RESUMEN
BACKGROUND: Chronic lung disease and pulmonary failure are complications that can occur after bone marrow transplantation (BMT) and are associated with severe morbidity and mortality. METHODS: We report on four patients who developed chronic, progressive, and irreversible lung disease 1 to 3 years after allogeneic BMT in childhood. These patients had chronic graft-versus-host disease (n=3) or radiation-related pulmonary fibrosis (n=1). Three patients underwent double lung transplants and one patient underwent a single lung transplant 2 to 14 years after BMT. RESULTS: All four patients tolerated the lung transplantation procedure well and showed significant clinical improvement with normalization of pulmonary function tests by 1 year posttransplant. One patient died from infectious complications 3 years after lung transplantation, and one patient died after chronic rejection of the transplanted lungs 6 years posttransplant. Two patients remain alive without significant respiratory impairment 2 and 7 years after lung transplantation. CONCLUSION: We conclude that lung transplantation offers a viable therapeutic option for patients who develop respiratory failure secondary to BMT.
Asunto(s)
Trasplante de Médula Ósea/efectos adversos , Enfermedades Pulmonares/etiología , Enfermedades Pulmonares/cirugía , Trasplante de Pulmón , Adolescente , Adulto , Niño , Preescolar , Resultado Fatal , Humanos , Masculino , Trasplante Homólogo , Resultado del TratamientoRESUMEN
PURPOSE: A retrospective analysis of the treatment of childhood acute lymphoblastic leukemia (ALL) in second remission (CR2) was undertaken at our institution to compare the outcome and prognostic factors of patients treated with chemotherapy or allogeneic bone marrow transplantation (BMT). PATIENTS AND METHODS: Seventy-five children who suffered a medullary relapse and achieved a second remission were treated with either an unmodified allogeneic HLA-matched sibling BMT after hyperfractionated total body irradiation (TBI) and cyclophosphamide (n = 38) or chemotherapy according to institutional chemotherapy protocols (n = 37). To avoid the bias of survival from the attainment of second remission in favor of BMT, the final comparative statistical analysis used the landmark approach and comprised 37 and 29 patients from the BMT and chemotherapy groups, respectively RESULTS: The disease-free survival (DFS) rate was 62% and 26% at 5 years, respectively, for the BMT and the chemotherapy groups (P = .03), with relapse rates of 19% and 67%, respectively, for these two groups (P = .01). There was an overall advantage for the BMT therapeutic approach, as compared with chemotherapy, for patients with ALL in CR2 (1) for patients with a WBC count (at diagnosis) of 20 x 10(9)/L or higher (DFS, 40% v 0%) and those with a WBC count of less than 20 x 10(9)/L (DFS, 73% v35%), (2) for patients whose duration of CR1 was less than 24 months (DFS 48% v 9%) and for patients whose duration of CR1 was 24 months or longer (DFS, 81% v 37%) and (3) for patients who were initially treated with intensive regimens incorporating more than five chemotherapy agents (DFS, 57% v 20%) and for patients treated with five agents or fewer (DFS, 72% v 32%). CONCLUSION: In our single-institution series, unmodified HLA-matched allogeneic sibling transplants using hyperfractionated TBI and cyclophosphamide for patients with ALL in CR2 have resulted in superior outcome with a significantly improved probability of DFS and a lower relapse rate, as compared with those for patients treated with chemotherapy, regardless of the duration of first remission, the disease characteristics at diagnosis, or the intensity of prior treatment during first remission.
