clinically evident inflammation that is mild and seems to resolve spontaneously. However, the total number of intraocular CD45+ cells, particularly T cells, remain elevated. Both innate and adaptive immune cells respond to intravitreal AAV regardless of prior immune status, but the adaptive response is delayed in AAV naive eyes.

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