RESUMEN
We report outcomes after myeloablative haematopoietic cell transplantation (HCT) from human leucocyte antigen (HLA)-matched sibling donors in 67 patients with sickle cell disease transplanted between 1989 and 2002. The most common indications for transplantation were stroke and recurrent vaso-occlusive crisis in 38% and 37% of patients respectively. The median age at transplantation was 10 years and 67% of patients had received >10 red blood cell transfusions before HCT. Twenty-seven percent of patients had a poor performance score at transplantation. Ninety-four percent received busulfan and cyclophosphamide-containing conditioning regimens and bone marrow was the predominant source of donor cells. Most patients achieved haematopoietic recovery and no deaths occurred during the early post-transplant period. Rates of acute and chronic graft-versus-host disease were 10% and 22% respectively. Sixty-four of 67 patients are alive with 5-year probabilities of disease-free and overall survival of 85% and 97% respectively. Nine patients had graft failure with recovery of sickle erythropoiesis, eight of who had recurrent sickle-related events. This report confirms and extends earlier reports that HCT from HLA-matched related donors offers a very high survival rate, with few transplant-related complications and the elimination of sickle-related complications in the majority of patients who undergo this therapy.
Asunto(s)
Anemia de Células Falciformes/cirugía , Trasplante de Células Madre Hematopoyéticas , Anemia de Células Falciformes/inmunología , Anemia de Células Falciformes/mortalidad , Supervivencia sin Enfermedad , Enfermedad Injerto contra Huésped , Prueba de Histocompatibilidad , Humanos , Recuento de Leucocitos , Neutrófilos/inmunología , Probabilidad , Sistema de Registros , Tasa de Supervivencia , Acondicionamiento Pretrasplante , Trasplante HomólogoRESUMEN
Certain cytokine gene polymorphisms have been shown to correlate with outcome of human leukocyte antigen (HLA) identical sibling donor stem cell transplantation (SCT), but in unrelated donor SCT such information is scarce. We have studied the association between cytokine gene polymorphism and transplant-related mortality (TRM) in 182 unrelated SCTs performed at a single center. We found association of polymorphism in the tumor necrosis factor alpha (TNF alpha) and interleukin-10 (IL-10) gene and TRM. Both the TNFd4 allele and the TNF alpha -1031C alleles are associated with high risk for TRM. Statistical analysis showed that both polymorphisms were present on a single haplotype. This haplotype was associated with high risk of TRM when present in recipient or donor, 55% (43%-67%) compared with 21% (12%-30%) when absent from both (P <.01). A further allele associated with this haplotype, TNFa5, is also associated with increased risk of TRM. For IL-10, presence of the donor R2-G-C-C haplotype was associated with decreased risk of TRM, 61% (43%-79%) versus 34% (25%-43%), P =.01. In contrast, possession of the R3-G-C-C haplotype by the donor predicted reduced risk of TRM, 30% (19%-41%, 95% CI) versus 53% (40%-66%, 95% CI), P =.01. No independent associations of cytokine polymorphisms with acute graft-versus-host disease were shown.
Asunto(s)
Haplotipos , Trasplante de Células Madre Hematopoyéticas/mortalidad , Interleucina-10/genética , Factor de Necrosis Tumoral alfa/genética , Adolescente , Adulto , Frecuencia de los Genes , Enfermedad Injerto contra Huésped/genética , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Polimorfismo Genético , Probabilidad , Pronóstico , Donantes de Tejidos , Trasplante Homólogo/efectos adversos , Trasplante Homólogo/mortalidad , Resultado del TratamientoRESUMEN
Sialic acid-binding immunoglobulin-like lectin (Siglec)-5 or CD170 is a CD33-related receptor, containing cytoplasmic immune receptor-based tyrosine signalling motifs, that has previously been reported to be myeloid-specific like CD33 and thus may be useful in the characterization of both normal and malignant haemopoiesis. This study showed that Siglec-5 had a distinct expression pattern to CD33 both on normal myeloid cells and in acute myeloid leukaemia (AML). In normal bone marrow and cord blood, myeloid cells predominantly expressed Siglec-5 at the later stages of granulocytic differentiation. Siglec-5 was not expressed at significant levels by CD34+ progenitors either from bone marrow or mobilized peripheral blood. During in vitro myeloid differentiation of cord blood purified CD34+ cells, Siglec-5 was upregulated later than CD33. Siglec-5 expression remained absent or very low on cultured CD34+ cells, unlike CD33, which was present on almost all CD34+ cells by day 4. However, analysis of blasts from 23 patients with AML revealed aberrant expression of Siglec-5 with CD34 in 50% (seven of 14) of patients with CD34+ AML; 61% (14 of 23) of AML cases were positive for Siglec-5 with an increased frequency in the French-American-British subtypes M3-5 (80%) compared with M0-2 (25%). All 13 acute lymphoblastic leukaemic (ALL) samples tested, including a CD33+ ALL, were Siglec-5 negative. These results support the further evaluation of Siglec-5 antibodies in the diagnosis and monitoring of AML.