Asunto(s)
Antineoplásicos/uso terapéutico , Trasplante de Médula Ósea , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Pronóstico , Recurrencia , Inducción de Remisión , Estudios Retrospectivos , Factores de Riesgo , Resultado del TratamientoAsunto(s)
Trasplante de Médula Ósea , Talasemia beta/terapia , Adolescente , Niño , Preescolar , Supervivencia sin Enfermedad , Etnicidad , Femenino , Homocigoto , Humanos , Lactante , Donadores Vivos , Masculino , Núcleo Familiar , Estudios Retrospectivos , Tasa de Supervivencia , Talasemia beta/genética , Talasemia beta/mortalidadRESUMEN
PURPOSE: To evaluate the reliability of CD34/CD33 subset enumeration as a predictor of hematopoietic repopulating potential in autologous blood stem-cell transplantation and to determine which patient and treatment-related factors affect the timing, quantity, and type of blood stem cells mobilized. PATIENTS AND METHODS: We analyzed blood stem-cell collections from 410 consecutive cancer patients who received mobilization therapy and evaluated factors, including CD34+ subset quantities, that might influence engraftment kinetics and transfusion requirements in autologous blood stem-cell recipients. RESULTS: The majority of patients (97%) mobilized CD34+33- cells, which were usually collected in the greatest quantity on the first day of apheresis. Patients who received only growth factor mobilized the highest percentage of CD34+33- cells. Extensive prior chemotherapy limited the collection of CD34+33- cells. In addition to patient diagnosis (P < .006) and total CD34+ cell dose (P = .0001), CD34+33- cell dose (P < .005) and percentage of CD34+33- cells (P < .005) were identified as independent factors significantly predictive of engraftment kinetics. CD34+33- cell dose (R2 < or = .177; P < .0001) was a strong and the only significant predictor of RBC and platelet transfusion requirements. Furthermore, independent of the total CD34+ cell dose, as the CD34+33- cell dose increased, days to neutrophil recovery, days to platelet recovery, and transfusion requirements decreased. CONCLUSION: These findings show that CD34+33- cells are readily collected in most cancer patients and significantly influence engraftment kinetics and transfusion requirements in autologous blood stem-cell recipients. CD34+33- cell quantity of the blood stem-cell graft appears to be a more reliable predictor of hematopoietic recovery rates than total CD34+ cell quantity in this setting.
Asunto(s)
Antígenos CD34/fisiología , Antígenos CD/fisiología , Antígenos de Diferenciación Mielomonocítica/fisiología , Supervivencia de Injerto/inmunología , Trasplante de Células Madre Hematopoyéticas , Trasplante Autólogo/fisiología , Adolescente , Adulto , Anciano , Recuento de Células Sanguíneas , Niño , Preescolar , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Supervivencia de Injerto/efectos de los fármacos , Movilización de Célula Madre Hematopoyética , Humanos , Subgrupos Linfocitarios/fisiología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Lectina 3 Similar a Ig de Unión al Ácido SiálicoRESUMEN
Peripheral blood progenitor cells (PBPC) reside within the mononuclear cell (MNC) component of the blood and can be collected using a number of apheresis devices, including the Fenwal CS3000 Plus Blood Cell Separator. Increased MNC collection efficiency, therefore, may reduce the number of apheresis required to achieve collection goals. In this study, patients were divided into groups by absolute MNC count to determine the effect of interface detector offset (I/O) adjustment on MNC collection efficiency. Apheresis products from 104 procedures collected using a standard I/O setting of 100 were compared with 121 collections for which the I/O setting was adjusted according to the preapheresis MNC count. Adjustment of the I/O setting in this manner had no statistically significant impact on the per kilogram dose of MNC collected. The data did show that MNC collection efficiency was reduced as both the MNC count and I/O setting increased, as the collection efficiency was greatest for patients with the lowest peripheral MNC counts and was inversely correlated with the preapheresis MNC count. Although contamination of the product with platelets was drastically reduced at higher I/O settings, there was a concomitant rise in RBC contamination. We conclude that a standard setting of 100 is preferable to adjustment of the I/O setting as a function of the preapheresis MNC count.
