RESUMEN
Strategies for the management of perioperative bleeding in patients with haemophilia and inhibitors have evolved rapidly as a result of the development of the bypassing agents Factor Eight Inhibitor Bypassing Activity, Anti-inhibitor Coagulant Complex (FEIBA) and activated recombinant factor VII (rFVIIa). However, there are currently no established guidelines for perioperative use of bypassing agents, and few controlled clinical studies have been carried out. Thus, case reports, such as those presented here, provide useful anecdotal evidence to guide the treatment of inhibitor patients. The purpose of this report was to describe experiences in the use of bypassing agents in a small cohort of patients with haemophilia A and inhibitors undergoing surgical procedures. Cases from five treatment centres were reviewed. Twenty-two procedures using FEIBA, rFVIIa or a combination of both agents were compiled from seven inhibitor patients (six with an alloantibody inhibitor and one with an acquired autoantibody inhibitor). Eleven procedures used FEIBA monotherapy, two employed rFVIIa monotherapy and nine were performed using combination therapy. Supplemental therapies were required to manage bleeding in some cases. Haemostatic control was achieved in all cases, and treatment regimens were generally well tolerated. One thrombotic adverse event was reported: evidence of disseminated intravascular coagulation (DIC) was found after rFVIIa use in one case, although the direct cause of DIC was unknown. The experiences in this case review demonstrate that both major and minor surgical procedures can be safely performed in patients with haemophilia and high-titre inhibitors under the cover of bypassing agents, with a high expectation of success.
Asunto(s)
Inhibidores de Factor de Coagulación Sanguínea/metabolismo , Factores de Coagulación Sanguínea/administración & dosificación , Pérdida de Sangre Quirúrgica/prevención & control , Factor VII/administración & dosificación , Hemofilia A/complicaciones , Adulto , Factores de Coagulación Sanguínea/efectos adversos , Preescolar , Quimioterapia Combinada , Factor VII/efectos adversos , Factor VIIa , Femenino , Hemofilia A/inmunología , Humanos , Lactante , Masculino , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
The Training Committee (TC) of the American Society of Pediatric Hematology/Oncology created a foundation of common goals and objectives that could provide a structure for fellowship programs. The TC conducted a survey of program directors for input into the structure of their programs and training methods and the results are presented here. Additionally, a suggested core program is outlined, taking into account the new common requirements as stipulated by the ACGME and ABP, and additional suggestions from the program directors. This paper highlights the suggested training objectives and educational opportunities that should be afforded all fellows in this sub-specialty. The goal of this consensus statement is to provide a model curriculum to improve quality and consistency of training and achieve compliance with new requirements while simultaneously recognizing the importance of alternative approaches that emphasize each program's unique strengths and character.
Asunto(s)
Curriculum , Educación de Postgrado en Medicina , Hematología/educación , Oncología Médica/educación , Pediatría/educación , Consenso , Becas , Humanos , Sociedades Médicas , Apoyo a la Formación Profesional , Estados UnidosRESUMEN
We present a patient with haemophilia undergoing cardiac surgery treated with continuous infusion factor VIII.
