Subject(s)
Cyclosporine/adverse effects , Hematopoietic Stem Cell Transplantation/methods , Neurotoxicity Syndromes/etiology , Transplantation Conditioning/methods , Transplantation, Homologous/methods , Adolescent , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Male , Neurotoxicity Syndromes/pathology , Treatment OutcomeABSTRACT
T cell therapies are increasingly used for the treatment of malignancies and viral-associated diseases. Initial studies focused on the use of unmanipulated T cell populations after allogeneic stem cell transplantation. More recently, the use of antigen-specific T cells has been explored. This chapter reviews the clinical experience with polyclonal Epstein-Barr virus (EBV)-specific cytotoxic T cells (CTL) for the treatment of EBV-associated malignancies. Strategies on how to improve the antitumor activity of EBV-specific CTL are being discussed. If effective, these strategies will have broad implications for T cell therapies for a range of human tumors with defined antigens.
Subject(s)
Immunotherapy, Adoptive , T-Lymphocytes/immunology , Animals , Herpesvirus 4, Human , Hodgkin Disease/therapy , Humans , Lymphoproliferative Disorders/therapy , Nasopharyngeal Neoplasms/therapy , T-Lymphocytes, Cytotoxic/immunology , Virus LatencyABSTRACT
Broader application of adoptive transfer of tumor-specific T-lymphocytes is accompanied by the need for effective suicide genes to ensure the safety of this cell-based therapy. In vivo elimination of T-lymphocytes expressing the herpes simplex virus-derived thymidine kinase gene has demonstrated the feasibility of this suicide gene as safety switch. However, improvements are required to overcome initial problems, such as immunogenicity. Here, newly developed suicide genes, including inducible Fas, inducible caspase and CD20 are discussed. In addition, problems of clinical application of marker genes and gene transfer techniques, which are prerequisites for suicide gene therapy, are addressed.
Subject(s)
Genes, Transgenic, Suicide , Immunotherapy, Adoptive/methods , T-Lymphocytes, Cytotoxic/transplantation , Antigens, CD20/genetics , Humans , Immunotherapy, Adoptive/adverse effects , T-Lymphocytes, Cytotoxic/immunology , Thymidine Kinase/genetics , fas Receptor/geneticsABSTRACT
Tumor-specific T-helper (Th) immunity was found to play a pivotal role in the natural and vaccine-induced immune defense against tumors. Since the majority of cervical cancers express human papillomavirus type 16 (HPV16) E7 oncoprotein, it is important to investigate the Th response against this target antigen in detail. By means of PBMC cultures from HLA-typed healthy donors, we identified the central part of HPV16 E7 (E7(41-72)) as the major immunogenic region within this antigen. Furthermore, we mapped 3 distinct Th epitopes within this region (DR15/E7(50-62), DR3/E7(43-77), DQ2/E7(35-50)). In a parallel approach, employing IFN-gamma ELISPOT analysis, we detected Th immunity against HPV16 E7 in subjects with HPV16+ lesions. Several of these responses matched with the 3 Th epitopes defined in our study. A number of other HPV16+ subjects did not display any E7-specific type 1 cytokine-producing T-cell immunity, indicating failure of the immune response. Our combined data argue for more extensive as well as longitudinal analysis of HPV16-specific T-cell immunity using the ELISPOT assay described, as well as for HPV-specific vaccination of individuals with HPV+ lesions.
Subject(s)
Major Histocompatibility Complex , Oncogene Proteins, Viral/immunology , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Helper-Inducer/metabolism , Uterine Cervical Neoplasms/virology , Cancer Vaccines , Carcinoma/chemistry , Cell Division , Cells, Cultured , Cytokines/metabolism , Epitope Mapping , Epitopes/chemistry , Female , Genes, MHC Class II , HLA-DQ Antigens/chemistry , HLA-DR Antigens/chemistry , HLA-DR Serological Subtypes , HLA-DR3 Antigen/chemistry , Humans , Immunologic Memory , Immunophenotyping , Inhibitory Concentration 50 , Interferon-gamma/metabolism , Leukocytes, Mononuclear/metabolism , Oncogene Proteins, Viral/chemistry , Papillomavirus E7 Proteins , Peptides/chemistry , Peptides/metabolism , Protein Binding , Protein Structure, Tertiary , Recombinant Proteins/metabolism , Recurrence , T-Lymphocytes, Helper-Inducer/chemistry , Uterine Cervical Neoplasms/chemistryABSTRACT
BACKGROUND: Airway hyperresponsiveness, induced sputum eosinophils, and exhaled nitric oxide (NO) levels have all been proposed as non-invasive markers for monitoring airway inflammation in patients with asthma. The aim of this study was to compare the changes in each of these markers following treatment with inhaled glucocorticosteroids in a single study. METHODS: In a randomised, double blind, placebo controlled, parallel study 25 patients with mild asthma (19-34 years, forced expiratory volume in one second (FEV1) >75% predicted, concentration of histamine provoking a fall in FEV1 of 20% or more (PC20) <4 mg/ml) inhaled fluticasone propionate (500 microg twice daily) for four weeks. PC20 to histamine, sputum eosinophil numbers, and exhaled NO levels were determined at weeks 0, 2, and 4, and two weeks after completing treatment. Sputum was induced by inhalation of hypertonic (4.5%) saline and eosinophil counts were expressed as percentage non-squamous cells. Exhaled NO levels (ppb) were measured by chemiluminescence. RESULTS: In the steroid treated group there was a significant increase in PC20, decrease in sputum eosinophils, and decrease in exhaled NO levels compared with baseline at weeks 2 and 4 of treatment. Subsequently, each of these variables showed significant worsening during the two week washout period compared with week 4. These changes were significantly different from those in the placebo group, except for the changes in sputum eosinophils and exhaled NO levels during the washout period. There were no significant correlations between the changes in the three markers in either group at any time. CONCLUSIONS: Treatment of asthmatic subjects with inhaled steroids for four weeks leads to improvements in airway hyperresponsiveness to histamine, eosinophil counts in induced sputum, and exhaled nitric oxide levels. The results suggest that these markers may provide different information when monitoring anti-inflammatory treatment in asthma.
