Association between Immune Recovery Uveitis and a Diverse Intraocular Cytomegalovirus-Specific Cytotoxic T Cell Response
Association between Immune Recovery Uveitis and a Diverse Intraocular Cytomegalovirus-Specific Cytotoxic T Cell Response
Helen P. Mutimer 1 2
Yoshiki Akatsuka 1 2 3
Thomas Manley 1 2
Elaine L. Chuang 1
Michael Boeckh 0 1 2
Robert Harrington 0 1
Thomas Jones 1 4
Stanley R. Riddell 0 1 2
0 Medicine, University of Washington , Seattle
1 Received 26 December 2001; revised 18 April 2002; electronically published 5 August 2002. Informed consent was obtained from patients, and the human experimen- tation guidelines of the US Department of Health and Human Services were followed in conducting this research. Financial support: National Institutes of Health (CA-18029 and AI-41754 to S.R.R.)
2 Program in Immunology, Fred Hutchinson Cancer Research Center, and Departments of
3 Present affiliation: Division of Immunology, Aichi Cancer Center , Nagoya , Japan. inson Cancer Research Ctr. , 1100 Fairview Ave. N, Seattle, WA 98109 (sriddell @fhcrc.org)
4 Wyeth Ayerst , Pearl River , New York
Cytomegalovirus (CMV) causes serious infection in individuals with deficient T cell immunity. In acquired immunodeficiency syndrome, the retina is a major site of progressive infection, despite the availability of therapy that targets CMV. The administration of highly active antiretroviral therapy to suppress human immunodeficiency virus frequently results in resolution of CMV retinitis, but this may be complicated by ocular inflammation termed “immune recovery uveitis” (IRU). To provide insight into the pathogenesis of IRU, the phenotype and specificity of intraocular T cells in a single patient were analyzed. The T cell infiltrate consisted of a diverse population of CD8+ CMV-specific T cells, but only a minority of these T cells recognized the CMV phosphoprotein 65 and immediate early protein 1, which have been considered major targets of the host response. These results imply that reconstitution of CMV-specific T cells plays a role in IRU and suggest that the specificity of T cells engaged in the control of CMV at local sites of reactivation may be broad.
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T cells are crucial for preventing cytomegalovirus (CMV)
disease. Before highly active antiretroviral therapy (HAART)
became available, individuals with T cell depletion due to
human immunodeficiency virus (HIV) commonly developed CMV
infection [1]. In such patients, retinitis is the most frequent
complication, resulting in vision loss due to cytopathic infection
of retinal cells and macular edema. The availability of HAART
has reduced the incidence of CMV retinitis, and it has been
possible to discontinue anti-CMV drugs in most patients with
retinitis who experience an increase in CD4 T cells [2].
A new syndrome, termed “immune recovery uveitis” (IRU),
which is characterized by ocular inflammation and decreased
vision without active CMV replication, is observed in
HIVpositive individuals who recover from CMV retinitis [3]. The
pathogenesis of IRU is unknown, but the association with
improvement in T cell numbers suggests that infiltration of T cells
Methods
Study participant. Vitreous humor was obtained from an
HIVpositive patient with IRU. This individual developed CMV retinitis
in 1996 while receiving lamivudine and stavudine for HIV infection
and ganciclovir for CMV enteritis. When CMV retinitis developed,
the patient’s CD4 T cell count was 20 cells/mm3, and the HIV
load was 73,000 copies/mL. Cidofovir was administered
intravenously, and CMV retinitis became inactive. Indinavir was added
to lamivudine and stavudine in October 1996. In March 1998, the
patient’s plasma HIV load was undetectable, and the CD4 T cell
count increased to 140 cells/mm3. In March 1999, the patient’s
CD4 T cell count increased to 370 cells/mm3, but inflammation
developed in the left eye, and visual acuity declined. Pars plana
vitrectomy was performed to improve vision, and vitreous humor
and blood samples were obtained for analysis.
Cell lines and viruses. Fibroblasts and Epstein-Barr virus–
transformed B lymphoblastoid cell lines (LCLs) were generated
and propagated as described elsewhere [4]. CMV AD169 was
obtained from the American Tissue Culture Collection, and
supernatant virus was produced by passage in fibroblasts [4]. The mutant
CMV strain RV798, which was constructed with a deletion of the
unique short (US) region, was propagated similarly [5]. Vaccinia
recombinant viruses encoding the immediate early protein 1 (Vac/
IE-1), pp65 (Vac/pp65), and gB (Vac/gB) were provided by William
Britt (University of Alabama, Birmingham).
T cell clones. Cells were pelleted from the vitreous humor and
resuspended in RPMI 1640 medium containing 10% human serum,
50 U/mL interleukin-2, and 30 ng/mL anti-CD3 monoclonal
antibody (MAb). Cells were plated at 0.5 cells/well with 7.5 104
gamma-irradiated peripheral blood mononuclear cells (PBMC) and
1 104 gamma-irradiated LCLs as feeder cells. T cells in wells in
which growth was evident after 14 days were expanded by
restimulation with anti-CD3. CD8 T cell cl (...truncated)