Asunto(s)
Antígenos CD/análisis , Antígenos de Diferenciación Mielomonocítica/análisis , Células de la Médula Ósea/inmunología , Lectinas/análisis , Leucemia Mieloide/inmunología , Enfermedad Aguda , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos/sangre , Anticuerpos/uso terapéutico , Antígenos CD/inmunología , Antígenos CD34/análisis , Antígenos de Diferenciación Mielomonocítica/inmunología , Biomarcadores/análisis , Estudios de Casos y Controles , Diferenciación Celular/inmunología , Niño , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Humanos , Inmunización Pasiva , Recién Nacido , Lectinas/inmunología , Leucemia Mieloide/terapia , Persona de Mediana Edad , Mielopoyesis/inmunología , Lectina 3 Similar a Ig de Unión al Ácido Siálico , Células Madre/inmunologíaRESUMEN
In postnatal life, mesenchymal stem cells (MSC) self-replicate, proliferate and differentiate into mesenchymal tissues, including bone, fat, tendon, muscle and bone marrow (BM) stroma. Possible clinical applications for MSC in stem cell transplantation have been proposed. We have evaluated the frequency, phenotype and differentiation potential of MSC in adult BM, cord blood (CB) and peripheral blood stem cell collections (PBSC). During culture, BM MSC proliferated to confluence in 10-14 d, maintaining a stable non-haemopoietic phenotype, HLA class-1+, CD29+, CD44+, CD90+, CD45-, CD34- and CD14 through subsequent passages. Using the colony forming unit fibroblasts assay, the estimated frequency of MSC in the BM nucleated cell population was 1 in 3.4 x 10(4) cells. Both adipogenic and osteogenic differentiation of BM MSC was demonstrated. In contrast, CB and PBSC mononuclear cells cultured in MSC conditions for two passages produced a population of adherent, non-confluent fibroblast-like cells with a haemopoietic phenotype, CD45+, CD14+, CD34-, CD44-, CD90- and CD29-. In paired experiments, cultured BM MSC and mature BM stroma were seeded with CB cells enriched for CD34+. Similar numbers of colony-forming units of granulocytes-macrophages were produced by MSC-based and standard stroma cultures over 10 weeks. We conclude that adult BM is a reliable source of functional cultured MSC, but CB and PBSC are not.
Asunto(s)
Células de la Médula Ósea/citología , Mesodermo/citología , Células Madre/citología , Adulto , Sangre , Recuento de Células , Diferenciación Celular , División Celular , Células Cultivadas , Ensayo de Unidades Formadoras de Colonias , Sangre Fetal , Citometría de Flujo , Humanos , InmunofenotipificaciónRESUMEN
Studies on monozygotic twins with concordant leukemia and retrospective scrutiny of neonatal blood spots of patients with leukemia indicate that chromosomal translocations characteristic of pediatric leukemia often arise prenatally, probably as initiating events. The modest concordance rate for leukemia in identical twins ( approximately 5%), protracted latency, and transgenic modeling all suggest that additional postnatal exposure and/or genetic events are required for clinically overt leukemia development. This notion leads to the prediction that chromosome translocations, functional fusion genes, and preleukemic clones should be present in the blood of healthy newborns at a rate that is significantly greater than the cumulative risk of the corresponding leukemia. Using parallel reverse transcriptase-PCR and real-time PCR (Taqman) screening, we find that the common leukemia fusion genes, TEL-AML1 or AML1-ETO, are present in cord bloods at a frequency that is 100-fold greater than the risk of the corresponding leukemia. Single-cell analysis by cell enrichment and immunophenotype/fluorescence in situ hybridization multicolor staining confirmed the presence of translocations in restricted cell types corresponding to the B lymphoid or myeloid lineage of the leukemias that normally harbor these fusion genes. The frequency of positive cells (10(-4) to 10(-3)) indicates substantial clonal expansion of a progenitor population. These data have significant implications for the pathogenesis, natural history, and etiology of childhood leukemia.
Asunto(s)
Desarrollo Embrionario y Fetal , Leucemia/genética , Proteínas de Fusión Oncogénica/genética , Factores de Transcripción/genética , Translocación Genética , Secuencia de Bases , Subunidad alfa 2 del Factor de Unión al Sitio Principal , ADN/sangre , Cartilla de ADN , Sangre Fetal/química , Humanos , Hibridación Fluorescente in Situ , Recién Nacido , Leucemia/embriología , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , ARN Mensajero/genética , Proteína 1 Compañera de Translocación de RUNX1 , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
In haploidentical transplantation, the mismatched haplotype of the donor can originate from either of the parents. We refer to such mismatched haplotypes as noninherited maternal antigens (NIMA haplotype) or noninherited paternal antigens (NIPA haplotype). To determine whether exposure to maternal HLA antigens benefits patients undergoing bone marrow transplantation, we analyzed graft failure and graft-versus-host disease (GVHD) after transplantations from parental or haploidentical sibling donors. We studied 269 patients receiving 1 or 2 HLA-A, -B, -DR antigen-mismatched sibling or parental non-T-cell-depleted bone marrow transplants for acute myelogenous leukemia, acute lymphoblastic leukemia, or chronic myelogenous leukemia between 1985 and 1997 that were reported to the International Bone Marrow Transplant Registry. Included were 121 (45%) NIMA-mismatched and 148 (55%) NIPA-mismatched transplantations. Sixty-three (52%) of the NIMA-mismatched transplants and 69 (47%) of the NIPA-mismatched transplants were from haploidentical sibling donors. Sibling transplantations mismatched for NIMA had similar rates of graft failure but lower rates of acute GVHD (P <.02) than NIPA-mismatched sibling transplantations. In the first 4 months after transplantation, mother-to-child transplantations involved significantly less chronic GVHD than father-to-child transplantations (P <.02). Treatment-related mortality (TRM) was significantly higher after parental transplantations (P =.009 for mother; P =.03 for father) than after haploidentical sibling transplantations mismatched for the NIMA. Non-T-cell-depleted bone marrow transplants donated by haploidentical siblings to recipients mismatched for NIPA and transplants donated by parents caused more acute and chronic GVHD and TRM than transplants donated by haploidentical siblings mismatched for NIMA.