Asunto(s)
Recolección de Muestras de Sangre/instrumentación , Separación Celular/instrumentación , Células Madre Hematopoyéticas/citología , Leucaféresis/instrumentación , Leucocitos Mononucleares/citología , Adulto , Anciano , Recuento de Células , Femenino , Neoplasias Hematológicas/terapia , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/terapiaRESUMEN
Children with severe aplastic anemia (SAA) are treated with bone marrow transplantation (BMT) if a human leukocyte antigen (HLA) compatible sibling donor is available, or alternatively with immunosuppressive therapy (IST). Three retrospective trials examining BMT vs IST in pediatric patients treated from 1970-1988 found BMT resulted in a superior survival rate. Advances have been made in general supportive care and in the approach to each of these treatment modalities in the last decade. To compare survival following BMT and IST in a more recent era, we retrospectively analyzed the results of 48 consecutively treated children with SAA presenting to Memorial Sloan-Kettering Cancer Center (MSKCC) between 1983 and 1992. In contrast to the previous studies, the estimated survival of the BMT and IST groups at 120 months are equivalent, 75.6% and 73.8%, respectively. The IST results in our series are superior to the 42-48% (2-10 year) survival previously published, but similar to survival data observed in more recent IST trials employing more intensive immunosuppression (antithymocyte globulin and cyclosporine). The overall BMT survival rates are similar to those previously published, although BMT results improved dramatically during the latter five years of this analysis, with all 11 patients transplanted surviving with a minimum follow-up of 3 years. No surviving BMT patient has extensive chronic graft-versus-host disease (GvHD), a major cause of long-term mortality post-BMT. Therefore, it is likely the BMT survival curve will remain stable. In contrast, the survival curve of the IST patients is likely unstable, since patients are still at risk for relapse or development of clonal disease. Thus, despite overall similar survival rates, we continue to recommend BMT as first-line therapy in pediatric SAA patients with matched sibling donors.
Asunto(s)
Anemia Aplásica/terapia , Trasplante de Médula Ósea , Terapia de Inmunosupresión , Adolescente , Adulto , Anemia Aplásica/mortalidad , Suero Antilinfocítico , Trasplante de Médula Ósea/mortalidad , Causas de Muerte , Niño , Preescolar , Estudios de Cohortes , Ciclosporina/uso terapéutico , Femenino , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/mortalidad , Histocompatibilidad , Humanos , Terapia de Inmunosupresión/efectos adversos , Inmunosupresores/uso terapéutico , Lactante , Trastornos Linfoproliferativos/etiología , Masculino , Núcleo Familiar , Remisión Espontánea , Estudios Retrospectivos , Análisis de Supervivencia , Linfocitos T/inmunología , Donantes de Tejidos , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Alkyl-lysophospholipid compounds which are selectively cytotoxic to neoplastic cells and relatively sparing of normal marrow progenitor cells are appealing as purging agents to rid remission marrows of residual leukemic cells. A multi-institutional phase II study was conducted in 57 patients with acute leukemia (50 AML and 7 ALL) in which remission marrows were purged in vitro and reinfused after ablative chemotherapy. The median time for granulocyte recovery to 500/microliter was 33 days and for platelet recovery to 25000/microliter was 46 days. The overall DFS and survival was 37% and 46% respectively. Transplantation in first remission gave a better survival than transplant in a subsequent remission.
Asunto(s)
Antineoplásicos/uso terapéutico , Trasplante de Médula Ósea/fisiología , Leucemia/terapia , Éteres Fosfolípidos/uso terapéutico , Adolescente , Anciano , Antineoplásicos/efectos adversos , Niño , Preescolar , Terapia Combinada , Femenino , Humanos , Leucemia/tratamiento farmacológico , Leucemia/cirugía , Masculino , Persona de Mediana Edad , Éteres Fosfolípidos/efectos adversos , Tasa de Supervivencia , Trasplante AutólogoRESUMEN
Bilateral renal enlargement was noted on ultrasonography during an extensive renal evaluation for severe hypokalemic metabolic acidosis with an increased anion gap in a 12-year-old Hispanic boy who had normal results of a physical examination and complete blood count. The patient was found to have acute lymphoblastic leukemia. Resolution of the lactic acidosis and bilateral renal enlargement occurred with initiation of chemotherapy and recurred with each subsequent relapse.
