De novo T-lymphocyte responses against baculovirus-derived recombinant influenzavirus hemagglutinin generated by a naive umbilical cord blood model of dendritic cell vaccination
Department of Infectious Diseases, Infection Control, and Employee Health, University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, United States. Vaccine
(Impact Factor: 3.62).
02/2009; 27(10):1479-84. DOI: 10.1016/j.vaccine.2009.01.017
Cancer patients and recipients of hematopoietic stem cell transplantation exhibit a negligible response to influenza vaccine. Toward the goal of addressing this issue, we developed an in vitro model of dendritic cell (DC) immunotherapy utilizing DCs generated from naïve umbilical cord blood (UCB). UCB DCs were loaded with purified rHA protein and used to stimulate autologous T-lymphocytes. Upon recall with HA-loaded autologous DC, a 4-10-fold increase in the number of IFN-gamma producing T-lymphocytes was observed in comparison to T-cells stimulated with control DCs. Antigen-specific T-cell functionality was determined by (51)Cr lytic assay. Using a peptide library of predicted HA binding epitopes, we mapped an HA-specific, DR15-restricted CD4 T-cell epitope and observed tetramer positive cells. This model demonstrates that HA-specific immune responses might possibly be generated in a de novo fashion and suggests that dendritic cell immunotherapy for the prevention of influenza in populations of immunosuppressed individuals could be feasible.
Available from: bloodjournal.org
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ABSTRACT: In the control of T-helper type I (Th-1) polarization, dendritic cells (DCs) must interpret a complex array of stimuli, many of which are poorly understood. Here we demonstrate that Th-1 polarization is heavily influenced by DC-autonomous phenomena triggered by the loading of DCs with antigenically matched major histocompatibility complex (MHC) class I and class II determinants, that is, class I and II peptide epitopes exhibiting significant amino acid sequence overlap (such as would be physiologically present during infectious processes requiring Th-1 immunity for clearance). Data were derived from 13 independent antigenic models including whole-cell systems, single-protein systems, and 3 different pairs of overlapping class I and II binding epitopes. Once loaded with matched class I and II antigens, these "Th-1 DCs" exhibited differential cytokine secretion and surface marker expression, a distinct transcriptional signature, and acquired the ability to enhance generation of CD8(+) T lymphocytes. Mechanistically, tRNA-synthetases were implicated as components of a putative sensor complex involved in the comparison of class I and II epitopes. These data provide rigorous conceptual explanations for the process of Th-1 polarization and the antigenic specificity of cognate T-cell help, enhance the understanding of Th-1 responses, and should contribute to the formulation of more effective vaccination strategies.
Blood 02/2009; 113(18):4213-23. DOI:10.1182/blood-2008-10-185470 · 10.45 Impact Factor
Available from: Patrick J Hanley
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ABSTRACT: The naive phenotype of cord blood (CB) T cells may reduce graft-versus-host disease after umbilical cord blood transplantation, but this naivety and their low absolute numbers also delays immune reconstitution, producing higher infection-related mortality that is predominantly related to CMV, adenovirus (Adv), and EBV. Adoptive immunotherapy with peripheral blood-derived virus-specific cytotoxic T lymphocytes (CTLs) can effectively prevent viral disease after conventional stem cell transplantation, and we now describe the generation of single cultures of CTLs from CB that are specific for multiple viruses. Using EBV-infected B cells transduced with a clinical-grade Ad5f35CMVpp65 adenoviral vector as sources of EBV, Adv, and CMV antigens, we expanded virus-specific T cells even from CB T cells with a naive phenotype. After expansion, each CTL culture contained both CD8(+) and CD4(+) T-cell subsets, predominantly of effector memory phenotype. Each CTL culture also had HLA-restricted virus-specific cytotoxic effector function against EBV, CMV, and Adv targets. The CB CTLs recognized multiple viral epitopes, including CD4-restricted Adv-hexon epitopes and immunosubdominant CD4- and CD8-restricted CMVpp65 epitopes. Notwithstanding their naive phenotype, it is therefore possible to generate trivirus-specific CTLs in a single culture of CB, which may be of value to prevent or treat viral disease in CB transplant recipients. This study is registered at www.clinicaltrials.gov as NCT00078533.
Blood 06/2009; 114(9):1958-67. DOI:10.1182/blood-2009-03-213256 · 10.45 Impact Factor
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ABSTRACT: Prophylactic vaccination of cancer patients and recipients of hematopoietic stem cell transplant is generally a simple, efficient and cost-effective manner by which to prevent unnecessary infection and enhance overall clinical outcomes. However, some neoplastic conditions, particularly B-cell malignancies, impart a degree of immunosuppression that complicates traditional prophylactic approaches. Here, we make the case that the application of dendritic cell (DC) immunotherapy for the prophylaxis of infectious disease is both appropriate and cost effective for certain niche populations who are at risk of increased morbidity and who respond poorly to traditional vaccination, particularly influenza vaccination. Here we review the full spectrum of our preclinical work in this area, results demonstrating that DCs loaded with subunit recombinant hemagglutinin can generate robust hemagglutinin-specific immune responses both in vitro and in vivo. In vivo data indicated that a single injection of hemagglutinin-loaded DC was sufficient to generate high-titer antibody responses that could mediate protective immunity to lethal influenza virus challenge. The results suggest that DC immunotherapy for influenza prophylaxis is safe and feasible and that clinical studies might be warranted.
Expert Review of Vaccines 07/2010; 9(7):721-30. DOI:10.1586/erv.10.68 · 4.21 Impact Factor
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