RESUMEN
BACKGROUND: A double-blind, placebo-controlled, randomized study was performed to assess whether immunoprophylaxis with basiliximab (Simulect) could reduce the incidence of acute rejection in kidney transplant recipients treated with cyclosporine (Neoral), steroids, and azathioprine. METHODS: Three hundred forty patients received either placebo or basiliximab at a dose of 20 mg, given intravenously on days 0 and 4. All patients received cyclosporine, steroids, and azathioprine. The primary endpoint was the incidence of acute rejection at 6 months. Secondary endpoints included the safety and tolerability of basiliximab and placebo, 1-year patient and graft survival, and significant medical events up to 12 months. RESULTS: During the first 6 months posttransplantation, acute rejection occurred in 20.8% of patients given basiliximab versus 34.9% of patients administered placebo (P=0.005). Similarly, there was a reduction in biopsy-proven acute rejection at 6 months in the patients receiving basiliximab (P=0.023). One-year patient survival was 97.6% with basiliximab and 97.1% with placebo, graft survival was 91.5% versus 88.4%, respectively (NS). The adverse-events profile of patients treated with basiliximab was indistinguishable from that of patients treated with placebo. The number of patients with infections was similar (65.5% for basiliximab vs. 65.7% for placebo), including cytomegalovirus infections (17.3% vs. 14.5%, P=0.245). Nine neoplasms (three in the basiliximab group, six in the placebo arm) were recorded up to 1 year from transplantation. CONCLUSIONS: Basiliximab in combination with cyclosporine, steroids, and azathioprine triple therapy was highly effective in reducing the incidence of acute renal allograft rejection without increasing the incidence of infections and other side effects.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Rechazo de Injerto/prevención & control , Inmunosupresores/uso terapéutico , Trasplante de Riñón , Medicina Preventiva/métodos , Proteínas Recombinantes de Fusión , Adulto , Anticuerpos Monoclonales/efectos adversos , Azatioprina/uso terapéutico , Basiliximab , Ciclosporina/uso terapéutico , Método Doble Ciego , Quimioterapia Combinada , Femenino , Rechazo de Injerto/epidemiología , Supervivencia de Injerto , Humanos , Inmunosupresores/efectos adversos , Incidencia , Masculino , Persona de Mediana Edad , Seguridad , Esteroides/uso terapéutico , Análisis de SupervivenciaRESUMEN
Pharmacokinetic sampling was performed in two multicenter trials in which basiliximab (anti-CD25 monoclonal antibody) was administered with triple immunosuppression consisting of cyclosporine microemulsion, corticosteroids, and either azathioprine or mycophenolate mofetil. Blood samples were collected over 12 wk post-transplant from 31 azathioprine-treated and 66 mycophenolate mofetil-treated patients. Empirical Bayes estimates of each patient's basiliximab disposition parameters were derived and the duration of CD25 saturation was estimated as the time over which serum concentrations exceeded 0.2 microg/mL as confirmed by flow cytometry measurements. Basiliximab clearance was 29+/-14 mL/h when coadministered with azathioprine and 18+/-8 mL/h with mycophenolate mofetil. Both were significantly lower compared with a clearance of 37+/-15 mL/h from a previous study of basiliximab with dual therapy (p<0.001). As a consequence of the lower clearance of basiliximab, the durations of CD25 saturation were prolonged in the presence of azathioprine (50+/-20 d; range, 13--84) and mycophenolate mofetil (59+/-17 d; range, 28--94) compared with dual therapy (36+/-14 d; range, 12--91). A total of 27 acute rejection episodes occurred during the first 6 months in the two studies. Durations of CD25 saturation were not different in these patients compared with those who remained rejection-free in each study. A single patient among 57 who were screened developed anti-idiotype antibodies to basiliximab. The average duration of CD25 saturation was prolonged by 39 and 64% in the presence of azathioprine and mycophenolate mofetil, respectively. This graded effect was also observed for basiliximab clearance and may be due in part to a differentially reduced humoral response to basiliximab. Nonetheless, the range of CD25 saturation durations and basiliximab clearances did not extend outside the range when basiliximab was used with dual therapy in the absence of these agents. Hence, no dosing adjustment is deemed necessary when basiliximab is used in triple immunosuppressive therapy including either azathioprine or mycophenolate mofetil.
