RESUMO
Immunoglobulin and specific antibody levels are well maintained in the recipients of T-cell-depleted allogeneic bone marrow transplants (BMT), even though up to 99% of mature T cells are removed from the donor graft. For 3-8 weeks after the procedure, natural killer (NK) cells with an activated pattern of target cell killing have been shown to circulate in the recipient. This study investigates whether these recipient NK cells spontaneously secrete lymphokines that modulate B cell function in a way analogous to that of in-vitro-activated NK cells from normal individuals. Large granular lymphocytes (LGLs) (which contain a high proportion of NK cells) have been prepared from the peripheral blood of 11 recipients of T-cell-depleted major-histocompatibility-complex-matched allografts. In the first 4-6 weeks after BMT these LGLs were found spontaneously to secrete interleukin 2, interferon gamma and B cell differentiation factor. While secretion of these factors declines by 20-24 weeks after BMT, the quantities are still greater than those seen from control donors. Patient LGLs are also able to activate autologous (donor) B cells, rendering them potentially responsive to the secreted factors. It appears likely that activated NK cells (or LGL) play a significant role in maintaining B cell function in vivo after T-cell-depleted BMT.
Assuntos
Linfócitos B/imunologia , Transplante de Medula Óssea , Células Matadoras Naturais/imunologia , Depleção Linfocítica , Antígenos de Diferenciação de Linfócitos B , Antígenos de Superfície/metabolismo , Diferenciação Celular , Humanos , Interferon gama/metabolismo , Interleucina-2/metabolismo , Células Matadoras Naturais/metabolismo , Leucemia Linfoide/imunologia , Leucemia Linfoide/terapia , Leucemia Mieloide/imunologia , Leucemia Mieloide/terapia , Ativação Linfocitária , Linfócitos T , Transplante HomólogoRESUMO
Low-density cells (LDC) prepared from peripheral blood by fractionation over hypertonic metrizamide contain 95% of cells with veiled morphology, almost all of which are HLA-DR-positive and have characteristics of antigen-presenting cells. In normal individuals the monoclonal antibodies RFD1 and RFD2 divide these cells into three phenotypically distinct populations, D1+D2-, D1-D2+ and D1-D2-. The RFD1-positive population is nonphagocytic. We have investigated the recovery of LDC in peripheral blood after (T cell-depleted) marrow transplantation, to assess whether defects in antigen-presenting cell (APC) subpopulations could contribute to the prolonged immune-paresis of marrow graft recipients. We find that APC of donor origin and with apparently normal morphology, phenotype, and function appear within 6 weeks of BMT. By three months the donor-derived nonphagocytic RFD1-positive subset has disappeared, although phagocytic RFD2-positive cells remain. The disappearance of the RFD1-positive subset is associated with a loss of antigen presentation by patients' LDC of the soluble protein antigen tetanus toxoid, though the capacity to present alloantigen and stimulate in a mixed lymphocyte reaction is retained. Donor-derived RFD1-positive cells and soluble antigen-presenting capacity do not reappear for one year or more. This biphasic recovery of RFD1-positive cells contrasted with the continued production of RFD2-positive APC, implies that the phenotypic and functional distinction between APC subpopulations in peripheral blood also reflects a separate ontogeny. Since these marrow graft recipients retain the phagocytic (RFD2-positive) APC but lose the nonphagocytic (RFD1-positive) APC subset, there is now an opportunity to explore the role of each subset in antigen processing and presentation.
