RESUMO
Normal volunteers received either initial or booster immunization with tetanus toxoid. Bone marrow and peripheral blood mononuclear cells were obtained for up to 28 d after immunization and were analyzed for synthesis of total Ig and specific antibodies to tetanus toxoid. Cells were cultured in vitro for 3 or 7 d with or without pokeweed mitogen (PWM). Synthesis of IgG and IgM antibodies to tetanus (IgG-Tet and IgM-Tet) and total IgG and IgM was determined by radioimmunoassay. Four functional B cell subpopulations were detected in the bone marrow after booster tetanus immunization: (a) B cells that spontaneously synthesized IgG-Tet appeared on day 7 after immunization but were undetectable by day 21; (b) B cells that synthesized IgG-Tet after stimulation with PWM appeared after day 21 and persisted for greater than 1 mo; (c) B cells that synthesized IgM-Tet in the presence of PWM were detectable before and after immunization; and (d) B cells that spontaneously synthesized IgM-Tet appeared on day 7 and were undetectable by day 21. In contrast to the other three types of bone marrow B cells described, this fourth subpopulation of PWM-independent IgM-Tet-synthesizing B cells was not detected in the peripheral blood. After primary immunization, no spontaneous antibody-producing cells were detected in the blood or bone marrow, although there was a small rise in IgM-Tet in two of three subjects. In the bone marrow, only IgM-Tet PWM-inducible cells were seen, although mitogen-responsive IgM and IgG-Tet cells were detected in the circulation. The IgM-Tet PWM-reactive cells were present even before primary antigen exposure and appear to represent the initial B cells involved in the antibody response. These data indicate that there are specific times after immunization when different functional classes of anti-Tet-synthesizing B cells and memory B cells appear in human bone marrow. Knowledge of these data may be important in developing a strategy for the transfer of immune memory from donors to recipients in the setting of bone marrow transplantation.
Assuntos
Medula Óssea/imunologia , Toxoide Tetânico/imunologia , Tétano/imunologia , Adulto , Formação de Anticorpos , Linfócitos B/imunologia , Células Cultivadas , Humanos , Imunização , Imunização Secundária , Imunoglobulina G/biossíntese , Imunoglobulina M/biossíntese , Mitógenos de Phytolacca americana/imunologia , Linfócitos T/imunologiaRESUMO
Posttransplant hematologic recovery was compared between 9 autologous and 11 allogeneic marrow transplant patients who received similar marrow-lethal chemoradiotherapies before transplantation. Although the autotransplant patients were infused with much lower marrow doses compared with the allotransplant patients, they showed adequate hematologic recovery with acceptable risk. Regardless of marrow doses, delayed platelet recovery and failure of platelet recovery were observed in 7 patients. All of these patients experienced early transplantation-related complications before engraftment. Despite the limited number of patients, a number of myeloid progenitor cells (CFUC) infused correlated significantly with the period for recovery of polymorphonuclear cells in autologous marrow recipients while there was no significant correlation found between marrow dose and hematologic recovery in both groups of patients. Furthermore, autotransplant patients showed a characteristic recovery pattern of peripheral blood lymphocytes in an early posttransplant period, whic was not observed in allotransplant patients.