Asunto(s)
Acidosis Láctica/etiología , Enfermedades Renales/etiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Niño , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , RecurrenciaRESUMEN
PURPOSE: To assess the immunosuppressive capacity of hyperfractionated total lymphoid irradiation and cyclophosphamide for transplantation of unmodified allogeneic marrow in sensitized aplastic anemia patients. METHODS AND MATERIALS: From February 1983 to September 1990, 23 multiply transfused aplastic anemia patients underwent unmodified bone marrow transplantation from HLA genotypically identical sibling donors following preparation with 6 Gy hyperfractionated total lymphoid irradiation and 160 mg/kg cyclophosphamide. Graft-versus-host disease prophylaxis included steroids in one patient, methotrexate in four, cyclosporine in seven, and methotrexate/cyclosporine in 12. There were 17 males and 6 females with a median age of 13 (range: 2.5-32). RESULTS: One patient died early before engraftment of bacterial sepsis. Twenty-two patients were evaluable for engraftment. Three experienced graft failure including one primary, and two late graft failures associated with cyclosporine withdrawal. Acute graft-versus-host disease occurred in 7/22 (> or = grade II in 6), and chronic graft-versus-host disease in 3/17 patients. Except for a patient who received total body irradiation for a second transplant, no patient in this series developed interstitial pneumonia. Fifteen patients are alive with follow-up of 38-125 months (median 68). The overall actuarial survival at 5 years is 69%, at 8 years it is 60%, with one late death. The survival of adult patients was similar to that of younger patients (> or = 16 years old: 63%, < 16 years old: 55%). The development of acute graft-versus-host disease adversely influenced survival (88% with Grade 0-I, 17% with grade II-IV; p = 0.002). No hypothyroidism or secondary malignancies have been documented in this series. CONCLUSION: Pretransplant immunosuppression with 6 Gy of hyperfractionated total lymphoid irradiation and 160 mg/kg CY reduces but does not eliminate the incidence of graft failure in sensitized aplastic anemia patients. The dose and the mode of administration of total lymphoid irradiation in this trial may be associated with a lower incidence of late side effects. Survival is comparable to that obtained using preparative regimens without radiation.
Asunto(s)
Anemia Aplásica/terapia , Transfusión Sanguínea , Trasplante de Médula Ósea/inmunología , Ciclofosfamida/uso terapéutico , Antígenos HLA/inmunología , Terapia de Inmunosupresión/métodos , Irradiación Linfática , Adolescente , Adulto , Envejecimiento/inmunología , Anemia Aplásica/inmunología , Trasplante de Médula Ósea/efectos adversos , Niño , Preescolar , Terapia Combinada , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Inmunización , Irradiación Linfática/métodos , Tejido Linfoide/inmunología , Tejido Linfoide/efectos de la radiación , Masculino , Dosificación RadioterapéuticaRESUMEN
A two-year-old girl with thrombocytopenia-absent radii syndrome underwent transplantation of allogeneic bone marrow from her histocompatible sibling to correct her persistently low platelet count. Six years after transplantation, she has durable engraftment of allogeneic marrow and a normal platelet count that will allow her to undergo necessary corrective orthopedic procedures.
Asunto(s)
Trasplante de Médula Ósea , Radio (Anatomía)/anomalías , Trombocitopenia/cirugía , Preescolar , Femenino , Humanos , Recuento de Plaquetas , Síndrome , Trombocitopenia/sangreRESUMEN
We prospectively evaluated the efficacy of T-cell-depleted bone marrow transplantation (BMT) in adults with de novo acute nonlymphocytic leukemia (ANLL) in first complete remission (CR), with regard to relapse-free survival and incidence of graft-versus-host disease (GvHD). Thirty-one patients older than 16 years (range, 16.5 to 43.2) received T-cell-depleted grafts for this purpose from related HLA/MLC-compatible donors. Twelve of the patients were older than 30 years at the time of transplantation. Patients were prepared with hyperfractionated total body irradiation (HFTBI; 1,375 to 1,500 cGy) and high-dose cyclophosphamide (120 mg/kg). T cells were removed from the marrow grafts by a two-step soybean lectin agglutination and sheep red blood cell (sRBC)-rosette procedure, achieving a 2.5- to 3-log depletion of clonable T lymphocytes. No additional prophylaxis against GvHD was administered. The median age at transplantation was 28.8 years; the median interval from diagnosis to transplantation was 3.8 months, and from CR was 2.7 months. Seventy-four percent received consolidation after remission induction therapy. The product-limit estimate of disease-free survival (DFS) at 3 years is 45% (95% confidence interval [CI], 24% to 66%), and the cause-specific probability of relapse is 13%. The median follow-up of the survivors is 72 months (range, 34.5 to 95.6). Median time to achieve a sustained absolute neutrophil count of 500 or greater was 16 days, and to maintain an untransfused platelet count of 20,000 or greater was 20 days. Five patients suffered immune-mediated graft rejection. Three patients developed grade I to II acute GvHD limited to the skin, which resolved promptly with brief courses of systemic steroids. None of the patients has developed clinically apparent chronic GvHD or a secondary lymphoproliferative disorder, and no patient is receiving immunosuppressive therapy. T-cell-depleted BMT by the method reported here is a favorable option as postremission therapy for adults with de novo ANLL in first remission who have an HLA/MLC-compatible related donor, and it is not associated with an increased risk of relapse posttransplant.