Assuntos
Células Apresentadoras de Antígenos/classificação , Transplante de Medula Óssea , Fenótipo , Adolescente , Adulto , Anticorpos Monoclonais , Células Apresentadoras de Antígenos/citologia , Células Apresentadoras de Antígenos/imunologia , Contagem de Células , Criança , Feminino , Antígenos HLA-DR/imunologia , Humanos , Estudos Longitudinais , Teste de Cultura Mista de Linfócitos , Masculino , Toxoide Tetânico/imunologia , Doadores de Tecidos , Transplante HomólogoRESUMO
Previous studies have shown that interleukin-4 (IL-4) may have both stimulatory and inhibitory effects on the growth of normal and malignant B-cells in vitro. We studied the effects of IL-4 on tumour necrosis factor (TNF) induced and spontaneous proliferation (3H-TdR incorporation) and spontaneous release of TNF and interleukin-6 (IL-6) by purified B-cell chronic lymphocytic leukaemia (CLL) cells in vitro. TNF (100 U/ml) increased 3H-TdR uptake in cells to 700 +/- 302% of control (mean +/- S.E., n = 9, p = 0.033). Recombinant IL-4 (10 ng/ml) consistently inhibited DNA synthesis in all CLL patients studied. When added at the start of 5 day cultures, IL-4 inhibited both spontaneous (41 +/- 17% inhibition, n = 3) and TNF induced (46 +/- 5% inhibition, n = 9, p = 0.01) 3H-TdR uptake. Similar results were obtained when IL-4 was added after 48 h of culture. This effect of IL-4 was dose dependent. Inhibition was not related to clinical stage. IL-4 (whether added at T0 or T48h) also inhibited spontaneous release of TNF and IL-6 measured at 48 and 120 h. TNF and IL-4 had no consistent effect on normal cord blood CD5+ B-cells. These data show that IL-4 has inhibitory effects on B-CLL DNA synthesis and also inhibits spontaneous release of IL-6 and TNF in vitro. IL-4 may have a role in vivo in reducing proliferation in these B-cell malignancies by inhibiting potential autocrine growth loops.
Assuntos
Citocinas/metabolismo , Interleucina-4/farmacologia , Leucemia Linfocítica Crônica de Células B/patologia , Linfócitos B/citologia , Linfócitos B/metabolismo , Divisão Celular , Humanos , Interleucina-6/metabolismo , Leucemia Linfocítica Crônica de Células B/metabolismo , Proteínas Recombinantes/farmacologia , Células Tumorais Cultivadas/metabolismo , Células Tumorais Cultivadas/patologia , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
There is now good evidence that tumour necrosis factor [TNF] stimulates DNA synthesis of B-chronic lymphocytic leukaemia (B-CLL) cells. The malignant clone produces TNF, and addition of exogenous TNF up-regulates the TNF mRNA in B-CLL cells. Interleukin-6 (rIL-6) may also be important in this growth loop. We studied the interaction of TNF and IL-6 in the regulation of DNA synthesis (3H-TdR uptake), cytokine release and cell survival in CLL cells in vitro. Addition of TNF (100 U/ml over 5 days) enhanced DNA synthesis from 718 +/- 284 (mean cpm +/- SE) to 2730 +/- 545 compared to cells cultured in medium alone (n = 16, p < 0.01). TNF-alpha induced DNA synthesis was inhibited in all cases studied by the addition of anti-TNF monoclonal antibody (5 micrograms/ml) to cell cultures. Spontaneous IL-6 protein release was enhanced in the presence of TNF (100 U/ml and 250 U/ml) by CLL cells at 48 hours of culture 143.6% and 172% (p < 0.05, n = 6). At 120 hours of culture, the increase was 323% and 412.5% (4 of 7 cases) of the control respectively. IL-6 (100 U/ml or greater) increased spontaneous DNA synthesis (3H-TdR uptake) but, in the presence of high concentrations of TNF-alpha, inhibited TNF induced DNA synthesis in a dose dependent manner. Cell survival was reduced in the presence of anti-IL-6 mAb, while IL-6 was able to protect CLL cells from spontaneous apoptosis. These results suggest that IL-6 in an autocrine manner may inhibit DNA synthesis but prolongs survival in CLL cells. Increased serum IL-6 levels were detected in 27 of 50 cases of CLL, the mean level being significantly higher in Rai Stage III and IV cases compared to Rai Stage O-II cases.
