RESUMEN
Epstein-Barr virus (EBV) is associated with several malignancies, including post-transplant lymphoproliferative disorder (PTLD). Conventional treatments for PTLD are often successful, but risk organ rejection and cause significant side effects. EBV-specific cytotoxic T lymphocytes (CTLs) generated in vitro from peripheral blood lymphocytes provide an alternative treatment modality with few side effects, but autologous CTLs are difficult to use in clinical practice. Here we report the establishment and operation of a bank of EBV-specific CTLs derived from 25 blood donors with human leucocyte antigen (HLA) types found at high frequency in European populations. Since licensure, there have been enquiries about 37 patients, who shared a median of three class I and two class II HLA types with these donors. Cells have been infused into ten patients with lymphoproliferative disease, eight of whom achieved complete remission. Neither patient with refractory disease was matched for HLA class II. Both cases of EBV-associated non-haematopoietic sarcoma receiving cells failed to achieve complete remission. Thirteen patients died before any cells could be issued, emphasizing that the bank should be contacted before patients become pre-terminal. Thus, this third party donor-derived EBV-specific CTL cell bank can supply most patients with appropriately matched cells and most recipients have good outcomes.
Asunto(s)
Infecciones por Virus de Epstein-Barr/terapia , Herpesvirus Humano 4/inmunología , Inmunoterapia Adoptiva , Trastornos Linfoproliferativos/terapia , Linfocitos T Citotóxicos/inmunología , Bancos de Tejidos/organización & administración , Adolescente , Aloinjertos , Neoplasias del Sistema Nervioso Central/terapia , Neoplasias del Sistema Nervioso Central/virología , Preescolar , Infecciones por Virus de Epstein-Barr/inmunología , Femenino , Antígenos HLA/análisis , Prueba de Histocompatibilidad , Humanos , Lactante , Leiomiosarcoma/terapia , Leiomiosarcoma/virología , Concesión de Licencias , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/virología , Trastornos Linfoproliferativos/etiología , Trastornos Linfoproliferativos/inmunología , Trastornos Linfoproliferativos/virología , Masculino , Persona de Mediana Edad , Nueva Zelanda , Complicaciones Posoperatorias/inmunología , Complicaciones Posoperatorias/terapia , Complicaciones Posoperatorias/virología , Inducción de Remisión , Sarcoma/terapia , Sarcoma/virología , Especificidad del Receptor de Antígeno de Linfocitos T , Linfocitos T Citotóxicos/trasplante , Bancos de Tejidos/normas , Resultado del Tratamiento , Adulto JovenRESUMEN
The addition of plerixafor to G-CSF decreases the risk of failed stem cell collection, but at considerable extra cost. Using a logistic regression model based on 354 autologous mobilizations, we have identified a local minimum peripheral blood CD34 count at which the probability of a successful collection is 50%. This seems an appropriate CD34 count at which to add immediate salvage plerixafor.
Asunto(s)
Movilización de Célula Madre Hematopoyética/métodos , Compuestos Heterocíclicos/uso terapéutico , Linfoma/terapia , Mieloma Múltiple/terapia , Trasplante de Células Madre/métodos , Trasplante Autólogo/métodos , Antígenos CD34/metabolismo , Bencilaminas , Eliminación de Componentes Sanguíneos , Peso Corporal , Análisis Costo-Beneficio , Ciclamas , Factor Estimulante de Colonias de Granulocitos/economía , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Movilización de Célula Madre Hematopoyética/economía , Compuestos Heterocíclicos/economía , Humanos , Leucemia Mieloide Aguda/terapia , Linfoma no Hodgkin/terapia , Análisis de Regresión , Estudios Retrospectivos , Trasplante de Células Madre/economía , Trasplante Autólogo/economía , Resultado del TratamientoRESUMEN
The CD40-CD154 pathway is important in the pathogenesis of inflammatory bowel disease. Here we show that injection of an agonistic CD40 mAb to T and B cell-deficient mice was sufficient to induce a pathogenic systemic and intestinal innate inflammatory response that was functionally dependent on tumor necrosis factor-alpha and interferon-gamma as well as interleukin-12 p40 and interleukin-23 p40 secretion. CD40-induced colitis, but not wasting disease or serum proinflammatory cytokine production, depended on interleukin-23 p19 secretion, whereas interleukin-12 p35 secretion controlled wasting disease and serum cytokine production but not mucosal immunopathology. Intestinal inflammation was associated with IL-23 (p19) mRNA-producing intestinal dendritic cells and IL-17A mRNA within the intestine. Our experiments identified IL-23 as an effector cytokine within the innate intestinal immune system. The differential role of IL-23 in local but not systemic inflammation suggests that it may make a more specific target for the treatment of IBD.