Asunto(s)
Puente de Arteria Coronaria , Factor VIII/uso terapéutico , Hemofilia A/tratamiento farmacológico , Hemostasis Quirúrgica , Insuficiencia de la Válvula Mitral/cirugía , Estenosis Coronaria/complicaciones , Estenosis Coronaria/cirugía , Hemofilia A/complicaciones , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Insuficiencia de la Válvula Mitral/complicacionesRESUMEN
PURPOSE: To determine the response rate of the combination of cyclophosphamide and topotecan in pediatric patients with recurrent or refractory malignant solid tumors. PATIENTS AND METHODS: A total of 91 pediatric patients, 83 of whom were fully assessable for response and toxicity, received cyclophosphamide (250 mg/m2/dose) followed by topotecan (0.75 mg/m2/dose), each given as a 30-minute infusion daily for 5 days. All patients received filgrastim (5 mcg/kg) daily until the absolute neutrophil count (ANC) was > or = 1,500 microL after the time of the expected ANC nadir. RESULTS: A total of 307 treatment courses were given to the 83 fully assessable patients. Responses (complete response plus partial response) were seen in rhabdomyosarcoma (10 of 15 patients), Ewing's sarcoma (six of 17 patients), and neuroblastoma (six of 13 patients). Partial responses were seen in two of 18 patients with osteosarcoma and in one patient with a Sertoli-Leydig cell tumor. Twenty-three patients had either minor responses (n = 6) or stable disease (n = 17); the median number of courses administered to patients with partial or complete response was six (range, two to 13 courses), and the median administered to those with stable disease was three (range, one to 11 courses). The toxicity of the combination was limited principally to the hematopoietic system. Of 307 courses, 163 (53%) were associated with grade 3 or 4 neutropenia, 84 (27%) with grade 3 or 4 anemia, and 136 (44%) with grade 3 or 4 thrombocytopenia. Despite the severe myelosuppression, only 34 (11%) of 307 courses were associated with grade 3 or 4 infection. Nonhematopoietic toxicity of grades > or = 3 was rare and consisted of nausea and vomiting (two courses), perirectal mucositis (one course), transaminase elevation (one course), and hematuria (two courses). CONCLUSION: The combination of cyclophosphamide and topotecan is active in rhabdomyosarcoma, neuroblastoma, and Ewing's sarcoma. Stabilization of disease was seen in osteosarcoma, although objective responses were rare in this disease. The therapy can be given with acceptable hematopoietic toxicity with the use of filgrastim support.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Adolescente , Adulto , Neoplasias Óseas/tratamiento farmacológico , Niño , Preescolar , Ciclofosfamida/administración & dosificación , Femenino , Humanos , Lactante , Infusiones Intravenosas , Masculino , Neuroblastoma/tratamiento farmacológico , Osteosarcoma/tratamiento farmacológico , Rabdomiosarcoma/tratamiento farmacológico , Sarcoma de Ewing/tratamiento farmacológico , Topotecan/administración & dosificaciónRESUMEN
The purpose of this study was to determine if KRN5500, a spicamycin derivative with a unique acyl tail, would induce programmed cell death (PCD) of myeloid leukemia cell lines and cryopreserved leukemic blasts from newly diagnosed children with acute leukemia (AL). Cells were incubated with varying concentrations (0-5 ng/ml) of KRN5500 and the percent PCD determined using a modified in situ end labeling (ISEL) technique with Klenow fragment. The percent PCD was calculated using the formula: Percent PCD (% PCD)=[number of apoptotic cells/(viable cells+apoptotic cells)]x100. DMSO (0.30% w/v) was added to the cells in culture as the positive control for PCD; the negative control was media or albumin. KRN5500 increased the amount of PCD significantly in all five of the tested cell lines; U937 41+/-1.8%, KG1a 40+/-0.3%, HEL 14+/-2.2%, HL-60 41+/-0. 9%, K562 36+/-2% (mean PCD+/-SD). Patient blasts exposed to KRN5500 had an increase in PCD when exposed to 2 ng/ml of agent from 2 to 8 h; acute myeloid leukemia patients 7.5+/-0.5% at 2 h to 43.5+/-1.6% at 8 h, and acute lymphocytic leukemia patients rose from 12.4+/-3.8% at 2 h to 29.9+/-11.6% after 8 h (mean+/-SE). Overall the PCD for the patient samples was 3.7 versus 28+/-4% at 2 and 8 h, respectively. PCD was proportional to the dose of KRN5500 and incubation time. Further pre-clinical and clinical studies are required.
Asunto(s)
Apoptosis/efectos de los fármacos , Leucemia Mieloide/patología , Niño , Humanos , Nucleósidos de Purina/farmacología , Células Tumorales CultivadasRESUMEN
We have used dual-energy x-ray absorptiometry (DXA) in evaluation and follow-up of a patient with osteopetrosis, before and after cord blood transplantation. Other methods of follow-up in such cases have been described, but the use of DXA has not previously been reported. We have shown that DXA offers a safe means of assessing disease progression, the timing of treatment, and response after therapy for osteopetrosis.