Assuntos
Apoptose/efeitos dos fármacos , Linfócitos B/efeitos dos fármacos , Inibidores do Crescimento/farmacologia , Interleucina-6/farmacologia , Leucemia Linfocítica Crônica de Células B/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/farmacologia , Linfócitos B/metabolismo , Linfócitos B/patologia , Divisão Celular/efeitos dos fármacos , Fragmentação do DNA , Replicação do DNA , DNA de Neoplasias/biossíntese , Feminino , Humanos , Imunofenotipagem , Interleucina-6/antagonistas & inibidores , Interleucina-6/imunologia , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Estadiamento de Neoplasias , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Proteínas Recombinantes/farmacologia , Fator de Necrose Tumoral alfa/farmacologiaAssuntos
Transplante de Medula Óssea/métodos , Hematopoese , Interleucina-2/uso terapêutico , Transplante de Medula Óssea/fisiologia , Citocinas/sangue , Citocinas/genética , Expressão Gênica , Granulócitos/fisiologia , Humanos , Leucemia Mieloide Aguda/cirurgia , Contagem de Leucócitos , Mieloma Múltiplo/cirurgia , RNA Mensageiro/genética , Transplante AutólogoRESUMO
Large granular lymphocyte clones were prepared from normal human mononuclear cells. Seven clones were studied in detail. All had high cytotoxic activity against the natural killer (NK) cell target K562 and all were T11- and DR-positive but T4- and T8-negative: none released migration inhibitory factor, a characteristic of helper T cell clones. When these NK cell clones were co-cultured with autologous B cells in a 1:1 ratio, 4 of the 7 induced both IgM and IgG synthesis. Ig production could not be further enhanced by the addition of B cell differentiation factors. The cells stimulated included antigen-specific memory B cells, as the Ig induced contained specific antibody to an antigen, tetanus toxoid, to which the B cell donors had recently been immunized. Supernatants from the helper/NK clones contained B cell differentiation factors, and were able to induce IgG synthesis from the lymphoblastoid cell line CESS and from co-cultured T and B cells. However, NK clone supernatants, unlike the clones themselves, were not effective at inducing Ig synthesis from purified B cells. Instead it appears that NK clones first activate B cells and thus render them responsive to the factors that the clones secrete.
Assuntos
Antígenos de Superfície/análise , Linfócitos B/imunologia , Células Matadoras Naturais/imunologia , Formação de Anticorpos , Antígenos de Diferenciação de Linfócitos B , Linfócitos B/citologia , Diferenciação Celular , Células Clonais , Humanos , Imunoglobulina G/metabolismo , Memória Imunológica , Interleucina-2/farmacologia , Linfócitos T/imunologiaRESUMO
One hundred and sixteen human tumours were transplanted to thymectomized, irradiated, antilymphocyte serum-treated mice. In 12 cases the recipient mice died rapidly, presumably from infection. With the remaining 104 tumours, three-quarters grew to a varying extent, retaining the characteristic histological features of the primary tumours. Implant nodules varied widely in composition, from solid tumour and stroma to dense fibrous tissue without recognizable tumour cells. There was no relation between degree of malignancy and ability to grow, and also some benign tumours grew.In 44 cases, mice were treated with the drug or drugs most likely to be used in the patients and the effects on the implants were assessed histologically. Two tumours were largely destroyed and one showed marked metaphase arrest. Three other tumours showed lesser changes that were attributable to the drug but were of equivocal significance.There appeared to be differences in drug sensitivity between structurally different clones of the same tumour, and some tumours treated with two alkylating agents were damaged by one and not the other, suggesting that this model may have substantial discriminatory power. Assays such as this should not be used to guide treatment of the patient without prior validation. The practical and ethical difficulties of validation by clinical trial may be insurmountable, and an alternative approach to validation is proposed which does not raise these difficulties.
