PubMed · 6364429
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N R Cooper, G R Nemerow. 1983. Complement, viruses, and virus-infected cells.. https://doi.org/10.1007/bf02116278
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Recipients of allogeneic transplants are at risk of cytomegalovirus (CMV) infection and disease during the period of immune compromise after transplantation. The limitations of current antiviral pharmacotherapy have led to attempts to develop alternative strategies for preventing or treating CMV infection, such as adoptive transfer of donor-derived virus-specific T cells. Methods for generating CMV-specific T cells either use live CMV to infect autologous antigen-presenting cells (APCs) or require some knowledge of the immunodominant peptides involved in the immune response. A novel culture system was developed that does not use live virions and in which the APCs are monocyte-derived dendritic cells (DCs). APCs were pulsed with CMV antigen and cocultured with autologous peripheral blood lymphocytes from donors seropositive for CMV. The culture-output cells consisted of both CD4- and CD8-expressing T cells. Proliferation, as determined by a tritium-thymidine-incorporation assay, showed significant CMV-antigen specificity in cultures from 15 of 15 donors seropositive for CMV. In cytotoxicity assays, cytotoxic T lymphocytes from 10 of 12 cocultures specifically lysed autologous CMV-infected fibroblasts or DCs but not HLA-mismatched or uninfected target cells, and this activity was shown to be blocked by HLA class 1 blocking antibodies. T-cell-receptor spectratyping of cells from the cultures typically showed complex size-distribution patterns, with all size classes of a normal preculture distribution present. However, a few size-class peaks were expanded compared with the preculture patterns and these may have represented expansions of CMV-specific T-cell clones. Advantages of this culture system are that it requires no live virions and no detailed knowledge of the antigenic peptides involved and it is applicable to CMV-seropositive donors of any HLA type.
Data from murine models of chronic viral infection suggest that CD4+ T-cell responses to viral pathogens are important in sustaining the number and/or function of CD8+ cytotoxic T-cell (CTL) effectors. In this study, we used cytokine flow cytometry (CFC), staining with HLA-A*0201-peptide tetramers, and peptide stimulation with epitopic peptides to study functional CD4+ and CD8+ T-cell responses to cytomegalovirus (CMV) in human subjects coinfected with CMV and the human immunodeficiency virus, type 1 (HIV-1). We show that strong CD4+ and CD8+ T-cell responses to CMV antigens are sustained over time in HIV-1-infected individuals. Those who maintain a strong CD4+ T-cell response to CMV are also likely to maintain higher frequencies of CD8+ T cells capable of binding to HLA-A*0201-CMV pp65 (A2-pp65) tetramers as well as responses to pp65 peptide stimulation with effector cytokine production. These data support the hypothesis that declines in frequencies of CD4+ T-cell responses to CMV are associated with an inability to sustain high levels of CMV-specific CD8+ T-cell responses in HIV-1-infected subjects. These declines may precede the onset of CMV-associated end organ disease.
Measles still causes high mortality in children younger than 1 year of age. Administration of high titre measles vaccines before 7 months of age led to increased overall mortality, raising questions as to the immunological effects of measles vaccine in young infants. We investigated the immune response to standard titre vaccines given to children in Bangladesh in a single dose at age 9 months, or two doses at 6 and 9 months. Of the children vaccinated at age 9 months, 95% serocoverted, compared with 70% at age 6 months. Delayed-type-hypersensitivity reactions to candida antigen were significantly reduced in both vaccine groups at 6 weeks post-vaccination, but responses to other recall antigens studied were not significantly different from controls. In both vaccine groups, peripheral blood lymphocytes isolated at 6 and 24 weeks after vaccination showed significantly higher expression of activation markers upon in vitro stimulation, and a sustained increase in IL-2 production. These findings suggest prolonged immune activation after measles vaccination at the same time as some reduction in delayed hypersensitivity responses. Further study of the clinical effects of these changes is warranted.