Assuntos
Transplante de Medula Óssea , Hematopoese , Leucemia/terapia , Linfoma/terapia , Doença Aguda , Adolescente , Adulto , Medula Óssea/patologia , Relação Dose-Resposta Imunológica , Feminino , Humanos , Leucemia/sangue , Leucemia/imunologia , Contagem de Leucócitos , Linfócitos/citologia , Linfoma/sangue , Linfoma/imunologia , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Transplante Autólogo , Transplante HomólogoRESUMO
KM2210, a conjugate of estradiol and chlorambucil (CBL), which was originally developed as an anti-breast cancer agent, inhibits proliferative response of human mononuclear cells to alloantigens in mixed lymphocyte culture in a dose-dependent manner, but has no effect on their response to phytohemagglutinin. Neither estradiol benzoate nor CBL alone showed these unique actions. The suppressive effect of KM2210 on MLC was abrogated by adding of anti-transforming growth factor-beta (TGF-beta) antibody to the culture, but was not affected by the addition of interleukin-2, suggesting that KM2210, unlike CBL, displays its actions via TGF-beta. In experimental allogeneic bone marrow transplantation using mice, daily oral administration of KM2210 (2 mg/kg/day) for 30 days posttransplant significantly inhibited the alloantigen-specific immune reactions. Furthermore, the survival rate of the KM2210-treated mice was significantly higher than that of the cyclosporine-treated (2 mg/kg/day, p.o.) mice, and no adverse effect of KM2210 on hematopoietic recovery was found. These results strongly suggest possible clinical benefits of KM2210 as a new immunosuppressive agent for the prevention and treatment of graft-versus-host disease and other allospecific immune reactions.
Assuntos
Transplante de Medula Óssea/imunologia , Clorambucila/análogos & derivados , Estradiol/análogos & derivados , Imunossupressores/farmacologia , Animais , Divisão Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Clorambucila/farmacologia , Epitopos , Estradiol/farmacologia , Citometria de Fluxo , Isoantígenos/imunologia , Isoantígenos/farmacologia , Articulação do Joelho , Contagem de Leucócitos , Linfonodos/anatomia & histologia , Ativação Linfocitária/efeitos dos fármacos , Teste de Cultura Mista de Linfócitos , Masculino , Camundongos , Tamanho do Órgão , Transplante HomólogoRESUMO
In order to identify an immunological role for decidual tissue in pregnancy we have prepared single cell suspensions from the tissues of normal pregnant women and examined the effects of these cells on one-way mixed-lymphocyte reactions (MLR). The separated cells were heterogeneous, containing classical decidual cells, glandular epithelial cells, granular endometrial cells, macrophages and small lymphoid cells. [3H]Thymidine incorporation at day 6 of the MLR was suppressed by addition of the cells at the initiation of the cultures and the degree of suppression was inversely correlated to the gestational age of the decidual tissue, apparently through inhibition of the antigen recognition phase of the MLR. These findings support the view that the cells of the human first trimester pregnancy endometrium may play an important role in protecting the feto-placental unit from rejection, at least in the early phase of pregnancy.
Assuntos
Decídua/imunologia , Tolerância Imunológica , Imunidade Celular , Primeiro Trimestre da Gravidez , Antígenos de Superfície/análise , Células Cultivadas , Feminino , Humanos , Interleucina-2/biossíntese , Queratinas/metabolismo , Teste de Cultura Mista de Linfócitos , GravidezRESUMO
We performed stem cell rescue and allogeneic skin transplantation on a lethally neutron-irradiated nuclear accident victim. HLA-DRB1 mismatched unrelated umbilical cord blood cells (2.08 x 10(7)/kg recipient body weight) were transplanted to an 8-10 Gy equivalent neutron-irradiated patient because of a lack of a suitable bone marrow or peripheral blood donor. Pre-transplant conditioning consisted of anti-thymocyte gamma-globulin alone, and GVHD prophylaxis was a combination of cyclosporine (CYA) and methylprednisolone (mPSL). Granulocyte colony-stimulating factor (G-CSF), erythropoietin (EPO), and thrombopoietin (TPO) were concurrently administered after transplantation. The absolute