Assuntos
Transplante de Neoplasias , Neoplasias Experimentais , Transplante Heterólogo , Animais , Clorambucila/uso terapêutico , Ciclofosfamida/uso terapêutico , Dactinomicina/uso terapêutico , Modelos Animais de Doenças , Feminino , Fluoruracila/uso terapêutico , Neoplasias Gastrointestinais , Humanos , Terapia de Imunossupressão , Masculino , Melfalan/uso terapêutico , Metotrexato/uso terapêutico , Camundongos , Camundongos Endogâmicos CBA , Metástase Neoplásica , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Neoplasias Ovarianas , Tiotepa/uso terapêutico , Timectomia , Triaziquona/uso terapêutico , Neoplasias da Bexiga Urinária , Vimblastina/uso terapêutico , Vincristina/uso terapêuticoRESUMO
Tumour necrosis factor (TNF) can act as an autocrine growth factor for hairy cell leukaemia (HCL) cells. The TNF produced by the malignant clone may also inhibit normal haematopoiesis thereby contributing to the cytopenias observed in patients with the disease. We have studied the effects of infusing a murine monoclonal anti-TNF antibody in three patients with HCL. In two patients receiving 0.5 mg of antibody/kg on alternate days for 12 d, the drug was well tolerated. The third patient received 2 mg/kg on alternate days and developed symptoms of serum sickness by day 9. In two patients with severe B-lymphocytopenia, circulating CD19 and CD20 positive, B-cells were restored to normal, the majority of which were negative for the HCL-associated marker CD11c. B-lymphocyte recovery was associated with a rise in serum immunoreactive IL-6 and with an early rise in immunoreactive TNF. These short courses of anti-TNF MAb treatment had modest effect on the tumour burden, producing a reduction in splenomegaly in one patient. Exploration of the effects of more prolonged administration of higher dose anti-TNF antibody will only be feasible when less immunogenic MAbs are available.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Leucemia de Células Pilosas/terapia , Fator de Necrose Tumoral alfa/imunologia , Animais , Antígenos CD/análise , Antígenos CD19 , Antígenos CD20 , Antígenos de Diferenciação de Linfócitos B/análise , Linfócitos B/imunologia , Antígenos CD11 , Humanos , Ensaio Imunorradiométrico , Interleucina-6/análise , Leucemia de Células Pilosas/sangue , Masculino , Camundongos , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/análiseRESUMO
Patients with acquired hypogammaglobulinaemia usually have near normal numbers of B cells and normal T cell function. When hypogammaglobulinaemia occurs in association with thymoma, then B cell numbers have been reported as low, and distinctive T cells are present which inhibit immunoglobulin production by normal cells. It has been suggested that these T cells are responsible for the observed hypogammaglobulinaemia. We report a patient with thymoma and hypogammaglobulinaemia who lacks these distinctive suppressor cells and has normal B cell numbers. It is therefore incorrect to propose a single pathogenic mechanism for hypogammaglobulinaemia in association with thymoma.
Assuntos
Agamaglobulinemia/imunologia , Linfócitos T Reguladores/imunologia , Timoma/imunologia , Neoplasias do Timo/imunologia , Agamaglobulinemia/etiologia , Idoso , Linfócitos B/imunologia , Feminino , Humanos , Imunoglobulinas/análise , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Fenótipo , Timoma/complicações , Neoplasias do Timo/complicaçõesRESUMO
Fetal hemoglobin (Hb F) and fetal cell (FC) levels in adults show considerable variation and are influenced by several genetic variants; the major determinants appear to be unlinked to the beta-globin gene cluster. Recently, a trans-acting locus controlling Hb F and FC production has been mapped to chromosome 6q23 in an Asian Indian kindred that includes individuals with heterocellular hereditary persistence of Hb F (HPFH) associated with beta thalassemia. We have extended the kindred by 57 members, bringing the total studied to 210, and have saturated the region with 26 additional markers. Linkage analysis showed tight linkage of the quantitative-trait locus (QTL) to the anonymous markers D6S976 (LOD score 11.3; recombination fraction .00) and D6S270 (LOD score 7.4; recombination fraction .00). Key recombination events now place this QTL within a 1-2-cM interval spanning approximately 1.5 Mb between D6S270 and D6S1626. Furthermore, haplotype analysis has led to a reevaluation of the genealogy and to the identification of additional relationships in the kindred.
