RESUMEN
Haplo-identical donors have been increasingly used as an alternative source of stem cells in patients with severe aplastic anemia in need of an allogeneic transplantation but lack a matched donor. Single cord blood (CB) transplant also offers a curative option for this disease, but few adult patients have been reported due to low number of progenitor cells leading to prolonged cytopenias and a high risk of infections. CB stem cell expansion may theoretically solve these pitfalls but has not been used previously in non-malignant diseases, likely due to fear of graft rejection and lack of availability of expanded CBs outside clinical trials. We report the first case of an adult patient with severe aplastic anemia who was successfully transplanted with a UM171-expanded CB graft. After a conditioning of rabbit antithymocyte globulin, fludarabine, cyclophosphamide, and total body irradiation, a UM171 expanded graft of 3.29 × 106 CD34 + cells/kg (a 51-fold increase) was infused. Full donor chimerism was observed on day + 14, with neutrophil and platelet engraftment on days + 23 and + 27. There was no severe infection or graft-vs-host disease. UM171-expanded grafts offer a valuable option for patients with aplastic anemia in need of transplantation but have no suitable donor.
Asunto(s)
Anemia Aplásica/terapia , Trasplante de Células Madre de Sangre del Cordón Umbilical , Células Madre Hematopoyéticas/efectos de los fármacos , Indoles/farmacología , Pirimidinas/farmacología , Anemia Aplásica/diagnóstico , Trasplante de Células Madre de Sangre del Cordón Umbilical/métodos , Rechazo de Injerto , Supervivencia de Injerto , Humanos , Índice de Severidad de la Enfermedad , Donantes de Tejidos , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Plasmacytoid dendritic cells (pDCs) initiate both innate and adaptive immune responses, making them attractive targets for post-transplantation immunotherapy, particularly after cord blood transplantation (CBT). Toll-like receptor (TLR) agonists are currently studied for pDC stimulation in various clinical settings. Their efficacy depends on pDC number and functionality, which are unknown after CBT. We performed a longitudinal study of pDC reconstitution in children who underwent bone marrow transplantation (BMT) and single-unit CBT. Both CBT and unrelated BMT patients received antithymocyte globulin as part of their graft-versus-host disease prophylaxis regimen. pDC blood counts were higher in CBT patients than in healthy volunteers from 2 to 9 months after transplantation, whereas they remained lower in BMT patients. We showed that cord blood progenitors gave rise in vitro to a 500-fold increase in functional pDCs over bone marrow counterparts. Upon stimulation with a TLR agonist, pDCs from both CBT and BMT recipients upregulated T cell costimulatory molecules, whereas interferon-alpha (IFN-α) production was impaired for 9 months after CBT. TLR agonist treatment is thus not expected to induce IFN-α production by pDCs after CBT, limiting its immunotherapeutic potential. Fortunately, in vitro production of large amounts of functional pDCs from cord blood progenitors paves the way for the post-transplantation adoptive transfer of pDCs.
Asunto(s)
Trasplante de Médula Ósea , Trasplante de Células Madre de Sangre del Cordón Umbilical , Células Dendríticas/inmunología , Inmunoterapia , Leucemia/terapia , Oligodesoxirribonucleótidos/uso terapéutico , Receptor Toll-Like 9/agonistas , Adolescente , Antígenos CD/genética , Antígenos CD/inmunología , Suero Antilinfocítico/uso terapéutico , Recuento de Células , Proliferación Celular , Niño , Células Dendríticas/efectos de los fármacos , Células Dendríticas/patología , Femenino , Expresión Génica , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Inmunosupresores/uso terapéutico , Interferón-alfa/antagonistas & inhibidores , Interferón-alfa/biosíntesis , Leucemia/genética , Leucemia/inmunología , Leucemia/patología , Estudios Longitudinales , Masculino , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/inmunología , Acondicionamiento Pretrasplante , Trasplante HomólogoRESUMEN
BACKGROUND: Identification of Staphylococcus aureus intracellularly in chronic rhinosinusitis (CRS) suggests an underlying cellular immunodeficiency. Supporting this, we have previously reported low CD8+ (cytotoxic) T-lymphocyte levels in a subpopulation of CRS patients and identified polymorphisms in the CD8A gene associated with CRS. In order to better understand the role of low CD8+ in CRS, we wished to determine the phenotype for CRS/Low CD8+ in comparison to that of conventional CRS. METHODS: Sixty-seven low CD8+ CRS patients identified during investigation of CRS were compared for demographics, disease evolution, and bacteriology on endoscopic culture were compared with an existing population of 480 patients with CRS with nasal polyposis previously recruited for genetic association studies. RESULTS: Mean level of CD8+ in the CRS/Low CD8+ population was 0.15 × 10(9)/L (range, 0.20-1.5 × 10(9)/L). There