Experimental Models to Study Viral Retinitis

Animal models have been developed to define the main characteristics of viral retinitis [4,33, 42,51,66]. Human cytomegalovirus has a different pattern of replication than that of HSV and VZV.

Pertinent permissive cell cultures, such as retinal glial cells or retinal pigment epithelial cells, have been used to study HCMV replication (Fig. 10.2). Virus replicates slowly and progressively [11,16]. In the era of highly active anti-retroviral therapy, intraocular inflammation, like cystoid macular edema, vitritis or papillitis, has been reported in patients presenting with completely cicatricial retinitis. It was therefore of interest to analyse different pathways involving antiviral immune responses that might potentially play a role in these situations. The model of retinal pigment epithelial cells was used to analyse virus-host interactions. The occurrence of HCMV retinitis in the late phase of immunosuppression may be related to perturbation of cytokine production and secretion, associated with the progressive loss of the CD3+CD4+ cell subset. The effects of different cytokines such as IFN-g, IFN-p, IL-1P, TGF-p and TNF-a, which are present in the eye under different immunopathological conditions, were studied to discover which of them play a role during HCMV replication in retinal pigment epithelial cells. IFN-g and IL-ip appeared to be the major antiviral cytokines in this in vitro system. The antiviral effect of IFN-g could be reversed by adding the amino acid L-tryptophan to the culture medium. Tryptophan is an essential amino acid for HCMV replication. IFN-g stimulates an enzyme, indoleamine 2, 3-dioxy-genase (IDO), which is responsible for the conversion of tryptophan and its derivatives to kynurenine. Tryptophan is an essential amino acid for HCMV replication. Cytokines such as IFN-g may drive the virus underground before viral proteins (the targets of the immune system) are expressed, thereby creating viral reservoirs that escape immune surveillance [8]. A lack of IFN-g in the final stage of immunosup-

Fig. 10.2. Confocal microscopy disclosing cytomegalic effects in CMV-infected human retinal pigment epithelial cells. Indirect immunofluorescence (green immediate early antigens, red late antigens)

pression could play a role in the pathogenesis of HCMV retinitis. Immune reconstitution may be associated with the infiltration of retina with leukocytes that recognize resident cells expressing latent viral antigens. Immune activation induces immune recovery uveitis in the absence of active viral replication.

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