Asunto(s)
Absorciometría de Fotón , Osteopetrosis/diagnóstico , Adyuvantes Inmunológicos/uso terapéutico , Transfusión Sanguínea , Progresión de la Enfermedad , Ergocalciferoles/uso terapéutico , Sangre Fetal , Estudios de Seguimiento , Humanos , Lactante , Interferón gamma/uso terapéutico , Masculino , Osteopetrosis/tratamiento farmacológico , Osteopetrosis/terapia , Factores de Tiempo , Resultado del TratamientoRESUMEN
Retroviral vectors capable of cytokine-inducible gene expression will be useful for a number of gene therapy applications. We explored one mechanism whereby cytokine inducibility may be imparted to the retroviral U3 promoter/enhancer by utilizing the JAK-STAT signal transduction pathway that is activated by a number of hematopoietic cytokines. We used PCR mutagenesis to insert a consensus binding site for the ubiquitous transcription factor Sp1 into the Moloney murine leukemia virus U3 followed by the insertion of multimers of a STAT-binding oligonucleotide with the core sequence 5'-TTCCCGGAA. After insertion of the modified U3s into a retroviral vector expressing the luciferase reporter gene and transduction of the HepG2 cell line, luciferase expression was induced with recombinant human IFN-gamma. The level of induction reached a maximum of 9.9-fold higher than the uninduced vector when the Sp1-U3 contained four STAT oligos. When this optimal vector was compared with the wild-type and Sp1 vectors, respective values of 17.9- and 16.7-fold higher expression were achieved with IFN-gamma treatment. Retroviral vectors incorporating these cytokine-inducible U3s will be useful for gene therapy in a number of situations involving gene transfer to hematopoietic, hepatic and other cytokine-responsive cell types.
Asunto(s)
Citocinas/genética , Terapia Genética/métodos , Vectores Genéticos/genética , Células Madre Hematopoyéticas/inmunología , Virus de la Leucemia Murina de Moloney/genética , Transfección/métodos , Línea Celular , Expresión Génica/efectos de los fármacos , Humanos , Interferón gamma/farmacología , Luciferasas/genética , Mutagénesis Insercional , Proteínas Recombinantes , Transducción de Señal/genética , Factor de Transcripción Sp1/genética , Transactivadores/genéticaRESUMEN
IL-2 augments the ability of natural killer (NK) cells to kill myeloid leukemia cells in vitro, and may have a role in the eradication of minimal residual disease (MRD) in AML patients. The ability to enhance lysis of AML cells without the toxicity of IL-2 would be a significant improvement in the use of biologics against AML. Recent interest in IL-12 suggested that this cytokine might meet these criteria. The aim of this study was to evaluate the ability of IL-12 to enhance the in vitro lysis of the non-lymphoid leukemia cell lines in a standard 51Chromium release assay. Effector cells from normal volunteers were incubated with varying concentrations of IL-12 or IL-2 for 18-20 h, then the 51Cr-labeled target cells from five different cell lines of AML origin were added for 4 h. Percent lysis was determined and plotted over four effector:target (E:T) ratios. Our results indicated that IL-12 was able to enhance lysis of all cell lines tested at > or =5 units/ml. When IL-2 was added to the culture at a low dose along with IL-12, there appeared to be a synergistic effect. Although anti-gamma interferon was able to inhibit the cytolytic potential of effectors activated by IL-12, the lysis could not be completely blocked. Thus, it appears that IL-12 has the ability to stimulate NK lysis indirectly through the induction of gamma interferon as well as an alternate mechanism not related to gamma interferon. Thus, IL-12 may have a beneficial role in the treatment of non-lymphoid leukemia.