Asunto(s)
Anticuerpos Monoclonales/farmacocinética , Azatioprina/farmacología , Inmunosupresores/farmacología , Inmunosupresores/farmacocinética , Trasplante de Riñón , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/farmacología , Proteínas Recombinantes de Fusión , Anticuerpos Antiidiotipos/análisis , Anticuerpos Monoclonales/administración & dosificación , Suero Antilinfocítico/administración & dosificación , Suero Antilinfocítico/inmunología , Azatioprina/administración & dosificación , Basiliximab , Ciclosporina/administración & dosificación , Método Doble Ciego , Interacciones Farmacológicas , Quimioterapia Combinada , Femenino , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Humanos , Inmunofenotipificación , Inmunosupresores/administración & dosificación , Masculino , Persona de Mediana Edad , Ácido Micofenólico/administración & dosificación , Receptores de Interleucina-2/análisisAsunto(s)
Anticuerpos Monoclonales/uso terapéutico , Azatioprina/uso terapéutico , Inmunosupresores/uso terapéutico , Trasplante de Riñón/inmunología , Proteínas Recombinantes de Fusión , Enfermedad Aguda , Adolescente , Adulto , Anciano , Antiinflamatorios/uso terapéutico , Basiliximab , Ciclosporina/uso terapéutico , Quimioterapia Combinada , Femenino , Rechazo de Injerto , Humanos , Infecciones/etiología , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/etiología , Prednisona/uso terapéuticoRESUMEN
The aim of the study was to analyze the factors influencing peripheral blood progenitor cell (PBPC) collection after high-dose cyclophosphamide (HDCYC) (7 g/m2) and hematopoietic recovery after autologous transplantation of HDCYC-mobilized PBPC (ABPCT) in 116 patients with aggressive multiple myeloma (MM). Following HDCYC 74 patients received hematopoietic growth factors (HGF), either G-CSF (n = 19) or GM-CSF (n = 55). All the patients were subsequently planned to undergo ABPCT. PBPC collection was possible for 106 patients. The most important prognostic factor for collection of more than 25 x 10(4) CFU-GM cells/kg and 2 x 10(6) CD34+ cells/kg was the use of HGF (P = 0.002 and 0.009, respectively). Previous use of an alkylating agent, response to treatment before HDCYC, and interval between diagnosis and HDCYC were also significant factors (P = 0.004, 0.025 and 0.001, respectively). The number of CFU-GM cells infused was the most important parameter for rapid and complete hematological recovery after ABPCT (P < 0.0001). Thus the use of HGF post-HDCYC is the major factor which, associated with reduced time between diagnosis and HDCYC and the use of an alkylating agent, could increase the numbers of hematopoietic progenitors collected, and subsequently improve hematopoietic recovery following ABPCT in MM patients.
Asunto(s)
Antineoplásicos/administración & dosificación , Ciclofosfamida/administración & dosificación , Movilización de Célula Madre Hematopoyética , Trasplante de Células Madre Hematopoyéticas , Mieloma Múltiple/sangre , Mieloma Múltiple/terapia , Adulto , Anciano , Análisis de Varianza , Femenino , Humanos , Leucaféresis , Masculino , Persona de Mediana Edad , Trasplante AutólogoAsunto(s)
Ciclosporina/administración & dosificación , Fibrosis Quística/complicaciones , Rechazo de Injerto/prevención & control , Inmunosupresores/administración & dosificación , Enfermedades Pulmonares/terapia , Trasplante de Pulmón , Adolescente , Adulto , Niño , Ciclosporina/farmacocinética , Femenino , Humanos , Inmunosupresores/farmacocinética , Cinética , Enfermedades Pulmonares/complicaciones , MasculinoRESUMEN
PURPOSE: To evaluate the impact of granulocyte-macrophage colony-stimulating factor (GM-CSF) or placebo on the durations of intravenous (IV) antibiotic use, hospitalization, neutropenia, and fever, as well as remission rates, after high-dose melphalan (HDM) without stem-cell transplantation (SCT) in patients with multiple myeloma (MM). PATIENTS AND METHODS: One hundred two patients with high-risk MM were randomized 2:1 in a prospective multicenter trial to receive 5 microg/kg/d GM-CSF (69 patients) or placebo (33 patients) starting the day after 140 mg/m2 IV melphalan for up to 21 days. RESULTS: GM-CSF significantly reduced neutropenia after HDM (median, 23.5 v 29 days; P = .0468), with a trend to reduce the duration of hospitalization (median, 32 v 38 days; P = .0841). Nevertheless, GM-CSF did not significantly reduce infectious toxicity as regards the number of days with fever (median, 5 v 3; P = .359), the number of days with IV antibiotics (median, 22 v 27; P = .14), or early deaths, with an 11.5% treatment-related mortality rate in the GM-CSF group (eight of 69 v two of 32 patients in the placebo group; P = .686). There was no difference in response rates between the two groups of patients. CONCLUSION: GM-CSF after HDM without SCT is feasible and significantly shortens neutropenia with a trend toward reduction of hospitalization duration, but does not significantly reduce the morbidity and mortality of such therapy. Thus, when intensive therapy is indicated, given that the mortality of HDM followed by SCT reported in the literature is less than 5% and patients are discharged at approximately day 15, despite the risk of contamination by clonogenic malignant cells, SCT appears to be preferable to GM-CSF after HDM.
