CD8+ T Lymphocytes and Cytomegalovirus Retinitis in Patients With the Acquired Immunodeficiency Syndrome

Lowder, Careen Y.; Butler, Carolyn P.; Dodds, Emilio M.; Secic, Michelle; Recillas-Gispert, Claudia

doi:10.1016/s0002-9394(14)72157-9

Cited by 24 publications

(11 citation statements)

References 20 publications

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“…Although both increased and decreased numbers of CD8 ϩ lymphocytes have previously been observed in patients with CMV disease [5,9], this is, to our knowledge, the first report demonstrating reduced numbers of CD4 ϩ and CD8 ϩ lymphocytes in renal transplant recipients before the clinical onset of CMV disease. Of interest, these patients develop CMV infection at considerably higher CD4 ϩ lymphocyte counts than do bone marrow transplant recipients or patients with AIDS, possibly reflecting that the immunologic abnormalities that predispose to CMV disease differ in these patient groups.…”

Section: Discussionsupporting

confidence: 45%

Immunologic Parameters as Predictive Factors of Cytomegalovirus Disease in Renal Allograft Recipients

Nordøy¹,

Müller²,

Nordal³

et al. 1999

J INFECT DIS

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Cytomegalovirus (CMV) disease is a major problem in renal transplant recipients, but few predictive markers of the disease are known. Several immunologic parameters of potential relevance for the defense against CMV were measured after renal transplantation in 25 patients before any manifestations of CMV infection occurred. In 10 patients who later developed CMV disease, plasma levels of interleukin-8 were significantly higher, whereas the levels of macrophage inflammatory protein-1alpha (MIP-1alpha) were significantly lower than in 15 patients who did not develop CMV disease. Also, lower numbers of CD4+ and CD8+ lymphocytes were observed in patients who later had CMV disease. These findings were independent of previous rejection therapy and were particularly pronounced in patients with primary CMV infection. Interleukin-8 and MIP-1alpha may be predictive markers of CMV disease and could be of potential use in selecting patients for prophylactic treatment.

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Section: Discussionsupporting

confidence: 45%

Immunologic Parameters as Predictive Factors of Cytomegalovirus Disease in Renal Allograft Recipients

Nordøy¹,

Müller²,

Nordal³

et al. 1999

J INFECT DIS

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“…For example, C M V pneumonias can be differentiated according to their presentations and severity in four dif ferent patient populations: solid-organ trans plant recipients, bone marrow transplant re cipients, AID S patients, and immunocompe tent patients [8], Whereas mortality due to C M V pneumonitis ranges from 40 to 70% and 70 to 85% in solid-organ and bone mar row transplant recipients, respectively, mor tality is relatively low in A ID S patients and nonexistent in immunocompetent patients [8], It is therefore not surprising that AIDSrelated C M V retinitis would not respond to passively administered immunoglobulin even though antibody immunotherapy is effective against C M V disease in transplant recipients. Indeed, there is increasing evidence that cellu lar immunity rather than humoral immunity plays a prominent role in protecting against E ffect o f A n tibody on C M V R etinitis during M A ID S C M V retinitis, CD8+ cytotoxic T cells being particularly important [21]. Support for this notion has been provided by a study in which antibodies to CD4+ or CD8+ T-cell subsets were found to increase the susceptibility of BALB/c mice to M C M V retinitis following subrctinal M C M V inoculation [19], In addi tion, we have recently reported that interleu kin-2, a Th 1 cytokine that activates T cells and natural-killer cells, significantly reduced intraocular M C M V titers and frequency of M C M V necrotizing retinitis in mice with M A ID S when administered systemically 2 days prior to subretinal M C M V inoculation [22].…”

Section: Discussionmentioning

confidence: 99%

Antibody Alone Does Not Prevent Experimental Cytomegalovirus Retinitis in Mice with Retrovirus-lnduced Immunodeficiency (MAIDS)

Dix

Cray

Cousins³

1997

Ophthalmic Res

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Passive-transfer studies were performed to assess the ability of antibody alone to reduce the frequency and/or severity of necrotizing retinitis caused by murine cytomegalovirus (MCMV) in C57BL/6 mice with retro-virus-induced immunodeficiency syndrome (MAIDS). Initial experiments showed a gradual decline in the ability of mice to initiate humoral immunity during the evolution of MAIDS so that neither MCMV-specific IgM nor IgG could be detected during late-stage MAIDS. Passively administered hyperimmune MCMV immunoglobulin, however, could be detected within the serum of mice with MAIDS for at least 9 days after intraperitoneal injection and protected these animals in preliminary experiments from systemic MCMV disease and death when administered 24 h prior to intraperitoneal challenge with a lethal dose of virus. Nonetheless, passive transfer of hyperimmune MCMV serum to mice with MAIDS failed to reduce intraocular MCMV titers, frequency of retinitis, or severity of retinitis when administered 24 h prior to subretinal MCMV inoculation. Whereas whole eyes of MAIDS animals that received normal mouse serum and were injected subretinally with MCMV had an ocular MCMV titer of 4.3 logio and a frequency of retinitis of 89% (severity score = 55%), whole eyes of antibody-treated mice with MAIDS had an ocular MCMV titer of 4.3 logio and a frequency of retinitis of 87% (severity score = 57%). Passive transfer of a neutralizing MCMV-specific monoclonal antibody also failed to reduce the frequency or severity of MCMV retinitis when administered to mice with MAIDS prior to subretinal MCMV inoculation. Our findings suggest that antibody immunotherapy alone will not be effective therapeutically for cytomegalovirus retinitis in patients with AIDS.