Asunto(s)
Interleucina-12/farmacología , Células Asesinas Activadas por Linfocinas/inmunología , Leucemia Mieloide/inmunología , Enfermedad Aguda , Muerte Celular/efectos de los fármacos , Células HL-60 , Humanos , Interferón gamma/biosíntesis , Interleucina-2/farmacología , Células Asesinas Activadas por Linfocinas/efectos de los fármacos , Leucemia Mieloide/patología , Células Tumorales CultivadasRESUMEN
BACKGROUND: Skeletal complications are responsible for significant morbidity in Gaucher patients. Plain radiographs have been unreliable in assessing bone marrow infiltration and activity. A way to assess bone marrow improvement is needed during enzyme therapy. OBJECTIVE: The purpose of this paper is to assess the usefulness of MR in following improvement of abnormal bone marrow in Gaucher patients on enzyme therapy. MATERIALS AND METHODS: Three patients aged 2, 7, and 24 years underwent serial MR scans of the lower extremities before and during treatment with Alglucerase (two patients) and Imiglucerase (one patient). T1-weighted, T2-weighted, STIR and FSE T2-weighted images were utilized. Two patients were imaged after 16 months of therapy, and one patient was imaged after 6 months of therapy. RESULTS: All patients had improvement in marrow signal consistent with partial reconversion to fatty marrow during treatment. The findings were more marked after prolonged therapy. T1-weighted images demonstrated findings most clearly. CONCLUSION: MR consistently showed improvement in marrow signal in Gaucher patients on enzyme therapy. As smaller doses of enzyme therapy are the trend, MR can be utilized to determine if therapy is effecting a change in the bone marrow.
Asunto(s)
Médula Ósea/patología , Enfermedad de Gaucher/diagnóstico , Imagen por Resonancia Magnética , Adulto , Médula Ósea/efectos de los fármacos , Niño , Preescolar , Enfermedad de Gaucher/tratamiento farmacológico , Glucosilceramidasa/uso terapéutico , Humanos , LactanteRESUMEN
PURPOSE: To determine the maximum-tolerated dose (MTD) and dose-limiting toxicity of topotecan when combined with cyclophosphamide in pediatric patients with recurrent or refractory malignant solid tumors. PATIENTS AND METHODS: A total of 33 patients received cyclophosphamide (250 mg/m2/dose) followed by topotecan in escalating doses (0.6 to 0.75 mg/m2/dose), each given as a 30-minute infusion daily for 5 days. A total of 154 fully assessable treatment courses were given to these patients. RESULTS: Neutropenia was the dose-limiting toxicity of the therapy at both topotecan dose levels. The addition of filgrastim allowed escalation of the topotecan dose to the 0.75-mg/m2 level with acceptable neutropenia. Other significant toxicities were anemia and thrombocytopenia. Nonhematopoietic toxicity of grades > or = 3 was not observed. Responses were reported in patients with Wilms' tumor (one complete response [CR], one partial response [PR]), neuroblastoma (one CR, one PR), rhabdomyosarcoma (one PR), and osteosarcoma (one PR). Pharmacokinetic studies indicate that cyclophosphamide administered on the schedule used in this study did not alter topotecan disposition on day 5. As with previous studies, a pharmacodynamic relation between systemic exposure and myelosuppression was noted. CONCLUSION: The combination of topotecan and cyclophosphamide shows activity in a wide variety of pediatric solid tumors and can be given with acceptable hematopoietic toxicity with the use of filgrastim support. We recommend that pediatric phase II trials use cyclophosphamide 250 mg/m2 followed by topotecan 0.75 mg/m2 daily for 5 days with filgrastim for amelioration of neutropenia.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/administración & dosificación , Recurrencia Local de Neoplasia/tratamiento farmacológico , Terapia Recuperativa , Topotecan/administración & dosificación , Adolescente , Niño , Preescolar , Ciclofosfamida/farmacocinética , Esquema de Medicación , Femenino , Humanos , Lactante , Masculino , Topotecan/farmacocinéticaRESUMEN
BACKGROUND: Pediatric patients with Langerhans cell histiocytosis (LCH) may become refractory to conventional therapy or present with repeated recurrences over several years. Current therapeutic options such as prednisone, vinblastine, etoposide, and cyclosporine are associated with significant acute toxicities and late effects. Recent reports suggested that 2-chlorodeoxyadenosine (2-CDA) may be an effective agent in adults with LCH. The purpose of this study was to determine the safety and efficacy of 2-CDA in children with LCH. METHODS: This report presents the data collected from the first three patients that have completed this trial. Patients were enrolled in a prospective study after informed consent was obtained. Patients had a confirmed diagnosis of LCH that had recurred several times or not responded to standard therapy. Patients were given a starting dose of 5 mg/M2 of daily continuous infusion for three days duration. Two patients had their dose increased to 6.5 mg/M2/ day. A total of 4-6 courses were given, and courses were repeated every 3-4 weeks. Thirteen of fifteen courses were given as outpatients at home. RESULTS: Each patient completed therapy with myelosuppression the primary toxicity. Pt. 1 initially received a higher dose of 2-CDA and developed sepsis. The dose was reduced to current study levels and no other incidence of infection, fever, and neutropenia, or blood product transfusion was required. All three patients are free of active disease 10-18 months after completing 2-CDA. CONCLUSION: Three patients with LCH refractory to standard therapy had CR to 2-CDA, given at 5-6.5 mg/M2/day for 3 days, without significant toxicity.