Asunto(s)
Purgación de la Médula Ósea , Trasplante de Médula Ósea , Leucemia Mieloide Aguda/cirugía , Linfocitos T , Adolescente , Adulto , Trasplante de Médula Ósea/efectos adversos , Femenino , Enfermedad Injerto contra Huésped , Humanos , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Inducción de Remisión , Trasplante HomólogoRESUMEN
Allogeneic bone marrow transplantation has been successfully utilized to correct the lymphoid and/or hematopoietic abnormalities characterizing a wide array of lethal genetic disorders. Examples include severe combined immunodeficiency, Wiskott-Aldrich syndrome, thalassemia major, sickle cell anemia, and several types of lysosomal storage diseases. Most marrow transplant recipients require preparation with myeloablative doses of chemotherapy, with or without additional radiation therapy, to ensure engraftment of allogeneic marrow. This approach has dramatically changed the long-term outlook for many children with otherwise lethal disorders.
Asunto(s)
Enfermedades de la Médula Ósea/cirugía , Trasplante de Médula Ósea/inmunología , Inmunodeficiencia Combinada Grave/cirugía , Talasemia/cirugía , Síndrome de Wiskott-Aldrich/cirugía , Trasplante de Médula Ósea/métodos , Trasplante de Médula Ósea/mortalidad , Humanos , Terapia de Inmunosupresión , Tasa de SupervivenciaRESUMEN
Since 1979, a total of 17 patients with Wiskott-Aldrich syndrome have undergone allogeneic bone marrow transplantation at Memorial Sloan-Kettering Cancer Center. Eleven patients received marrow from either human leukocyte antigen (HLA) genotypically identical siblings (nine patients) or an HLA phenotypically identical parent (two patients). Six patients received marrow grafts from HLA-disparate parents. Cytoreduction was accomplished with busulfan and cyclophosphamide for the HLA-identical recipients and total-body irradiation followed by high-dose cytarabine therapy in the mismatched recipients. All 11 recipients of HLA-identical marrow had successful grafts, and 10 of 11 are alive and well 28 to 145 months after transplantation. One patient died 10 months after transplantation of chronic graft-versus-host disease and interstitial pneumonitis caused by cytomegalovirus. Only one of the six mismatched graft recipients survives, 52+ months after transplantation; the other patients have died of extensive chronic graft-versus-host disease (one patient), lymphoma (three patients), or progressive pancytopenia accompanying Candida sepsis (one patient). Thus bone marrow transplantation represents the treatment of choice in patients with Wiskott-Aldrich syndrome who have an HLA-identical donor. However, our approach for patients lacking a histocompatible family donor requires modifications to overcome allogeneic resistance and decrease the posttransplantation immunoincompetence in these patients.