neutrophil count reached 0.5 x 10(9)/l on day 15, the reticulocyte count rose above 1% on day 23, and the platelet count was over 50 x 10(9)/l on day 27, respectively. Cytogenetic studies of blood and marrow showed donor/recipient mixed chimerism. Rapid autologous hematopoietic recovery was recognized after withdrawal of CYA and mPSL. Repeated pathological examinations of the skin revealed no evidence of acute GVHD. Eighty-two days after the irradiation, skin transplantation was performed to treat radiation burns. Almost 90% of the transplanted skin engrafted. Immunological examination after autologous hematopoietic recovery revealed an almost normal T cell count. However, immune functions were severely impaired. The patient died from infectious complication 210 days after the accident.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Lesões por Radiação/terapia , Liberação Nociva de Radioativos , Adulto , Evolução Fatal , Sangue Fetal/citologia , Sobrevivência de Enxerto , Teste de Histocompatibilidade , Humanos , Sistema Imunitário/crescimento & desenvolvimento , Masculino , Nêutrons , Doses de Radiação , Lesões por Radiação/patologia , Síndrome do Desconforto Respiratório/etiologia , Transplante de Pele , Quimeras de Transplante , Transplante HomólogoRESUMO
A new non-T cell, non-B cell lymphoma cell line, designated IN-1, was established from the ascitic fluid of a patient with non-Hodgkin lymphoma. The IN -1 cells did not show any T cell and B cell immunophenotypes. There were rearrangements of T cell receptor beta- and gamma-chain gene, but no rearrangement of T cell receptor delta-chain gene and immunoglobulin JH gene. Electron microscopically, the cell had numerous pseudopods, mitochondria, vesicles, a conspicuous nucleolus, and scattered heterochromatin at the periphery of the nucleus. They reacted with only OKT9 monoclonal antibody. Molecular analysis revealed that cellular DNA from the IN-1 cells did not hybridize with Bam HI W fragment of EB virus DNA. Cytogenetic analysis showed that the chromosome number of the IN-1 was in the range of 61 -63 whose karyotype analysis demonstrated multiple numerical and structural chromosome changes. The IN-1 cells were resistant to etoposide in comparison with an IC50 of K562 (human chronic myelogenous leukemia). Interestingly, this IN-1 cell possessed 85 KD protein, but not P-glycoprotein, both of which are considered to be multidrug resistance-related proteins.
Assuntos
Rearranjo Gênico da Cadeia beta dos Receptores de Antígenos dos Linfócitos T , Rearranjo Gênico da Cadeia gama dos Receptores de Antígenos dos Linfócitos T , Linfoma não Hodgkin/genética , Proteínas de Neoplasias/análise , Células Tumorais Cultivadas , Idoso , Tolerância a Medicamentos , Etoposídeo/farmacologia , Feminino , Humanos , Cariotipagem , Linfoma não Hodgkin/patologia , Proteínas de Neoplasias/fisiologiaRESUMO
Postoperative erythrodermia (POED) is a rare disease appearing several days after surgery for which blood transfusion has been required, characterized by erythrodermia, fever, pancytopenia, hepatic insufficiency or diarrhea. Most affected patients die within four weeks. The etiology remains unknown, but some assume it to be a type of graft-versus-host reaction (GVHR) caused by transfused lymphocytes. In this study, skin biopsies taken from 9 POED patients were examined to clarify whether POED is a type of GVHR. In seven samples, changes compatible with GVHR, such as lymphocyte infiltration in the basal layer and occasional eosinophilic or vacuolar degeneration of the epidermal cells, with occasional satellitosis, were noted. Immunopathologically, infiltrating lymphocytes mostly expressed suppressor/cytotoxic T cell markers like those in GVHR. Meanwhile, immunostaining with anti-HLA-A type specific antibodies failed to differentiate infiltrating lymphocytes from host cells. Thus, the present morphologic and in vivo marker study suggested POED to be a type of GVHR, while in vivo HLA-A typing showed two contradictory possibilities: first, that POED is a GVHR in which major histocompatibility antigen-matched donor lymphocytes attack host cells, and secondly that POED is not a GVHR, the infiltrating lymphocytes being of host origin.