Asunto(s)
Cladribina/uso terapéutico , Histiocitosis de Células de Langerhans/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Adolescente , Preescolar , Femenino , Histiocitosis de Células de Langerhans/diagnóstico por imagen , Humanos , Estudios Prospectivos , Radiografía , Recurrencia , Cráneo/diagnóstico por imagenRESUMEN
Lupus anticoagulants (LAs) represent a diverse group of antibodies directed against phospholipids. Patients with LAs may be free of symptoms but can have thrombotic complications including stroke, placental infarction, and fetal loss. Rarely hemorrhagic symptoms have been reported. We describe six previously healthy children who were first seen with clinical bleeding and prolonged activated partial thromboplastin time. Laboratory evaluation revealed positive results on mixing studies and evidence of phospholipid dependence of the anticoagulant, suggesting LAs. Four of six patients had anticardiolipin antibodies, and all four who were tested had reduced factor II activity levels. In all patients, bleeding symptoms resolved spontaneously within 3 months, and laboratory findings returned to normal within 6 months. The hemorrhagic LA syndrome should be considered in previously healthy children with new-onset bleeding and prolonged activated partial thromboplastin time. This clinical entity probably represents pathogenic mechanism distinct from thrombotic LA syndromes.
Asunto(s)
Encéfalo/fisiopatología , Hemorragia/fisiopatología , Inhibidor de Coagulación del Lupus/inmunología , Trombosis , Niño , Preescolar , Femenino , Humanos , Lupus Eritematoso Sistémico , Masculino , Tiempo de Tromboplastina Parcial , Fosfolípidos/inmunología , Tiempo de Protrombina , SíndromeRESUMEN
PURPOSE: To present two patients as illustrations of the risk of developing secondary acute myelogenous leukemia (sAML) when theoretically safe doses of etoposide (VP-16) are used. PATIENTS AND METHODS: Patient no. 1 was a 15-year-old white girl diagnosed with stage IIa Hodgkin's disease. She was treated with a combination of vincristine, doxorubicin, bleomycin, and VP-16 (2 g/m2 total) over 4 months, followed by 25.5 Gy of involved-field radiotherapy. Patient no. 2 was an 11-year-old white boy diagnosed with virus-associated hemophagocytic syndrome (VAHS). He was treated with VP-16 intravenously (IV) and orally (0.3 g and 2.8 g/m2, respectively). RESULTS: Patient no. 1 developed AML 16 months from the diagnosis of Hodgkin's disease. Patient no. 2 developed AML 26 months from diagnosis. Both bone marrows were consistent with French-American-British (FAB) M4 disease. Both patients had abnormalities of the long arm of chromosome 11. CONCLUSION: The use of low-dose or oral VP-16 can be associated with the development of sAML. Clinicians should be cautious in the use of VP-16 in low-risk diseases.