Asunto(s)
Trasplante de Médula Ósea/inmunología , Antígenos HLA/inmunología , Síndrome de Wiskott-Aldrich/cirugía , Adulto , Trasplante de Médula Ósea/métodos , Niño , Preescolar , Enfermedad Injerto contra Huésped/prevención & control , Prueba de Histocompatibilidad , Humanos , Lactante , MasculinoRESUMEN
Thymulin, a peptide secreted by human thymic epithelial cells, circulates in peripheral blood. Levels of plasma thymulin (FTS-Zn) activity were analyzed in 21 patients with lethal combined immunodeficiency disorders who were treated with transplantation of HLA-haplotype-mismatched parental bone marrow depleted of T cells by differential agglutination with soybean agglutinin and E-rosetting (SBA-E-BMT). Among these 21 infants, 15 were patients with severe combined immunodeficiency (SCID) and 6 had combined immunodeficiency (CID) with Omenn's syndrome or CID with T cell predominance (CIDTP). In contrast to normal infants who possess high levels of plasma thymulin activity, 20 of the 21 patients demonstrated undetectable or low plasma thymulin levels for their age at admission prior to transplantation. Following SBA-E-BMT, however, thymulin became detectable in the plasma of 17 of 18 evaluable patients and reached normal or near-normal levels between 21 and 125 days posttransplant. In patients in whom the timing of engraftment could be established by emergence of donor lymphocytes, thymulin appeared in the plasma at approximately the same time as lymphoid chimerism was detected, and in all patients who were engrafted and immunologically reconstituted, the increment in thymulin levels preceded development of immune functions. These studies support the concept that normal marrow-derived cells in the graft can provide a stimulus necessary for induction of thymic epithelial secretory function in patients with thymic dysplasia. Further, immunologic reconstitution in these patients was not seen following SBA-E-BMT unless and until recovery of thymus function had been observed.
Asunto(s)
Trasplante de Médula Ósea/métodos , Síndromes de Inmunodeficiencia/terapia , Depleción Linfocítica , Linfocitos T/inmunología , Factor Tímico Circulante/análisis , Hormonas del Timo/análisis , Quimera , Femenino , Humanos , Síndromes de Inmunodeficiencia/inmunología , Lactante , Recién Nacido , Masculino , Fitohemaglutininas/farmacología , Lectinas de PlantasRESUMEN
Over 80% of infants with severe combined immunodeficiency (SCID) of unknown genetic etiology are males, yet less than a third of these affected males have a family history of X-linked disease. To help identify new mutations of the X-linked SCID gene and to provide genetic counseling, X chromosome inactivation patterns in T cells from 16 women who had sons with sporadic SCID were examined. Between 9 and 35 human/hamster hybrids that selectively retained the active human X chromosome were produced from the T cells of each woman and analyzed with an X-linked restriction fragment length polymorphism for which the woman in question was heterozygous. Exclusive use of a single X as the active X was seen in the T cell hybrids from 7 of the 16 women, identifying these women as carriers of X-linked SCID. Studies on additional family members confirmed the mutant nature of the inactive X and revealed the source of the new mutation in three families. To determine whether there were any laboratory characteristics that might differentiate the boys whose mothers were identified as carriers of X-linked SCID from those whose mothers were not, the clinical records of both groups were compared to each other and to a group of 14 boys with a family history of X-linked SCID. The most consistent finding in the 21 patients with X-linked SCID was an elevated proportion of B cells. These data demonstrate the high incidence of spontaneous mutation for the X-linked SCID gene and help clarify the characteristic presenting features of this disorder.
Asunto(s)
Síndromes de Inmunodeficiencia/genética , Cromosoma X , Linfocitos B/inmunología , Células Cultivadas , ADN/sangre , ADN/genética , Sondas de ADN , Femenino , Humanos , Células Híbridas/inmunología , Masculino , Mutación , Factores Sexuales , Linfocitos T/inmunologíaRESUMEN
Lymphocytes from children with severe combined immunodeficiency who had been immunologically reconstituted with haploidentical T cell-depleted bone marrow were analyzed with regard to their immunologic recognition of donor, host, or third party alloantigens. When compared with freshly isolated donor lymphocytes, the engrafted donor cells exhibited markedly reduced to absent responses toward host Ag in primary or secondary MLC and cell-mediated lympholysis assays. However, under limiting dilution conditions, cytotoxic responses to host Ag could be demonstrated, indicating that small numbers of host reactive cells were present, although down-regulated at high responder cell doses. These results are consistent with prior observations in limiting dilution cultures that indicate that cells with the potential to lyse autologous target cells exist in the peripheral blood of all normal individuals. The number of host reactive cells present in these patients is significantly less than that present in cells isolated directly from the marrow donors, and is also less than the number of autocytotoxic cells normally seen in peripheral blood. Together, these observations indicate that two mechanisms contribute to donor host tolerance in these patients. The majority of host reactive cells appear to have undergone clonal deletion or inactivation, whereas the small residual host-reactive population appears to be under ongoing immunoregulatory control.
