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1.
Transplantation ; 102(9): 1569-1575, 2018 09.
Article in English | MEDLINE | ID: mdl-29509573

ABSTRACT

BACKGROUND: Cytomegalovirus (CMV) infection is implicated in endothelial dysfunction and graft damage after pediatric heart transplantation. CMV-specific immune responses are thought to be necessary for CMV viral control but there is little data in pediatric heart transplantation. METHODS: We studied 28 consecutive pediatric heart transplant recipients for 1 year posttransplant. CMV T-cell expressing IFN-γ, TNF-α, and IL-2 in response to ex vivo stimulation with CMV lysates or peptides were measured. Circulating cytokines were measured in plasma. Generalized Additive Models were applied to the data to model changes of cell population dynamics over time. RESULTS: CMV-specific T cell-mediated responses were impaired in the first 8 weeks posttransplant. During this period, 25% of patients had CMV viremia, of which those with VLs of 10 000 or more CMV deoxyribonucleic acid copies/mL were given ganciclovir. In this group, the frequency of CD4+ and CD8+ T cells producing IFN-γ and the CD8+CD57+ granzyme B+ T-cell population increased at 12 to 24 weeks and remained elevated for the duration of the study. CONCLUSIONS: We have shown that CMV viremia is associated with CMV-specific immune responses and increased CD8+CD57+ granzyme B+ cells at 1 year posttransplant; however, early responses were not predictive of impending CMV viremia. It remains to be seen if the early CMV immune response detected is associated with endothelial and allograft damage, in light of previous studies demonstrating increased vasculopathy in pediatric patients with CMV viremia.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Cytomegalovirus Infections/immunology , Cytomegalovirus/immunology , Heart Transplantation/adverse effects , Opportunistic Infections/immunology , Adolescent , Age Factors , Antiviral Agents/therapeutic use , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/virology , Child , Child, Preschool , Cytomegalovirus/drug effects , Cytomegalovirus Infections/blood , Cytomegalovirus Infections/drug therapy , Cytomegalovirus Infections/virology , Female , Ganciclovir/therapeutic use , Host-Pathogen Interactions , Humans , Immunity, Cellular , Infant , Interferon-gamma/blood , Interferon-gamma/immunology , Interleukin-2/blood , Interleukin-2/immunology , Longitudinal Studies , Male , Opportunistic Infections/blood , Opportunistic Infections/drug therapy , Opportunistic Infections/virology , Prospective Studies , Time Factors , Treatment Outcome , Tumor Necrosis Factor-alpha/blood , Tumor Necrosis Factor-alpha/immunology , Viral Load
2.
AIDS ; 30(12): 1867-76, 2016 07 31.
Article in English | MEDLINE | ID: mdl-27124901

ABSTRACT

OBJECTIVES: Many children with HIV infection now survive into adulthood. This study explored the impact of vertically acquired HIV in the era of antiretroviral therapy on the development of humoral immunity. DESIGN: Natural and vaccine-related immunity to pneumococcus and B-cell phenotype was characterized and compared in three groups of young adults: those with vertically-acquired infection, those with horizontally acquired infection and healthy controls. METHODS: Serotype-specific pneumococcal (Pnc) immunoglobulin M and G concentrations before and up to 1 year post-Pnc polysaccharide (Pneumovax) immunization were determined, and opsonophagocytic activity was analysed. B-cell subpopulations and dynamic markers of B-cell signalling, turnover and susceptibility to apoptosis were evaluated by flow cytometry. RESULTS: HIV-infected patients showed impaired natural Pnc immunity and reduced humoral responses to immunization with Pneumovax; this was greatest in those viraemic at time of the study. Early-life viral control before the age of 10 years diminished these changes. Expanded populations of abnormally activated and immature B-cells were seen in both HIV-infected cohorts. Vertically infected patients were particularly vulnerable to reductions in marginal zone and switched memory populations. These aberrations were reduced in patients with early-life viral control. CONCLUSION: In children with HIV, damage to B-cell memory populations and impaired natural and vaccine immunity to pneumococcus is evident in early adult life. Sustained viral control from early childhood may help to limit this effect and optimize humoral immunity in adult life.