Asunto(s)
Antineoplásicos Alquilantes/efectos adversos , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Melfalán/efectos adversos , Mieloma Múltiple/tratamiento farmacológico , Neutropenia/prevención & control , Adulto , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Alquilantes/uso terapéutico , Método Doble Ciego , Esquema de Medicación , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/administración & dosificación , Humanos , Masculino , Melfalán/administración & dosificación , Melfalán/uso terapéutico , Persona de Mediana Edad , Neutropenia/inducido químicamente , Estudios Prospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Basiliximab is an interleukin-2 receptor (IL-2R; CD25) chimeric monoclonal antibody for immunoprophylaxis against acute rejection in renal transplantation. Its pharmacokinetics were characterized in a multicenter open-label, prospective dose-escalation study to identify a single-dose regimen providing IL-2R-saturating serum concentrations in the critical first posttransplant month. METHODS: Thirty-two recipients of primary, mismatched cadaver kidneys were enrolled: 20 men and 12 women, who were 47+/-11 years old and weighed 65+/-12 kg. The immunosuppression regimen consisted of steroids and azathioprine from day 0 and cyclosporine from day 10. Basiliximab was infused over 30 min as a single dose preoperatively. RESULTS: Thirty patients were evaluable for basiliximab pharmacokinetics: 24 received 40 mg and 6 received 60 mg. Basiliximab was well tolerated without evidence of cytokine-release syndrome, hypersensitivity reactions, or anti-idiotype antibody response. Peak concentration and area under the concentration curve increased proportionally with dose. Postinfusion concentrations declined in a biphasic manner with a terminal half-life of 6.5+/-2.1 days. Weak, widely dispersed correlations were noted between body weight versus distribution volume (r=0.29) and versus clearance (r=0.45), suggesting no clinical relevance for weight-adjusted dosing. There were no apparent gender-related differences in basiliximab disposition. Previous phase II data indicated that serum concentrations in excess of 0.2 microg/ml are sufficient to saturate IL-2R epitopes on circulating T lymphocytes. Concentrations were above this threshold for 26+/-8 days (range 16 to 46) at the 40-mg dose level and for 32+/-11 days (range 22 to 51) at the 60-mg dose level. CONCLUSIONS: Total basiliximab doses of 40-60 mg were well tolerated, nonimmunogenic, and estimated to provide immunoprophylaxis to cover the first posttransplant month.