Asunto(s)
Trasplante de Médula Ósea/inmunología , Tolerancia Inmunológica , Síndromes de Inmunodeficiencia/inmunología , Supervivencia Celular , Células Clonales , Supervivencia de Injerto , Antígenos HLA/análisis , Histocompatibilidad , Humanos , Síndromes de Inmunodeficiencia/cirugía , Activación de Linfocitos , MasculinoRESUMEN
In May 1979, Memorial Sloan-Kettering embarked on a programme of hyperfractionated TBI (HFTBI), 1320 cGy in 11 fractions over 4 days with partial lung shielding (1 HVL), followed by cyclophosphamide (60 mg/kg/d x 2d) for cytoreduction prior to allogeneic bone marrow transplantation (BMT). Anterior and posterior chest wall electron "boosts" were given to the areas blocked (600 cGy in 2 fractions) on the last two days of treatment. Since then, we have treated over 600 patients with HFTBI, the majority for allogeneic BMT. Several modifications have occurred over the years. We have added a "boost" electron dose of 400 cGy to the testes in all male leukemic patients; this reduced testicular relapses from a rate of 14% (4/28) to 0%. In an attempt to increase engraftment of T-depleted BMTs, we added one additional fraction; since our present dose/fraction was also increased to 125 cGy, we now deliver a total dose of 1500 cGy in 12 fractions over 4 days for allogeneic transplants. Tolerance to HFTBI has been excellent relative to the single dose (SD) regimen utilised prior to May, 1979. The incidence of fatal interstitial pneumonitis (IP) decreased from 50% in the SD regimen to 18% after the introduction of HFTBI. In children, the incidence of IP was only 4% with HFTBI. With the introduction of T-depleted marrows, fatal IP in adults has decreased also, e.g. to less than 10% in CML patients. With conventional BMT after HFTBI, relapse at 5 years has been exceedingly low (e.g. in children, 13% for ALL, 2nd remission and 0% for AML, 1st remission) and engraftment has been 100%. With matched T-depleted BMT, rejections have occurred in 15% overall; the incidence of graft failure has not been reduced by the higher dose of HFTBI. Relapses in this setting are equivalent to relapses with conventional BMT for AML, but appear to be increased for ALL. Radiobiological findings related to HFTBI will also be discussed.
Asunto(s)
Trasplante de Médula Ósea , Leucemia/radioterapia , Irradiación Corporal Total/métodos , Trasplante de Médula Ósea/métodos , Protocolos Clínicos , Terapia Combinada , Ciclofosfamida/uso terapéutico , Femenino , Supervivencia de Injerto , Granulocitos/efectos de la radiación , Hepatitis/etiología , Humanos , Leucemia/tratamiento farmacológico , Leucemia/cirugía , Linfocitos/efectos de la radiación , Masculino , Fibrosis Pulmonar/etiología , Dosificación Radioterapéutica , Recurrencia , Irradiación Corporal Total/efectos adversosRESUMEN
We have studied the tolerance of engrafted T cells from a severe combined immunodeficiency disease patient sequentially transplanted with T-cell-depleted bone marrow from both HLA haploidentical parents. The T cells from this patient were shown by HLA typing and cytogenetic analysis to be of material origin (donor of the second graft) while HLA typing of peripheral E--populations and of an Epstein-Barr virus-transformed B-cell line established 2 1/2 years after transplantation revealed the presence of host, maternal, and paternal (donor of the first graft) HLA antigens. When tested at 30 and 60 months after the last transplant, engrafted T cells from this patient had only weak mixed lymphocyte culture reactivity to paternal cells which could be inhibited by monoclonal antibodies to HLA-DQ and DR but not by anti-DP. T cells obtained 60 months after transplant were stimulated with paternal cells in both bulk and limiting dilution cultures and failed to generate typical allocytotoxic cells to paternal T- or B-cell targets. Mixed lymphocyte cultures performed at 71 months revealed an increased proliferative response by patient cells to paternal antigens; however, the engrafted T cells remained tolerant to maternal and host antigens. Limiting dilution analysis performed at this time revealed the presence of cytolytic cells directed to paternal antigens. There were no detectable B cells (only identified source of paternal antigen) as measured by immunofluorescent analysis of peripheral blood, nor any evidence of B-cell function as assessed by in vitro assays (proliferation to staphylococcus aureus Cowen strain A and mitogen-stimulated immunoglobulin production) or in vivo production of serum immunoglobulin at 60 and 71 months. The appearance of alloreactivity associated with the loss of B cells in this patient further supports the conclusion that the maintenance of tolerance to major histocompatibility complex disparate cells requires the continued in vivo presence of cells bearing the tolerizing antigens.
