Immune Consequences of Intraocular Administration of Modified Adenoviral Vectors

Abstract

To investigate the immune consequences of intraocular administration of modified adenoviral vectors, C57BL/6 normal and retinal degeneration C57BL/6 (rd/rd) mice were immunized with subcutaneous, subretinal, vitreal, or anterior chamber injections of replication-deficient adenovirus (AdV) containing the Escherichia coli beta-galactosidase gene (AdV-LacZ). Fourteen days after the initial inoculation, the animals were immune challenged with an injection of AdV-LacZ in the right ear pinna. Antigen-induced delayed type hypersensitivity (DTH) was measured by determining relative ear swelling. Normal C57BL/6 mice immunized with subretinal, vitreal, or anterior chamber injections did not demonstrate a DTH response. The rd/rd C57BL/6 mice injected in the anterior chamber with the viral construct also did not respond with DTH in a manner similar to normal mice responding to intraocular injection and subsequent challenge. However, the rd/rd C57BL/6 mice immunized by the subretinal or vitreal route did respond to immune challenge with a DTH response. Histologic examination of the eyes showed a lack of infiltration by inflammatory cells. Although these results suggest that the potential for immune consequences is reduced when modified adenoviral vectors are used in the normal ocular environment, these vectors used in the vitreal cavity of rd/rd animals may induce a systemic response to the vectors.

Generation of Activated Sialoadhesin-Positive Microglia during Retinal Degeneration

“…It is hoped that the anatomic and immunologic properties of the eye will be advantageous, yet exaggerated systemic immune responses can occur when substances are injected into the subretinal space of a dystrophic murine retina when compared with normal mice. 30 Although only a few DEC205 Ϫ CD11c ϩ cells were observed subretinally, further assessment of immune responses in draining lymph nodes is warranted, to assess whether antigen capture and traffic has the potential to lead to systemic priming, particularly after gene transfer.…”

Looking beyond Self-Protection: The Eyes Instruct Systemic Immune Tolerance Early in Life

“…The eyes are the premier visual sensory organs. They, however, provide themselves with immune tolerance when challenged with foreign antigens [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 ]. This property emerges from a complex network of interactions established among the cellular and acellular components within the eyes and between the eyes and the lymphoid organs across the body [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ].…”

“…Immune tolerance, on the other hand, is set up by regulatory T lymphocytes early in life [ 30 , 31 ]. It is known that immune tolerance induced by the eyes promotes the formation of regulatory T lymphocytes [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ]. Thus, it could be that the systemic immune tolerance instructed by the eyes and the benefits it brings to the body are primed early in life.…”