Asunto(s)
Antineoplásicos Fitogénicos/efectos adversos , Etopósido/efectos adversos , Leucemia Mieloide Aguda/inducido químicamente , Neoplasias Primarias Secundarias/inducido químicamente , Administración Oral , Adolescente , Antineoplásicos Fitogénicos/administración & dosificación , Niño , Etopósido/administración & dosificación , Femenino , Histiocitosis de Células no Langerhans/tratamiento farmacológico , Histiocitosis de Células no Langerhans/virología , Enfermedad de Hodgkin/tratamiento farmacológico , Humanos , MasculinoRESUMEN
PURPOSE: Patients with Ehlers-Danlos syndrome (EDS), especially types IV, VI, and VIII, are at increased risk of bleeding, and most do not have specific hemostatic deficiencies that would be amenable to replacement therapy. We have investigated the ability of DDAVP (desmopressin acetate) to control bleeding in EDS. PATIENTS AND METHODS: Two children with EDS, types VIII and VI, presented with hemorrhagic symptoms and scheduled surgical procedures. Ivy bleeding times (BTs) were measured before and after intravenous (i.v.) DDAVP challenge, and i.v. DDAVP was used prophylactically for their procedures. Laboratory testing was performed to rule out other hemostatic disorders. RESULTS: Both patients had prolonged BTs that corrected following i.v. DDAVP therapy; all other laboratory values were normal. Both patients had excellent clinical hemostasis with surgery, and one has continued to use intranasal DDAVP to control epistaxis and gingival bleeding. CONCLUSIONS: The bleeding time in both patients was corrected with DDAVP, and the patients did not have any postoperative bleeding. DDAVP should be considered in other patients who have EDS with bleeding tendencies.
Asunto(s)
Desamino Arginina Vasopresina/uso terapéutico , Síndrome de Ehlers-Danlos , Hemorragia/tratamiento farmacológico , Fármacos Renales/uso terapéutico , Tiempo de Sangría , Niño , Femenino , Hemostasis/efectos de los fármacos , Humanos , MasculinoRESUMEN
Studies of the effects of yogurt on immunity and atopic diseases have suggested improvements in cytokine (interleukin-2 and interferon-gamma) responses and clinical scores in patients with allergic rhinitis. This study compares prospectively immune parameters of participants who received 16 oz of yogurt versus 16 oz of milk/day in a randomized cross-over design. Yogurt that contained live, active Lactobacillus bulgaricus and Streptococcus thermophilus or 2% milk was consumed for one month each. Twenty otherwise healthy adults with atopic histories documented by skin testing were enrolled. Immune studies were performed at the beginning and end of the two 1-month study phases, separated by a 2-week washout period. These studies included measurements of cellular, humoral, and phagocytic function. No adverse events were noted in either group. No significant improvements in any immune parameter were noted. The consumption of yogurt that contained the live active bacteria L bulgaricus and S thermophilus does not appear to enhance immune function in atopic individuals at the dosage and duration used in this study.
Asunto(s)
Dieta , Inmunidad/inmunología , Yogur , Adulto , Animales , Femenino , Humanos , Pruebas Inmunológicas , Lactobacillus/metabolismo , Masculino , Persona de Mediana Edad , Leche/metabolismo , Estado Nutricional , Streptococcus/metabolismoRESUMEN
Wilms' tumor (WT) is associated with chromosomal deletions and loss of heterozygosity (LOH) of alleles at 11p13. The authors report the youngest known patient with diffusely anaplastic WT and, to their knowledge, the first case to demonstrate telomeric fusions as a chromosomal mechanism for the loss of bands 11p13 and 11p15 in WT. Recurrent clonal telomeric association (tas) initiated breakage/fusion cycles that resulted in deletions of chromosome bands 11p15, 11p13, and, subsequently, the entire short arm of chromosome 11. In addition, tas involving the long arms of chromosomes 7 and 9 resulted in the subsequent deletion of the long arm of chromosome 7. This report expands the spectrum of chromosomal mechanisms that can account for the loss of alleles on the short arm of chromosome 11 in WT by providing evidence that the progressive loss of critical chromosome regions associated with tumor suppression may occur as a result of chromosomal instability initiated by tas.
