Cell-mediated immune response and stability of intraocular transgene expression after adenovirus-mediated delivery

Invest Ophthalmol Vis Sci. 1997 Oct;38(11):2224-33.

Abstract

Purpose: To evaluate the role of cell-mediated immunity in the stability of ocular adenovirus-mediated transgene expression.

Methods: Adenovirus (4 x 10(6) pfu) containing lacZ (Ad.CMVlacZ) was injected intravitreally or subretinally into one or both eyes of immunocompetent (+/+) and immunocompromised (nu/nu) CD-1 mice. Control eyes received injections of saline. Additional +/+ mice received subretinal injections of Ad.CMVlacZ with coadministration of 200 microg of human immunoglobulin (Ig) G or CTLA4Ig by intraperitoneal, intravitreal, or subretinal injection. The mice were killed at various times after injection, and their eyes were examined histologically and immunohistochemically.

Results: LacZ expression was extended from 1 week to more than 5 weeks in the corneal endothelium, iris, and trabecular meshwork of nu/nu mice compared with time of expression in +/+ mice when adenovirus was administered intravitreally. In contrast, subretinal injection resulted in only a minimal increase in transgene stability in nu/nu mice compared with that in +/+ mice. Neither systemic nor intraocular administration of IgG or CTLA4Ig affected the stability of lacZ expression in the retina or retinal pigment epithelium after subretinal injection in +/+ mice. Immunoglobulin G and CTLA4Ig enhanced the stability of transgene expression in the trabecular meshwork.

Conclusions: A T-cell-mediated immune response appears to play a role in the loss of adenovirus-mediated lacZ expression after intravitreal but not after subretinal injection. This result implies that the subretinal space is an immune-privileged site and a favorable site for gene transfer.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Abatacept
  • Adenoviridae / genetics*
  • Animals
  • Anterior Eye Segment / enzymology
  • Anterior Eye Segment / virology
  • Antigens, CD
  • Antigens, Differentiation / administration & dosage
  • CTLA-4 Antigen
  • Cytomegalovirus / genetics
  • DNA Primers / chemistry
  • Enzyme-Linked Immunosorbent Assay
  • Gene Expression*
  • Histocytochemistry
  • Immunity, Cellular
  • Immunoconjugates*
  • Immunoenzyme Techniques
  • Immunoglobulin G / administration & dosage
  • Immunosuppressive Agents / administration & dosage
  • Lac Operon / genetics*
  • Mice
  • Mice, Mutant Strains
  • Retina / enzymology
  • Retina / virology
  • T-Lymphocytes / immunology*
  • Transgenes / genetics*
  • beta-Galactosidase / metabolism

Substances

  • Antigens, CD
  • Antigens, Differentiation
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Ctla4 protein, mouse
  • DNA Primers
  • Immunoconjugates
  • Immunoglobulin G
  • Immunosuppressive Agents
  • Abatacept
  • beta-Galactosidase