Asunto(s)
Anticuerpos Monoclonales/farmacocinética , Trasplante de Riñón/inmunología , Receptores de Interleucina-2/inmunología , Adulto , Anticuerpos Monoclonales/uso terapéutico , Cadáver , Esquema de Medicación , Femenino , Rechazo de Injerto/tratamiento farmacológico , Supervivencia de Injerto/efectos de los fármacos , Histocompatibilidad , Humanos , Terapia de Inmunosupresión/métodos , Inmunosupresores/administración & dosificación , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Proteínas Recombinantes de FusiónRESUMEN
PURPOSE: The aims of the current study were to evaluate in patients with high-risk multiple myeloma (MM) the feasibility and usefulness of high-dose chemotherapy or chemoradiotherapy followed by hematopoietic stem-cell support with autologous peripheral-blood progenitor cells (PBPC) harvested after high-dose cyclophosphamide (HDCYC). PATIENTS AND METHODS: Seventy-three patients with high-risk MM were entered onto the study. Before the procedure, all patients had received HDCYC to collect PBPC by leukapheresis. One patient died of infection after HDCYC. All other patients subsequently received high-dose melphalan (HDM) (140 mg/m2) either alone (n = 1) or associated with either busulfan (16 mg/kg; n = 4) or total-body irradiation (TBI) (8 to 15 Gy; n= 67). In addition, three of the latter patients received cyclophosphamide (120 mg/kg). Thereafter, PBPC were reinfused either alone in 61 patients or together with back-up bone marrow cells in 11 patients in whom the granulocyte-macrophage colony-forming unit (CFU-GM) cell content of the leukapheresis was low. RESULTS: One patient died of acute cardiac failure after reinfusion of PBPC; three patients did not respond after autologous blood progenitor cell transplantation (ABPCT), while the other 68 patients achieved either a complete response (CR; n = 32) or partial response (PR; n = 36). Thirty-six patients relapsed or progressed after a median response duration of 14.5 months (range, 3 to 43) and 19 of these subsequently died. Four other patients died while still responsive of lung cancer (n = 1) or infection (n = 3). The remaining 28 patients are currently alive and still responding with a median follow-up duration of 27 months (range, 6 to 66). The 3-year probability of survival was 66% +/- 12% (95% confidence interval [CI] after ABPCT and 77% +/- 51% (95% CI) from diagnosis. CONCLUSION: High-dose chemotherapy or chemoradiotherapy followed by autologous PBPC support in MM is feasible and efficient. Further studies are needed to confirm these encouraging, although preliminary, results and to compare this technique with other therapeutic strategies.
Asunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Mieloma Múltiple/cirugía , Adulto , Anciano , Análisis de Varianza , Busulfano/administración & dosificación , Quimioterapia Adyuvante , Ciclofosfamida/administración & dosificación , Estudios de Factibilidad , Femenino , Humanos , Masculino , Melfalán/administración & dosificación , Persona de Mediana Edad , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/radioterapia , Pronóstico , Modelos de Riesgos Proporcionales , Dosificación Radioterapéutica , Radioterapia Adyuvante , Factores de Riesgo , Análisis de Supervivencia , Trasplante Autólogo , Resultado del TratamientoAsunto(s)
Ciclosporina/farmacocinética , Fibrosis Quística/cirugía , Trasplante de Corazón-Pulmón/inmunología , Inmunosupresores/uso terapéutico , Trasplante de Riñón/inmunología , Trasplante de Hígado/inmunología , Trasplante de Pulmón/inmunología , Administración Oral , Adolescente , Adulto , Azatioprina/uso terapéutico , Disponibilidad Biológica , Niño , Ciclosporina/administración & dosificación , Ciclosporina/sangre , Fibrosis Quística/metabolismo , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Masculino , Tasa de Depuración Metabólica , Esteroides/uso terapéutico , Factores de TiempoAsunto(s)
Bilis/metabolismo , Colestasis/complicaciones , Ciclosporina/farmacocinética , Ciclosporina/uso terapéutico , Trasplante de Hígado/inmunología , Administración Oral , Adulto , Enfermedades Autoinmunes , Ciclosporina/administración & dosificación , Drenaje , Femenino , Hepatitis C/complicaciones , Humanos , Inyecciones Intravenosas , Absorción Intestinal , Cirrosis Hepática/inmunología , Cirrosis Hepática/cirugía , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Systemic Malassezia furfur (Mf) infections are only seen in neonates and immunocompromised patients. CASE REPORT: A 2-year-8-month-old boy was given chemotherapy for mediastinal T cell lymphoma. Meningeal relapse supervened 10 months later, requiring polychemotherapy plus CNS irradiation followed by bone marrow transplantation. Three days after transplantation, fever associated with neutropenia required administration of ceftazidime, amikacin, vancomycin plus acyclovir followed by amphotericin B, cefotaxime plus erythromycin. Blood cultures were negative, but blood swears showed yeasts into polynuclear cells after cytocentrifugation; these yeasts were also present in the central catheter removed after a few days course of amphotericin B, flucytosine plus fluconazole. The patient was then given GM-CSF subcutaneously (5 micrograms/kg/day), followed by progressive correction of aplasia and cure of the Mf infection. CONCLUSION: This is a new case of systemic Mf infection seen in an immunocompromised child receiving parenteral nutrition with lipids.