Assuntos
Dermatite Esfoliativa/patologia , Reação Enxerto-Hospedeiro , Complicações Pós-Operatórias/patologia , Adulto , Idoso , Dermatite Esfoliativa/etiologia , Epiderme/patologia , Feminino , Antígenos HLA-A/análise , Humanos , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Pele/patologiaRESUMO
Human granulocyte colony-stimulating factor (G-CSF) specifically stimulates granulocyte production and enhances functions of mature granulocytes. It also proliferates myeloid leukemic cells. The molecule was purified and molecularly cloned in 1986. In this study, 51 patients received single daily injections with recombinant human (rh) G-CSF (2-20 micrograms/kg) after bone marrow transplantation were compared with control 36 patients. Blood neurophilic recovery was accelerated remarkably by rhG-CSF administration without any adverse effects including delay in reticulocyte and platelet recoveries. Furthermore, the duration for the management in laminar airflow room and febrile days greater than or equal to 38 degrees C were shortened in rhGS-CSF treated group. In 6 patients with myeloid leukemia in relapse, we also tested the effects of the rhG-CSF-combined conditioning regimen. In all the patients tested, the leukemic cells responded to rhG-CSF. Clinically no relapse was observed and 3 patients are well on day 224-357 for the time being. These findings indicate that rhG-CSF is very useful in bone marrow transplantation.
Assuntos
Transplante de Medula Óssea , Fatores Estimuladores de Colônias/uso terapêutico , Leucemia Mieloide Aguda/terapia , Cuidados Pós-Operatórios , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Feminino , Fator Estimulador de Colônias de Granulócitos , Humanos , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/cirurgia , Contagem de Leucócitos , Masculino , Neutrófilos , Cuidados Pré-Operatórios , Proteínas Recombinantes/uso terapêutico , Irradiação Corporal TotalRESUMO
Between January 1993 and June 1994, the JMDP facilitated marrow donations from unrelated donors for 171 patients with malignant and non-malignant disorders. The median age of the patients was 21 years. All patients received marrow from phenotypically HLA -A, -B, -DR identical donors. About half of the patients wrer treated with total body irradiation (TBI)-containing regimens and about 80% of the patients received short-courses methotrexate and cyclosporine for graft-versus-host disease (GVHD) prophylaxis. Eight out of 171 patients, (4.7%) had graft failure and 63 out of 144 patients (44%), who survived for more than 30 days posttransplant, developed grade II to IV acute GVHD. The incidence of chronic GVHD was 47% (extensive form; 27%); most of them were progressive/quiscent type. The incidence of moderate to severe acute GVHD was higher than that observed in sibling transplants. On the other hand, the incidence of chronic GVHD was similar to that observed in sibling transplants. Overall survival at 1.5 years posttransplant was about 50% with no significant differences between diseases. The age correlated significantly with the survival in standard risk leukemia but not in high-risk leukemia. Despite the risk of graft failure and acute GVHD, this preliminary analysis demonstrates that transplantation of marrow from unrelated donors can be an effective treatment for certain hematologic disorders.
Assuntos
Transplante de Medula Óssea , Doenças Hematológicas/terapia , Bancos de Tecidos , Doadores de Tecidos , Doença Aguda , Adolescente , Adulto , Feminino , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Transplante Homólogo , Falha de Tratamento , Resultado do TratamentoRESUMO
Four patients with fresh Hodgkin's disease were treated with MOPP/ABV hybrid regimen using nitrogen mustard-N-oxide hydrochloride (NH2-O). All patients responded well to this therapy and achieved complete remission. Toxicity was minimum except for an older patient. He was 70 years old and developed arrhythmia after MOPP therapy but recovered without any treatment. The continuation of therapy was possible by dose reduction in this case. We conclude MOPP/ABV regimen using NH2-O is valuable for the treatment of Hodgkin's disease.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Adulto , Idoso , Bleomicina/administração & dosagem , Doxorrubicina/administração & dosagem , Esquema de Medicação , Feminino , Humanos , Masculino , Mecloretamina/administração & dosagem , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Procarbazina/administração & dosagem , Indução de Remissão , Vimblastina/administração & dosagem , Vincristina/administração & dosagemRESUMO