Asunto(s)
Trasplante de Médula Ósea , Síndromes de Inmunodeficiencia/inmunología , Formación de Anticuerpos , Linfocitos B/análisis , Pruebas Inmunológicas de Citotoxicidad , Femenino , Antígenos HLA/análisis , Humanos , Tolerancia Inmunológica , Síndromes de Inmunodeficiencia/terapia , Recuento de Leucocitos , Activación de Linfocitos , Prueba de Cultivo Mixto de Linfocitos , MasculinoRESUMEN
Congenital agranulocytosis is a disorder characterized by severe neutropenia and a profound deficiency of identifiable neutrophil progenitors in bone marrow. In an attempt to stimulate neutrophil production and thereby reduce the morbidity and mortality associated with this disease, we administered recombinant human granulocyte colony-stimulating factor (rhG-CSF) in doses of 3 to 60 micrograms per kilogram of body weight per day to five patients with congenital agranulocytosis. In all five patients, an increase in the number of neutrophils was noted eight to nine days after the initiation of the effective dosage (the dose at which the neutrophil count reached 1000 cells per microliter or more and the bone marrow showed granulocyte maturation beyond the myelocyte stage). The absolute neutrophil counts rose from less than 100 to between 1300 and 9500 cells per microliter. Marrow aspirates obtained after 14 days at the effective dosage showed maturation to the mature neutrophil stage. The side effects that were observed were medullary pain, splenomegaly, and an elevation of levels of leukocyte alkaline phosphatase. All five patients have had sustained neutrophil counts of 1000 cells per microliter or more for 9 to 13 months while receiving subcutaneous maintenance therapy. Preexisting chronic infections have resolved clinically, and the number of new infectious episodes and the requirement for intravenous antibiotics have decreased. We conclude that treatment with rhG-CSF can lead to a large increase in the numbers of functional neutrophils in patients with congenital agranulocytosis.
Asunto(s)
Agranulocitosis/terapia , Factores Estimulantes de Colonias/uso terapéutico , Granulocitos , Neutropenia/terapia , Adulto , Agranulocitosis/congénito , Anticuerpos/análisis , Médula Ósea/patología , Niño , Preescolar , Factores Estimulantes de Colonias/efectos adversos , Factores Estimulantes de Colonias/inmunología , Femenino , Factor Estimulante de Colonias de Granulocitos , Humanos , Recuento de Leucocitos , Masculino , Neutrófilos/patología , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/uso terapéuticoRESUMEN
Since the introduction of methods for depleting T lymphocytes from human allogeneic marrow grafts in 1980, such transplants have been increasingly used as a source of lymphoid progenitors for the curative treatment of patients with lethal genetic disorders of immunity who lack an HLA matched sibling donor. This review of the results of HLA-haplotype disparate T-cell depleted marrow grafts applied to the treatment of severe combined immunodeficiency (SCID) indicates that such transplants can lead to durable engraftment and successful reconstitution of immune function without severe graft vs. host disease in a high proportion of cases. Resistance to engraftment and selective abnormalities of B cell development and function in the post transplant period constitute major obstacles to the success of these transplants. However, considerable progress has been made towards the elucidation of the cellular mechanisms responsible for graft resistance, graft-host tolerance and either the full or limited immunologic reconstitutions achieved.