Asunto(s)
Anemia de Células Falciformes/terapia , Anticonvulsivantes/efectos adversos , Trasplante de Médula Ósea , Hipersensibilidad a las Drogas , Rechazo de Injerto/inducido químicamente , Fenitoína/efectos adversos , Anticonvulsivantes/administración & dosificación , Niño , Femenino , Humanos , Masculino , Fenitoína/administración & dosificación , Síndrome , Trasplante HomólogoRESUMEN
We report a retrospective analysis of 11 children with Down syndrome (DS) treated by SCT in eight German/Austrian SCT centres. Indications for transplantation were acute lymphoblastic leukaemia (N=8) and acute myeloid leukaemia (N=3). A reduced intensity conditioning (RIC) containing 2 Gy TBI was given to two patients, another five received a myeloablative regimen with 12 Gy TBI. Treosulphan or busulphan was used in the remaining four children. Four of eleven (36%) patients are alive. All of them were treated with a myeloablative regimen. One of the four surviving children relapsed 9 months after SCT and is currently receiving palliative outpatient treatment. The main cause of death was relapse (5/11). Two children died of regimen-related toxicity (RRT), one from severe exfoliative dermatitis and multiorgan failure after a treosulphan-containing regimen, the other from GvHD-related infections after RIC. Acute GvHD of the skin was observed in 10 of 10 evaluable patients, and chronic GvHD in 4 of 8. Our data show that DS patients can tolerate commonly used, fully myeloablative preparative regimens. The major cause of death is relapse rather than RRT resulting in an event-free survival of 18% and over all survival of 36%.
Asunto(s)
Síndrome de Down/complicaciones , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Leucemia Mieloide Aguda/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Niño , Preescolar , Femenino , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Masculino , Recurrencia , Estudios Retrospectivos , Acondicionamiento Pretrasplante/efectos adversos , Insuficiencia del TratamientoRESUMEN
Post transplant lymphoproliferative disease (PTLD) is a severe complication after solid organ or bone marrow transplantation. In pediatric transplant recipients PTLD is the most common malignancy. The aim of this study was to evaluate a possible role for positron emission tomography with [18F]-2-fluoro-2-desoxy-glucose (FDG) in the initial staging and in therapy monitoring of pediatric patients suffering from biopsy-proven CD20-positive PTLD after solid organ transplantation. Seven pediatric patients were included. All available imaging studies - CT (n=15), MRI (n=16) and PET/PETCT (n=16) - were reviewed on a lesion by lesion base. The performance of FDG-PET in the initial staging and during therapy with a chimeric anti-CD20 antibody was compared to conventional cross sectional imaging and correlated with the clinical outcome. FDG-PET identified all sites of disease as shown by CT/MRI and helped to clarify the significance of equivocal findings. The initial stage of disease was correctly identified by FDG-PET alone when compared to CT/MRI. During therapy, FDG-PET was superior to conventional cross-sectional imaging in the early evaluation of response.
Asunto(s)
Fluorodesoxiglucosa F18 , Trastornos Linfoproliferativos/diagnóstico por imagen , Trasplante de Órganos , Tomografía de Emisión de Positrones/métodos , Complicaciones Posoperatorias/diagnóstico por imagen , Radiofármacos , Adolescente , Niño , Preescolar , Femenino , Humanos , Trastornos Linfoproliferativos/etiología , Masculino , Estudios RetrospectivosRESUMEN
Acute lymphoblastic leukemia (ALL) cells are particularly poor at generating anti-leukemia immunity, despite residing in lymphoid organs. To assess a potential role of dendritic cells (DC) in poor anti-leukemia immunity, we analyzed peripheral blood DC in 55 pediatric ALL patients at the time of initial diagnosis and 19 age-matched healthy controls. Dendritic cells were identified by their expression of HLA-DR, lack of B, T, NK, and monocyte markers, and expression of CD11c (myeloid DC(mDC)) or BDCA-2 (plasmacytoid DC(pDC)) using flow cytometry. We found that in children with B-lineage ALL, numbers of both mDC and pDC were significantly reduced (P = 0.0001). In contrast, T-lineage ALL patients showed normal pDC and significantly elevated mDC (P = 0.003) levels, with normal expression of HLA-DR and co-stimulatory molecules. A decrease in DC could not be explained by general impairment of myelopoiesis, as we could not demonstrate a correlation of DC numbers with granulocyte/monocyte numbers in patients with B-lineage ALL. However, aberrant expression of myeloid surface markers on leukemic blasts was frequent in patients lacking myeloid DC indicating a potential block of DC differentiation. Thus, depletion of DC in B-lineage ALL patients may contribute to poor anti-leukemia immune responses.