was no difference between both groups in terms of history of allergy, asthma, eczema, acetylsalicylic acid (ASA) intolerance or smoking. The bacteriology was similar between both groups (S. aureus: CRS/Low CD8+: 35%; CRS 32%, p = 0.643). Evolution of disease was somewhat milder in CRS/Low CD8+, with fewer patients requiring surgery, and first surgery performed at a more advanced age. However, antibiotic use was higher in CRS/Low CD8+. Subgroup analysis restricted to CRS with nasal polyposis (CRSwNP)/Low CD8 or CRS without nasal polyposis (CRSsNP)/Low CD8 phenotypes did not substantially alter these results. CONCLUSION: Low CD8+ levels are often identified in CRS patients; however, these patients have disease remarkably similar to those with conventional CRS. This suggests that immune deficiency, whether systemic or locally mediated, is well tolerated and may be present in other forms in CRS. CRS patients with low CD8+ levels may possibly require antibacterial therapies as part of ongoing management.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Utilización de Medicamentos/estadística & datos numéricos , Síndromes de Inmunodeficiencia/inmunología , Pólipos Nasales/inmunología , Rinitis/inmunología , Sinusitis/inmunología , Infecciones Estafilocócicas/inmunología , Staphylococcus aureus/inmunología , Linfocitos T Citotóxicos/inmunología , Adulto , Antibacterianos/uso terapéutico , Linfocitos T CD8-positivos/microbiología , Células Cultivadas , Enfermedad Crónica , Progresión de la Enfermedad , Femenino , Humanos , Síndromes de Inmunodeficiencia/tratamiento farmacológico , Síndromes de Inmunodeficiencia/microbiología , Masculino , Persona de Mediana Edad , Pólipos Nasales/tratamiento farmacológico , Pólipos Nasales/microbiología , Rinitis/tratamiento farmacológico , Rinitis/microbiología , Sinusitis/tratamiento farmacológico , Sinusitis/microbiología , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Linfocitos T Citotóxicos/microbiologíaRESUMEN
BACKGROUND: Beta-hemolytic Group A Streptococcus invasive disease (iGASd) has been subject to intense research since its re-emergence in the late 1980s. In Quebec, an increase in the number of severe iGASd cases has recently been observed. Because of the inter-individual variability in the severity of iGASd, a hereditary predisposition to invasive disease can be suspected. Given that iGASd occurs in MyD88- and IRAK4-deficient patients, although rarely, the increasing frequency of iGASd in the population of French-Canadian children may be associated with a deficiency in the host's innate immune response. METHODS: In this report, we assessed the influence of: (i) bacterial genotype and virulence factors, (ii) immune-cellular features, and (iii) Myd88/IRAK4-dependent response to GAS in vitro on the susceptibility to iGASd in a paediatric cohort of 16 children: 11 French-Canadian and 5 from diverse origin. FINDINGS: GAS virulence factors and genotype are not implicated in the susceptibility toward iGASd, and cellular and MyD88/IRAK4 deficiencies are excluded in our patients. CONCLUSIONS: Although it has been shown that the MyD88/IRAK4-dependent signal is involved in the response to invasive GAS, our data indicates that a MyD88/IRAK4-mediated signalling defect is not the main factor responsible for the susceptibility to severe iGASd in a paediatric population from the province of Quebec.
RESUMEN
CMV and varicella zoster virus (VZV) are significant causes of morbidity and mortality following umbilical cord blood transplantation (UCBT). However, the kinetics of reconstitution and protective potential of antiviral cell-mediated immune responses following UCBT remain poorly characterized. In this study, the reconstitution of CMV- and VZV-specific T cell responses was assessed using IFN-γ ELISPOT in 28 children who underwent UCBT to treat hematological or inherited disorders. Barely detectable in the first 3 mo posttransplantation, CMV- and VZV-specific T cell responses were observed in 30.4% and 40.3% of study subjects after 36 mo of follow-up. Four of five CMV-seropositive subjects developed detectable levels of circulating CMV DNA (DNAemia), and 5 of 17 VZV-seropositive patients experienced herpes zoster during the posttransplant period. Four CMV-seronegative subjects developed IFN-γ responses against CMV, and four subjects developed a VZV-specific IFN-γ response without clinical signs of infection. No CMV- or VZV-related events were observed in study subjects following the development of CMV- or VZV-specific responses > 150 spot-forming units/10(6) PBMCs, consistent with T cell-mediated protection. Finally, famciclovir prophylaxis did not strictly prevent the reconstitution of the VZV-specific T cell repertoire, because the frequency of T cells producing IFN-γ in response to VZV Ags reached levels consistent with protection in two nonzoster subjects. Monitoring of CMV- and VZV-specific cell-mediated immunity could inform immunocompetence and guide the initiation and cessation of antiherpetic prophylaxis in UCBT recipients.