Subject(s)
B-Lymphocyte Subsets/immunology , HIV Infections/immunology , HIV Infections/transmission , Immunity, Humoral , Infectious Disease Transmission, Vertical , Streptococcus pneumoniae/immunology , Adolescent , Adult , Antibodies, Bacterial/blood , Child , Disease Transmission, Infectious , Female , Flow Cytometry , Humans , Immunoglobulin G/blood , Immunoglobulin M/blood , Male , Opsonin Proteins/blood , Phagocytosis , Pneumococcal Infections/immunology , Pneumococcal Vaccines/administration & dosage , Pneumococcal Vaccines/immunology , Young Adult
3.
J Infect Dis ; 198(4): 481-5, 2008 Aug 15.
Article in English | MEDLINE | ID: mdl-18582200

ABSTRACT

Levels of circulating naive and memory B cells were measured in human immunodeficiency virus (HIV)-infected children and control subjects to determine whether the irreversible depletion of memory B cells described in HIV-infected adults occurs in children with HIV infection. Depletion of circulating IgD+ memory B cells was seen in HIV-infected children despite control of the HIV load with highly active antiretroviral therapy (HAART) (P =. 04). IgD+ memory B cell percentages did not correlate with CD4+ cell percentages (P =. 027) or disease duration (P =. 026). Naive/transitional and IgD- memory B cell numbers were not affected. Pediatric HIV infection is associated with selective depletion of circulating IgD+ memory B cells despite control of the HIV load with HAART.


Subject(s)
Antiretroviral Therapy, Highly Active , B-Lymphocytes , HIV Infections/immunology , HIV-1/immunology , Immunoglobulin D/blood , Immunologic Memory , Adolescent , Child , Child, Preschool , Female , HIV Infections/virology , HIV-1/drug effects , Humans , Male , Pediatrics , Viral Load/statistics & numerical data
4.
J Biol Chem ; 277(8): 6153-61, 2002 Feb 22.
Article in English | MEDLINE | ID: mdl-11748224

ABSTRACT

During normal developmental tissue growth and in a number of diseases of the cardiopulmonary system, adventitial and interstitial fibroblasts are subjected to increased mechanical strain. This leads to fibroblast activation and enhanced collagen synthesis, but the underlying mechanisms involved remain poorly understood. In this study, we have begun to identify and characterize mechanical strain-responsive elements in the rat procollagen alpha 1(I) (COL1A1) gene and show that the activity of COL1A1 promoter constructs, transiently transfected into cardiac fibroblasts, was increased between 2- and 4-fold by continuous cyclic mechanical strain. This was accompanied by an approximately 3-fold increase in the levels of total active transforming growth factor-beta (TGF-beta) released into the medium. Inclusion of a pan-specific TGF-beta neutralizing antibody inhibited strain-induced COL1A1 promoter activation. Deletion analysis revealed the presence of two potential strain response regions within the proximal promoter, one of which contains an inverted CCAAT-box overlapping a GC-rich element. Both mechanical strain and exogenously added TGF-beta1 enhanced the binding activity of CCAAT-binding factor, CBF/NF-Y, at this site. Moreover, this element was sufficient to confer strain-responsiveness to an otherwise unresponsive SV40 promoter. In summary, this study demonstrates that strain-induced COL1A1 promoter activation in cardiac fibroblasts is TGF-beta-dependent and involves increased binding of CCAAT-binding factor at the proximal promoter. Furthermore, these findings suggest a novel and potentially important TGF-beta response element in the rat COL1A1 gene.


Subject(s)
CCAAT-Binding Factor/metabolism , Collagen Type I/genetics , Collagen/genetics , Fibroblasts/metabolism , Gene Expression Regulation , Promoter Regions, Genetic/drug effects , Transcription, Genetic , Transforming Growth Factor beta/pharmacology , Animals , Base Sequence , Binding Sites , Cells, Cultured , Collagen Type I, alpha 1 Chain , Consensus Sequence , Culture Media, Conditioned , Embryo, Mammalian , Gene Expression Regulation/drug effects , Heart/embryology , Heart/physiology , Rats , Rats, Sprague-Dawley , Stress, Mechanical , Transcriptional Activation
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