Asunto(s)
Antígeno CD11c/biosíntesis , Células Dendríticas/inmunología , Lectinas Tipo C/biosíntesis , Glicoproteínas de Membrana/biosíntesis , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Receptores Inmunológicos/biosíntesis , Adolescente , Antígenos CD/biosíntesis , Antígenos de Diferenciación Mielomonocítica/biosíntesis , Linfocitos B/inmunología , Linfocitos B/patología , Antígenos CD13/biosíntesis , Recuento de Células , Niño , Preescolar , Estudios de Cohortes , Femenino , Citometría de Flujo/métodos , Humanos , Inmunofenotipificación , Recuento de Leucocitos , Masculino , Monocitos/patología , Neutrófilos/patología , Peroxidasa/biosíntesis , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Sensibilidad y Especificidad , Lectina 3 Similar a Ig de Unión al Ácido SiálicoRESUMEN
The widely expressed tumour antigens hTERT and CYP1B1 are commonly expressed in multiple myeloma (MM) cells. Several trials targeting these antigens by immunotherapy have been initiated. The aim of this study was to explore whether patients with MM have an endogenous pre-existing immune response against recently identified epitopes from hTERT and CYP1B1. Peripheral blood T cells from 27 HLA-A*0201+ multiple myeloma patients at different stages of disease and 20 healthy HLA-A*0201+ donors were enriched and studied for the presence of hTERT- and CYP1B1-specific cytotoxic T cells using MHC tetramer detection and short-term ex vivo expansion. No significant expansion of tetramer-positive cells was detected in the peripheral blood of either MM patients or healthy controls when cells were stained with tetramers containing the dominant hTERT-derived epitope or two peptides derived from CYP1B1. A single ex vivo peptide stimulation led to the detection of a small population (0.3-0.5%) of hTERT-specific cells in two of 27 patients with MM. None of the patients or controls showed significant expansion of CYP1B1-specific cells after a single peptide stimulation. Thus, endogenous in vivo priming of T cells against hTERT and CYP1B1 is a rare event in MM patients. These results suggest that strategies targeting hTERT and CYP1B1 may have to utilize techniques to induce T cell responses from a naive precursor frequency.
Asunto(s)
Antígenos de Neoplasias/inmunología , Hidrocarburo de Aril Hidroxilasas/inmunología , Proteínas de Unión al ADN/inmunología , Epítopos/inmunología , Mieloma Múltiple/inmunología , Linfocitos T Citotóxicos/inmunología , Telomerasa/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Proliferación Celular , Células Cultivadas , Citocromo P-450 CYP1B1 , Citotoxicidad Inmunológica , Femenino , Humanos , Interferón gamma/análisis , Masculino , Persona de Mediana Edad , Isoformas de Proteínas/análisisRESUMEN
Despite encouraging scientific and therapeutic advances, chronic lymphocytic leukemia (CLL) principally remains an incurable disease. Allogeneic transplantation represents the only curative approach, but is marked by high mortality. Novel and less toxic treatment modalities are needed. Immunotherapeutic approaches have clearly demonstrated potential effectiveness in CLL and other B-cell malignancies. To successfully direct immunity against CLL, highly immunogenic tumor cells or tumor-antigen-loaded antigen-presenting cells are necessary. The CD40-CD40L interaction has been shown to significantly increase antigen presentation in normal and malignant B-cells. Here we discuss biology and potential therapeutic applications of the CD40-system in CLL.