Asunto(s)
Trasplante de Médula Ósea/efectos adversos , Fungemia/etiología , Malassezia , Preescolar , Fungemia/inmunología , Humanos , Huésped Inmunocomprometido , Masculino , Nutrición Parenteral/efectos adversosRESUMEN
We report on eight children with severe diarrhea beginning in the first 6 months of life (< 1 month in six cases), who had a number of features in common. All were small for gestational age and had an abnormal phenotype, including facial dysmorphism, hypertelorism, and woolly, easily removable hair with trichorhexis nodosa. Two were products of consanguineous marriages. Severe secretory diarrhea persisted despite bowel rest (n = 7). Jejunal biopsy specimens showed total or subtotal villous atrophy with crypt necrosis, and inconstant T-cell activation in some cases (n = 3). Colon biopsy specimens showed moderate nonspecific colitis. All the patients had defective antibody responses despite normal serum immunoglobulin levels, and defective antigen-specific skin tests despite positive proliferative responses in vitro. Three had monoclonal hyper-immunoglobulinemia A. The course was marked by diffuse erythroderma in two cases and mental retardation in three. Treatment included bowel rest, intravenous administration of immune globulins, administration of corticosteroids (n = 6) and cyclosporine (n = 2), and bone marrow transplantation (n = 1). Five patients died between the ages of 2 and 5 years (of sepsis or cirrhosis), two are being fed enterally, and one continues to receive total parenteral nutrition. The cause of the combined low birth weight, dysmorphism, severe diarrhea, trichorrhexis, and immunodeficiency is unclear. These features may constitute a specific syndrome within the group of intractable diarrheas of infancy.
Asunto(s)
Diarrea , Cara/anomalías , Cabello/anomalías , Síndromes de Inmunodeficiencia , Enfermedad Crónica , Dermatitis Exfoliativa , Diarrea/inmunología , Diarrea/patología , Resultado Fatal , Femenino , Cabello/patología , Humanos , Hipertelorismo , Lactante , Recién Nacido , Intestinos/patología , Masculino , Fenotipo , SíndromeRESUMEN
Twelve of 15 patients with juvenile chronic myelomonocytic leukemia (JCMML) referred to our unit underwent allogeneic bone marrow transplantation (BMT) between 1982 and 1992. BMT was not performed in the remaining three cases because of poor overall condition in two and disease progression in one. Six patients received marrow from HLA-identical siblings after a chemotherapy conditioning regimen in five cases. BMT failed in one case. Long-term remission was achieved in three patients and two others are in remission 6 and 11 months after BMT. Remission was associated with autologous recovery in one patient and minimal mixed chimerism in another. In one patient, a first BMT procedure resulted in autologous recovery and relapse. A second transplant, with chemotherapy conditioning including TBI, was successful. BMT with marrow from a matched unrelated donor was also successful. IN contrast, BMT with marrow from mismatched related donors (five patients) failed because of graft failure and/or relapse. This single-center series indicates that HLA-identical BMT is an appropriate treatment for JCMML. However, on the basis of these results it cannot be ascertained whether chemotherapy or splenectomy are necessary prior to BMT. The best chemotherapy conditioning regimen remains to be defined, as regimens consisting exclusively of chemotherapy resulted either in long-term remission or in autologous recovery with relapse.
Asunto(s)
Trasplante de Médula Ósea , Leucemia Mielomonocítica Crónica/terapia , Antineoplásicos/uso terapéutico , Trasplante de Médula Ósea/inmunología , Niño , Preescolar , Terapia Combinada , Femenino , Francia/epidemiología , Histocompatibilidad/inmunología , Humanos , Incidencia , Lactante , Leucemia Mielomonocítica Crónica/epidemiología , Masculino , Donantes de Tejidos , Trasplante Homólogo , Irradiación Corporal TotalRESUMEN
High-dose cyclophosphamide (HD-CY; 7 g/m2) was administered to patients suffering from high risk multiple myeloma (MM). The safety of this procedure, the recirculation and collection of peripheral blood stem cells (PBSC) and the effect of rhGM-CSF and HD-CY were studied. Group I patients (n = 21) were treated with HD-CY alone. Group II patients (n = 10) received 5 micrograms/kg/day rhGM-CSF iv after HD-CY. Neutropenia was shorter in group II (p = 0.01). In group II, the number of circulating colony forming units (CFU-GM) after 14 days was correlated with the number of circulating CFU-GM after 7 days (r = 0.85, p < 0.0001) and with the number of CD34+ cells (r = 0.839, p = 0.01). The total number of mononuclear cells (MNC) and CFU-GM collected per patient was two and seven-fold higher, respectively, in group II (p = 0.01 and p = 0.03). Recovered MNC and CFU-GM were 1.7 and 7-fold higher, respectively, in group II (p = 0.01 and p = 0.004). Our data show that HD-CY is an efficient means of collecting functional PBSC in MM. We suggest that rhGM-CSF is able to further enhance this yield in MM.