Assuntos
Cromossomos Humanos Par 6 , Hemoglobina Fetal/genética , Característica Quantitativa Herdável , Mapeamento Cromossômico , Feminino , Hemoglobina Fetal/biossíntese , Ligação Genética , Genótipo , Haplótipos , Humanos , Masculino , Repetições de Microssatélites , LinhagemRESUMO
After T-cell depleted marrow transplantation, there is a rapid recovery of cytotoxic effector cells, with activity against targets not susceptible to killing by 'resting' natural killer cells. These targets include Epstein-Barr virus transformed B cells and leukaemic cell lines. Activated killer cell function declines by 3 months after transplantation. We find that when CD3 negative effector cells are obtained from these patients and cultured in vitro with interleukin 2 there is a further enhancement of cytotoxic activity against a range of target cells in the early post-transplant period, and a restoration of high level cytotoxic activity to effector cells obtained 3 months or more after the procedure. These results may have relevance to attempts to reduce the incidence of leukaemic relapse, and EBV + ve lymphoma outgrowth after T-cell depleted BMT.
Assuntos
Transplante de Medula Óssea , Interleucina-2/farmacologia , Células Matadoras Naturais/fisiologia , Linfócitos T/imunologia , Adolescente , Adulto , Separação Celular , Criança , Testes Imunológicos de Citotoxicidade , Humanos , Leucócitos Mononucleares/imunologiaRESUMO
Induction of tissue factor (TF) expression on monocytes and endothelial cells is central to the development of septic coagulopathy. Serum concentrations of endotoxin in septic patients who develop disseminated intravascular coagulation (DIC) do not, however, reach the levels that would directly stimulate TF expression on either monocytes or endothelium. We show, using an in vitro coculture system, that the interaction of monocytes with endothelium induces the expression of significant levels of TF. Unstimulated cocultures of monocytes (2 x 10(4)/well) and endothelial cells (2 x 10(4)/well) produced 35.3 +/- 8.5 mU of PCA/well, representing a 5-fold increase over the combined PCA of each cell type cultured alone (7.1 +/- 1.5 mU, n = 6, P < 0.001). Significant enhancement was also found in the presence of low concentrations of LPS. Induction of TF protein was confirmed by Western blotting. Fixation of monocytes with paraformaldehyde completely abolished TF induction in cocultures, whereas fixation of endothelium had no effect, suggesting that TF induction occurred in monocytes rather than endothelial cells. Induction of TF in cocultures could be further augmented by preincubating the endothelial cells with IFN-gamma. When endothelium was prestimulated with 500 U/ml IFN-gamma there was 142 +/- 11% increase over unstimulated cocultures (n = 5, P < 0.01). TF induction was inhibited by 32 +/- 6% in the presence of anti-ICAM-1 mAb (n = 5, P < 0.01). Our results suggest that monocyte interactions with vascular endothelium, regulated by inflammatory cytokines, and mediated by adhesive ligand binding, leads to the induction of functional monocyte TF protein, which may be responsible for the initiation of DIC in sepsis.