A patient with stage III testicular cancer was treated by 3 courses of BEP therapy and a partial response was obtained. Afterwards he underwent resection of pulmonary residual tumors and was treated by 2 courses of PE therapy immediately after operation. However, a new pulmonary tumor appeared after the first course of PE therapy was completed. He was treated by high-dose chemotherapy (etoposide 1200 mg/m2, cyclophosphamide 120 mg/kg, CDDP 60 mg/m2) with autologous bone marrow transplantation. Three weeks after high-dose chemotherapy his metastatic pulmonary tumor showed cavity formation which disappeared after 3 months. Fifteen months after the high-dose chemotherapy, no evidence of disease has been seen even without maintenance therapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Medula Óssea , Teratoma/tratamento farmacológico , Neoplasias Testiculares/tratamento farmacológico , Adulto , Bleomicina/administração & dosagem , Cisplatino/administração & dosagem , Terapia Combinada , Ciclofosfamida/administração & dosagem , Resistência a Medicamentos , Etoposídeo/administração & dosagem , Humanos , Masculino , Indução de Remissão , Teratoma/cirurgia , Neoplasias Testiculares/cirurgia , Transplante AutólogoRESUMO
Plasma concentration of cytosine arabinoside (Ara-C) was determined in elderly patients with myelodysplastic syndromes or acute myelocytic leukemia who were treated with subcutaneous injection of Ara-C (Ara-C s.c.; 10 mg/m2/12 hr, 14-21 days), continuous drip infusion of Ara-C (Ara-C d.i.v.; 20 mg/m2/day, 24 hr 14 days) and/or oral administration of cytarabine ocfosfate (SPAC) (SPAC p.o.; 100 mg-300 mg/body/day, 14 days) by radioimmunoassay. In the Ara-C s.c. patients, the peak plasma level (Cmax) of Ara-C was 103 ng/ml and the time to reach Cmax was 15 min. The elimination half-like (t1/2) was 25 min and no accumulation was detected after 14 days of consecutive Ara-C s.c. administrations. In the SPAC p.o. patients, Cmax of Ara-C was 3-8 ng/ml and it took 3-5 days to reach Cmax. The plasma concentration level of Ara-C remains almost at the Cmax level during the SPAC p.o. administration and it remained higher than 0.32 ng/ml for as long as 15 days after the end of administration. In a Ara-C d.i.v. patient, plasma level of Ara-C was detected 4-7 ng/ml during the administration (day 7 through day 14). In all patients bone marrow suppression was observed after chemotherapy regardless of regimen, and there was no significant difference between nadir peripheral cell blood counts of Ara-C s.c. patients and SPAC p.o. patients.
Assuntos
Antineoplásicos/farmacocinética , Arabinonucleotídeos/farmacocinética , Citarabina/farmacocinética , Monofosfato de Citidina/análogos & derivados , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Arabinonucleotídeos/administração & dosagem , Citarabina/administração & dosagem , Monofosfato de Citidina/administração & dosagem , Monofosfato de Citidina/farmacocinética , Feminino , Humanos , Infusões Intravenosas , Injeções Subcutâneas , Leucemia Mieloide Aguda/sangue , Masculino , Síndromes Mielodisplásicas/sangueRESUMO
We investigated the efficacy of cord blood transplantation (CBT) for adult acute lymphoblastic leukemia (ALL) by reviewing medical records of 256 patients reported to the Japan Cord Blood Bank Network between June 1997 and August 2006. Cumulative incidence of neutrophil engraftment at day 100 was 78%. Infused CD34-positive cell dose (>1 × 10(5) cells/kg) was associated with successful neutrophil engraftment. Cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) at day 100 was 37%. A 2-year disease-free and overall survival (OS) rates were 36% and 42%, respectively. Multivariate analysis showed that age (51 or older vs younger than 50) (hazard ratio 1.9, 95% confidence interval (CI), 1.3-2.8, P=0.001), disease status (non-remission vs remission) (hazard ratio 2.2, 95% CI, 1.5-3.2, P<0.0001), grade III-IV acute GVHD (hazard ratio 2.0, 95% CI, 1.2-3.2, P=0.006) and absence of chronic GVHD (hazard ratio 2.4, 95% CI, 1.1-5.1, P=0.02) were negatively associated with OS. CBT is effective for some patients with advanced ALL. It is worth considering for further evaluation.