Asunto(s)
Trasplante de Médula Ósea/métodos , Trasplante de Células Madre Hematopoyéticas , Mieloma Múltiple/cirugía , Adulto , Separación Celular/métodos , Ensayo de Unidades Formadoras de Colonias , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos y Macrófagos/efectos adversos , Hematopoyesis , Células Madre Hematopoyéticas/patología , Humanos , Leucaféresis , Masculino , Persona de Mediana Edad , Mieloma Múltiple/sangre , Mieloma Múltiple/tratamiento farmacológico , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversosRESUMEN
We report a successful allogeneic BMT for the treatment of juvenile chronic myelogenous leukemia (JCML) in a 9-month-old Laotian boy using an HLA-matched sibling donor with HbH disease (--SEA/aaCS). In addition, before BMT the recipient had a complex haemoglobinopathy associating heterozygous state AE along with HbH disease (--SEA/-a3,7) without haemoglobin Constant Spring (HbCS). Because various haemoglobinopathies are frequently encountered in southeast Asia, when BMT is performed in Asian families the results may be evaluated by the differing haemoglobin characteristics of recipient and donor. However, there is also a significant risk of transmitting a new haemoglobinopathy to the recipient. Because transplantation from HLA-identical siblings offers the only chance of cure for JCML, the presence of HbH disease with mild clinical expression in the donor should not be taken as a contra-indication to BMT.
Asunto(s)
Trasplante de Médula Ósea , Leucemia Mielógena Crónica BCR-ABL Positiva/cirugía , Donantes de Tejidos , Talasemia alfa/patología , Contraindicaciones , Femenino , Humanos , Lactante , Laos , Leucemia Mielógena Crónica BCR-ABL Positiva/complicaciones , Masculino , Linaje , Talasemia alfa/complicaciones , Talasemia alfa/genéticaRESUMEN
Malignant osteopetrosis is characterized by impaired osteoclast activity. Osteoclasts derive from hematopoietic stem cells. In osteopetrosis, marrow cavities fail to develop, resulting in extramedullary hematopoiesis and the presence of stem cells in the bloodstream. Resistance to 1,25-(OH)2D3 may be involved in the pathogenesis of the disease. Sensitivity to 1,25-(OH)2D3, calcitonin sensitivity, and expression of the osteoclast-associated vitronectin receptor (VR) was examined in cultures of circulating mononuclear cells of seven osteopetrotic infants (1.5-6 months old). Since peripheral blood from age-matched children contains few stem cells, umbilical cord blood was used as control. Mononucleated cells were isolated by the Ficoll-Hypaque method and cultured (10(6) cells per ml) in alpha-MEM containing 20% horse serum in presence or absence of added 1,25-(OH)2D3. VR was identified by immunochemical staining with MAb 23C6. 1,25-(OH)2D3 at 10(-8) M significantly stimulated the formation of multinucleated cells (MNC) in cultures from all osteopetrotic patients and cord blood samples. Cells from three of five patients responded to 10(-9) M 1,25-(OH)2D3, the minimal stimulatory concentration for cord blood. Salmon calcitonin (100 ng/ml) partially inhibited the 10(-8) M 1,25-(OH)2D3-induced MNC formation in cultures from three of six patients and in cultures of all cord blood samples. In both types of cultures mononuclear cells and MNC cross-reacted with MAb 23C6, and 1,25-(OH)2D3 concentration did not influence the number and percentage of these cells. This study does not support the hypothesis of 1,25-(OH)2D3 resistance in osteopetrotic infants and shows that mononuclear cells expressing VR, possibly osteoclast progenitors, develop in cultures of circulating mononuclear cells from these infants. 1,25-(OH)2D3 may not be closely involved in VR expression.