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 11 , Heterocigoto , Neoplasias Renales/genética , Telómero , Tumor de Wilms/genética , Genes del Tumor de Wilms , Humanos , Lactante , Neoplasias Renales/patología , Masculino , Tumor de Wilms/patologíaAsunto(s)
Conducta del Adolescente , Cooperación del Paciente , Leucemia-Linfoma Linfoblástico de Células Precursoras/psicología , Adolescente , Humanos , Control Interno-Externo , Masculino , Grupo de Atención al Paciente , Grupo Paritario , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Apoyo SocialRESUMEN
Human immunodeficiency virus type-1 (HIV-1)-infected individuals exhibit functional impairment in various forms of cell-mediated cytotoxicities (CMC) at all stages of disease. The purpose of this study was to determine (i) if peripheral blood mononuclear cells (PBMC) obtained from HIV-1-infected patients could be stimulated in vitro to yield lymphokine-activated killer (LAK) activity; (ii) if non-MHC-restricted gp120-specific CMC could be preserved; and (iii) what effect zidovudine (AZT) would have on LAK activity. Fourteen asymptomatic HIV-1 seropositive adults and five healthy seronegative adults (controls) were evaluated. PBMCs were isolated and incubated in media or supplemented with IL-2 for 4 or 72 hr. Lysis of the NK resistant target cell line, Daudi, was similar for the control and experimental group. The increase in activity after stimulation was elevated to a similar degree in both seronegative and seropositive groups (P less than 0.001). LAK activity was significantly decreased (P = 0.011) when AZT was added to LAK cultures. In addition, virus production may not have been completely inhibited by AZT in LAK cultures. Thus, PBMCs from asymptomatic HIV-1-infected patients could be stimulated to yield LAK activity. However, AZT can impair LAK generation. It is unclear if LAK activation results in virus production that cannot be inhibited by AZT in this system. Further definition in other patient populations is required prior to applying this information to clinical trials.
Asunto(s)
Infecciones por VIH/inmunología , VIH-1 , Células Asesinas Activadas por Linfocinas/efectos de los fármacos , Zidovudina/farmacología , Productos del Gen gag/análisis , Proteína p24 del Núcleo del VIH , Humanos , Interleucina-2/farmacología , Células Asesinas Activadas por Linfocinas/inmunología , Células Asesinas Naturales/inmunología , Proteínas del Núcleo Viral/análisisRESUMEN
HIV-1-specific cell-mediated cytotoxicity (CMC) is a form of antibody-dependent cellular cytotoxicity (ADCC) in which HIV-1-specific antibodies arm NK cells directly to become cytotoxic for targets bearing HIV-1 antigenic determinants. This non-MHC-restricted cytotoxic activity is present in early stages of disease and declines markedly with disease progression. To understand the cellular and humoral factors contributing to the reduction in this activity, the conditions under which maximal arming of cells occurs was examined in vitro. With the use of a large patient cohort, a strong positive correlation was found between the capacity of a serum to direct lysis in standard ADCC assays and its ability to arm NK cells. Patients with minimal HIV-1-specific ADCC-directing antibodies exhibited low levels of CMC and were unable to arm normal effector cells in vitro. The lack of sufficient ADCC-directing antibodies was found to be one cause of defective CMC in some patients. Unlike asymptomatics, only a weak positive correlation was found between arming and ADCC with sera from AIDS patients, indicating that a factor other than absolute HIV-1 specific antibody titer was responsible for decreased CMC in this patient population. Another group of patients was found to have diminished CMC despite the presence of antibodies in the serum that were fully capable of arming normal effector cells to become cytotoxic for gp120-expressing targets. When compared with those of normal individuals, lymphocytes from seropositive patients mediated significantly reduced levels of cytotoxicity in ADCC and arming assays with the use of a high titered HIV-1-specific serum. In both assay systems, the magnitude and frequency of dysfunction in antibody-dependent cytolysis was found to be greater among AIDS patients than among asymptomatic individuals. The demonstration of both cellular and humoral defects in the ability of seropositive individuals to manifest ADCC reactivities strongly suggests that HIV-1 infection may significantly compromise the effectiveness of this potentially important cytolytic reactivity in vivo.