Assuntos
Coagulação Intravascular Disseminada/etiologia , Endotélio Vascular/fisiologia , Monócitos/fisiologia , Tromboplastina/biossíntese , Anticorpos Monoclonais/farmacologia , Western Blotting , Adesão Celular/fisiologia , Comunicação Celular/fisiologia , Técnicas de Cocultura , Coagulação Intravascular Disseminada/metabolismo , Endotélio Vascular/efeitos dos fármacos , Humanos , Molécula 1 de Adesão Intercelular/imunologia , Interferon gama/farmacologia , Monócitos/metabolismoRESUMO
Major histocompatibility complex-unrestricted lymphokine-activated killer (LAK) cells have been proposed as therapy for a variety of hematologic malignancies. Because these cells recognize and kill their targets independently of their antigen specific CD3 receptor, it is unclear how they might discriminate between normal and malignant cells. We now propose one such mechanism for the selective killing of myeloid leukemia blasts. While both CD2+ and CD2- activated killer cells may inhibit the clonogenic growth of myeloid leukemia cells, only the CD2+ subset effectively inhibits the growth of normal myeloid (granulocyte-macrophage and granulocyte) progenitors. This difference appears to reflect differential requirements for cell adhesion molecule recognition between normal and malignant progenitor cells. Inhibition of the growth of normal granulocyte-macrophage colonies by CD2+ LAK cells is blocked by antibodies to the CD2-lymphocyte function-associated antigen 3 (LFA-3) (CD58) cell adhesion system. In contrast, these antibodies have no effect on CD2+ LAK-mediated inhibition of malignant cell clonogenic growth. Instead, antibodies to the LFA-1 (CD11a/CD18)-intercellular adhesion molecule 1 (ICAM-1) (CD54) adhesion system reduce inhibition. These differences correspond to differential expression of the CD54 cell adhesion molecule by normal and malignant myeloid progenitor cells because less than 15% of normal CD34 positive cells are CD54+ while greater than 85% of CD34+ acute myeloid leukemia blasts express the CD54 antigen. LFA-3, the ligand for CD2, is strongly expressed by erythrocytes, and these cells competitively inhibit killing of normal but not malignant clonogenic cells in an analogous way to the effects of monoclonal antibody to the CD2-LFA-3 adhesion system. The operation of this effect in vivo may be a basis for selective cytotoxicity by CD2+ LAK against clonogenic myeloid blast cells, and could be exploited further with infusion of appropriate monoclonal antibodies.
Assuntos
Citotoxicidade Imunológica , Células Matadoras Ativadas por Linfocina/imunologia , Leucemia Mieloide Aguda/imunologia , Antígenos CD/análise , Antígenos CD/imunologia , Antígenos CD34 , Antígenos de Diferenciação/análise , Antígenos de Diferenciação/imunologia , Antígenos de Diferenciação de Linfócitos T/análise , Antígenos de Diferenciação de Linfócitos T/imunologia , Antígenos de Superfície/imunologia , Antígenos CD2 , Antígenos CD58 , Adesão Celular/imunologia , Moléculas de Adesão Celular/análise , Moléculas de Adesão Celular/imunologia , Humanos , Molécula 1 de Adesão Intercelular , Glicoproteínas de Membrana/imunologia , Receptores Imunológicos/análise , Receptores Imunológicos/imunologiaRESUMO
Recombinant tumour necrosis factor (TNF) promotes survival and induces proliferation in the tumour cells from two malignancies of B lymphocytes--hairy-cell leukaemia and B-chronic lymphocytic leukaemia. Culture with TNF also induces TNF mRNA and protein, so the cytokine may act as an autocrine tumour growth factor. These growth promoting effects are antagonised by alpha but not by gamma interferon.
Assuntos
Leucemia de Células Pilosas/patologia , Leucemia Linfoide/patologia , Fator de Necrose Tumoral alfa/farmacologia , Linfócitos B , Divisão Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Humanos , Leucemia de Células Pilosas/metabolismo , Leucemia Linfoide/metabolismo , Receptores de Superfície Celular/metabolismo , Receptores do Fator de Necrose Tumoral , Timidina/metabolismo , Células Tumorais Cultivadas , Fator de Necrose Tumoral alfa/metabolismoRESUMO
To test the effect of transplantation of T-cell-depleted bone marrow on recipient immune function the results of pre-transplantation immunisation with tetanus toxoid and hepatitis-B vaccine were studied in 38 donor-recipient pairs. Immunisation of the donor alone resulted in transfer of an antibody response to the recipient; immunisation of both donor and recipient resulted in potentiation of the antibody response in both magnitude and duration. These findings indicate that donor T-cell-depleted marrow can transfer humoral immunity to the recipient and that appropriate pre-transplant immunisation schedules may be of benefit to the recipient.