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Calcitriol/farmacología , Osteoclastos/efectos de los fármacos , Osteopetrosis/metabolismo , Receptores de Citoadhesina/metabolismo , Resorción Ósea , Calcitonina/farmacología , Células Cultivadas , Dentina/fisiología , Humanos , Lactante , Recuento de Leucocitos , Osteoclastos/metabolismo , Osteopetrosis/sangre , Receptores de VitronectinaRESUMEN
Polyethylene glycol (PEG)-modified bovine adenosine deaminase (ADA) is used for replacement therapy of severe combined immunodeficiency disease due to inherited ADA deficiency. We monitored IgG anti-ADA antibody in 17 patients treated by intramuscular injections of PEG-ADA for 1 to greater than 5.5 yr. ELISA-detectable anti-ADA IgG appeared in 10 patients, usually between the third and eighth months of treatment. Anti-ADA levels did not correlate with trough plasma ADA activity, which averaged 1.8-5 times normal blood (erythrocyte) ADA activity, depending on dose (15-60 U/kg per wk). ELISA-detectable anti-ADA antibodies were directed primarily at bovine-specific peptide (rather than PEG-containing) epitopes. Enhanced enzyme clearance, mediated by antibody that directly inhibited native and PEG-modified bovine ADA, and native, but not PEG-modified human ADA, occurred in two patients. In one, tolerance was induced; in the second, twice weekly injections of PEG-ADA compensated for accelerated clearance. We speculate that inhibitory antibodies recognize conserved, relatively PEG-free epitope(s) encompassing the active site, and that in human, but not bovine, ADA a PEG-attachment site "shields" the active site from immune recognition. We conclude that PEG-modification largely prevents the development of high affinity, or high levels of clearing antibodies to bovine ADA, and that PEG-modified human ADA should be further investigated as a possible treatment for ADA deficiency.
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Adenosina Desaminasa/deficiencia , Adenosina Desaminasa/química , Adenosina Desaminasa/inmunología , Adenosina Desaminasa/farmacocinética , Adenosina Desaminasa/uso terapéutico , Inhibidores de la Adenosina Desaminasa , Animales , Especificidad de Anticuerpos , Autoanticuerpos/inmunología , Bovinos , Niño , Preescolar , Humanos , Inmunoglobulina G/inmunología , Lactante , Polietilenglicoles/química , Especificidad de la EspecieRESUMEN
Adenosine deaminase (ADA) deficiency is one the causes of severe combined immunodeficiency syndrome. Treatment was, until now, based on bone marrow transplantation. HLA identical bone marrow transplantation yields excellent results while those of HLA haploidentical bone marrow transplantation are not so good. A new therapeutic approach was developed recently, consisting of the intramuscular infusion of ADA enzyme covalently linked to polyethylene glycol (PEG-ADA). We report the results of this treatment in a 14 month-old child presenting with a partial form of ADA deficiency revealed by an opportunistic infection. This treatment corrected the immunodeficiency and the biochemical abnormalities as well. PEG-ADA infusions were well tolerated. The onset of an immunization against the ADA enzyme led to a drop in immunologic functions, which could be partially overcome by more frequent (biweekly) administration of the product. After a 18 month-follow-up the child is doing well, living normally at home. PEG-ADA represents a possible alternative for children presenting with ADA deficiency without any available HLA identical donor.
Asunto(s)
Adenosina Desaminasa/administración & dosificación , Adenosina Desaminasa/deficiencia , Polietilenglicoles/administración & dosificación , Inmunodeficiencia Combinada Grave/tratamiento farmacológico , Adenosina Desaminasa/uso terapéutico , Combinación de Medicamentos , Femenino , Estudios de Seguimiento , Humanos , Lactante , Polietilenglicoles/uso terapéutico , Inmunodeficiencia Combinada Grave/etiologíaRESUMEN
The rare autosomal recessive Nijmegen breakage syndrome is characterised by severe immunodeficiency, microcephaly associated with mental retardation, and typical chromosomal rearrangements in peripheral T lymphocytes. This syndrome, though similar to ataxia telangiectasia, does not exhibit the neurological and cutaneous signs of this disorder. We report here the first patient with Nijmegen breakage syndrome ascertained in France. Chromosome analysis detected, in addition to the specific aberrations, two clonal T cell proliferations which do not involve the usual bands 14q11.2 and 14q32.1.