Asunto(s)
Linfocitos B/inmunología , Antígenos CD40/inmunología , Leucemia Linfocítica Crónica de Células B/inmunología , Vacunación/métodos , Presentación de Antígeno/inmunología , Ligando de CD40/inmunología , Humanos , Leucemia Linfocítica Crónica de Células B/terapia , Activación de Linfocitos/inmunología , Transducción de Señal/inmunologíaRESUMEN
Although high frequencies of T lymphocytes specific for certain tumor-associated antigens have been detected in some cancer patients, increasing evidence suggests that these T cells may be functionally defective in vivo and fail to induce meaningful clinical responses. One strategy to overcome this limitation is to target novel antigens that are ignored during the natural antitumor immune response but are nevertheless capable of triggering effector T-cell responses against tumors after optimal presentation by antigen-presenting cells. Here, we show that the telomerase catalytic subunit (hTERT)-a nearly universal tumor antigen identified by epitope deduction rather than from patient immune responses-is immunologically ignored by patients despite progressive tumor burden. Nevertheless, HLA-A2-restricted CTLs against hTERT are equivalently induced ex vivo from patients and healthy individuals and efficiently kill human tumor cell lines and primary tumors. Thus, telomerase-specific T cells from cancer patients are spared functional inactivation because of immunological ignorance. These findings support clinical efforts to target the hTERT as a tumor antigen with broad therapeutic potential.
Asunto(s)
Neoplasias/inmunología , Linfocitos T Citotóxicos/inmunología , Telomerasa/inmunología , Adulto , Anciano , Proteínas de Unión al ADN , Epítopos de Linfocito T/inmunología , Femenino , Antígeno HLA-A2/inmunología , Humanos , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/inmunologíaRESUMEN
Tumour immunology has seen many exciting developments in the last few years. In addition to tumour antigens that are defined by antitumour T- and B-cell responses in patients, the human telomerase reverse transcriptase has been identified by 'reverse immunology' as the first truly universal tumour antigen. Molecular remission has been associated with a cancer vaccine that targets the clonal idiotype of B-cell malignancies, and sophisticated cellular vaccines (including fusions of tumour cells and antigen-presenting cells) have demonstrated promising results. Moreover, our capabilities of measuring immunity have been significantly enhanced by novel technology, such as major histocompatibility complex (MHC)-peptide tetramers and ELISPOT analysis. We are now capable of tracking antigen-specific T cells at a single cell level. This review will analyse recent developments and highlight some important issues that need to be addressed in the future.
Asunto(s)
Vacunas contra el Cáncer/inmunología , Inmunoterapia/tendencias , Receptores de Antígenos de Linfocitos T/fisiología , Linfocitos T/fisiología , Antígenos de Neoplasias/inmunología , Proteínas de Unión al ADN , Humanos , Inmunidad Celular , Complejo Mayor de Histocompatibilidad , Linfocitos T/inmunología , Telomerasa/metabolismoRESUMEN
The disclosure of the human genome sequence and rapid advances in genomic expression profiling have revolutionized our knowledge about molecular changes in malignant diseases. Rapidly growing gene expression databases and improvements in bioinformatics tools set the stage for new approaches using large-scale molecular information to develop specific therapeutics in cancer. On one hand, the ability to detect clusters of genes differentially expressed in normal and malignant tissue may lead to widely applicable targeting of defined molecular structures. On the other hand, analyzing the 'molecular fingerprint' of an individual tumor raises the possibility of developing customized therapeutics. One approach to use the emerging new datasets for the development of novel therapeutics is to identify genes that are specifically expressed in tumors as targets for immune intervention. This review will focus on the process from in silico analysis of expression databases and screening of potential candidate genes by bioinformatics to the in vitro and in vivo analysis to determine the immunogenicity of candidate tumor antigens. Basic biological principles of 'reverse immunology' as well as technical advantages and difficulties will be addressed.