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“…It is therefore intriguing to speculate that HIV-1-induced AIDS in humans is also associated with a retrovirus-induced downregulation of the perforin cytotoxic pathway, thereby rendering the patient susceptible to HCMV retinitis. Previous studies attempting to correlate immune status and onset and severity of retinitis during AIDS have focused exclusively on the quantification of individual immune cell populations, such as CD4 ϩ -and CD8 ϩ -T-cell counts (30,32), but not on functional aspects of the immune response. Findings with an established MAIDS model of experimental MCMV retinitis (10) predict that loss of effector cell function (i.e., the perforin cytotoxic pathway) as opposed to loss of individual effector cell populations might be more important in predisposing to onset of HCMV retinitis in the HIV-1-immunosuppressed patient.…”

Section: Discussionmentioning

confidence: 99%

“…Although AIDS-related HCMV retinal disease occurs during HIV-1-induced immunosuppression, the precise effector mechanism(s) that fails during the immunopathogenesis of AIDS to allow onset and progression of HCMV retinitis remains unclear. Clinical studies attempting to correlate immune function to onset and severity of HCMV retinitis during AIDS have focused on quantification of absolute numbers of effector cell populations such as CD4 ϩ T cells (30) and/or CD8 ϩ T cells (32). These studies indicate that HCMV retinitis does not occur until late in the course of the disease when peripheral blood CD4…”

mentioning

confidence: 99%

Loss of the Perforin Cytotoxic Pathway Predisposes Mice to Experimental Cytomegalovirus Retinitis

Dix

Podack²,

Cousins

2003

J Virol

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AIDS-related human cytomegalovirus (HCMV) retinitis continues to be a chronic ophthalmologic problem among human immunodeficiency virus type 1 (HIV-1)-infected patients who do not respond to highly active antiretroviral therapy. Although HCMV retinitis occurs during HIV-1-induced immunosuppression, the precise effector mechanism(s) that fails during the immunopathogenesis of AIDS to allow onset and progression of HCMV retinal disease remains unclear. We therefore performed a series of experiments to explore the relative roles of distinct pathways of lymphocyte-mediated cytotoxicity in either resistance or susceptibility to experimental murine cytomegalovirus (MCMV) retinitis in mice. Whereas mutant C57BL/6 mice deficient in the Fas/FasL cytotoxic pathway (gld mice) were identical to normal C57BL/6 mice and exhibited absolute resistance to retinal necrosis following subretinal MCMV inoculation, knockout C57BL/6 mice deficient in the perforin cytotoxic pathway (PKO mice) were susceptible to MCMV retinitis. Susceptibility of PKO mice to MCMV retinitis correlated with increased ocular MCMV titers when compared with ocular MCMV titers of gld and normal mice. Since mice with retrovirus-induced immunodeficiency syndrome (MAIDS) exhibited a frequency and severity of MCMV retinitis that were equivalent to those observed in PKO mice, we hypothesized that susceptibility to MCMV retinitis during MAIDS correlates with a decrease in the perforin cytotoxic pathway. To test this hypothesis, we developed a quantitative competitive reverse transcription-PCR assay to measure mouse perforin mRNA levels in the splenic T lymphocytes and MCMV-inoculated eyes of normal mice or mice with MAIDS. Perforin mRNA levels in splenic T lymphocytes were significantly decreased during MAIDS, by ϳ100-fold, from perforin mRNA levels in normal mice. Moreover, MCMV-inoculated eyes destined to develop retinitis during MAIDS also showed a significant decrease in perforin mRNA levels from the perforin mRNA levels of MCMV-inoculated eyes of normal mice destined to be resistant to retinitis. As expected, perforin mRNA could not be detected in unmanipulated and uninfected eyes of normal mice. These results provide the first evidence that the perforin cytotoxic pathway is more important than the Fas/FasL cytotoxic pathway in providing resistance to experimental MCMV retinitis and that loss of the perforin cytotoxic pathway predisposes to MCMV retinitis.

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CD8+ T Lymphocytes and Cytomegalovirus Retinitis in Patients With the Acquired Immunodeficiency Syndrome

Cited by 24 publications

References 20 publications

Immunologic Parameters as Predictive Factors of Cytomegalovirus Disease in Renal Allograft Recipients

Immunologic Parameters as Predictive Factors of Cytomegalovirus Disease in Renal Allograft Recipients

Antibody Alone Does Not Prevent Experimental Cytomegalovirus Retinitis in Mice with Retrovirus-lnduced Immunodeficiency (MAIDS)

Loss of the Perforin Cytotoxic Pathway Predisposes Mice to Experimental Cytomegalovirus Retinitis

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