Assuntos
Linfócitos B/imunologia , Transplante de Medula Óssea , Imunização Passiva , Leucemia/terapia , Linfócitos T/imunologia , Adolescente , Adulto , Anemia Aplástica/imunologia , Anemia Aplástica/terapia , Formação de Anticorpos , Células Produtoras de Anticorpos/imunologia , Linfócitos B/transplante , Medula Óssea/imunologia , Células da Medula Óssea , Criança , Pré-Escolar , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Imunização Secundária , Imunoglobulina G/análise , Técnicas In Vitro , Lactente , Leucemia/imunologia , Pessoa de Meia-Idade , Talassemia/imunologia , Talassemia/terapiaRESUMO
Hepatitis C virus (HCV) is responsible for the majority of cases of post transfusion non-A non-B (NANB) hepatitis in thalassaemia major (TM). Twelve multi-transfused TM patients with serological, biochemical, histological and molecular biological evidence of HCV infection have been treated for 6 months with recombinant alpha-interferon (IFN). Ten (83%) responded as assessed by a fall of at least 50% of pre-treatment serum transaminase levels. Histological improvement was observed in 6/7 responders tested. Natural killer (NK) cell activity 24 h after the first dose of IFN was significantly increased in responders as compared to non-responders (P < 0.05). HCV RNA disappeared from serum in 5/12 and from liver tissue in 2/5 of the responders. The degree of induction of peripheral blood mononuclear cell 2'5' oligoadenylate synthetase messenger RNA (2-5 OAS mRNA), an enzyme induced by IFN, after the first dose of IFN did not correlate with response. IFN was generally well tolerated. We conclude that the response rate in multi-transfused TM patients infected with HCV and treated with IFN is similar to that in non-multi-transfused patients.
Assuntos
Hepatite C/terapia , Interferon-alfa/uso terapêutico , Talassemia beta/complicações , Adolescente , Adulto , Sequência de Bases , Criança , Doença Crônica , Feminino , Hepacivirus/genética , Hepatite C/sangue , Hepatite C/patologia , Humanos , Interferon alfa-2 , Interferon-alfa/efeitos adversos , Células Matadoras Naturais/patologia , Fígado/patologia , Masculino , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , RNA Viral/análise , Proteínas Recombinantes , Transaminases/sangue , Reação TransfusionalRESUMO
Following T cell-depleted bone marrow transplantation, helper T cell numbers remain depressed for some months. Nonetheless, functional B cells can be adoptively transferred to the recipients of such grafts, where they continue to secrete antibody. We now show that immunoglobulin production by these transferred B cells is induced by activated large granular lymphocytes (LGL) which circulate in the recipients in substantial numbers during the immediate post-transplant period. The LGL are CD3 negative and therefore provide help in an antigen-unlinked manner. Helper effects for autologous (donor) B cells are augmented by the addition of anti-LFA-2 (anti-CD2) which appears to act by blocking recruitment of LGL inhibitory to developing B cells. In contrast antibody to the beta chain of LFA-1, which effectively reduces natural killer activity of LGL, does not influence their helper function. The peripheral blood LGL fraction thus contains both helper and cytotoxic activity, which can be distinguished by appropriate monoclonal antibodies.
Assuntos
Formação de Anticorpos , Transplante de Medula Óssea , Células Matadoras Naturais/fisiologia , Cooperação Linfocítica , Antígenos de Superfície/imunologia , Linfócitos B/imunologia , Linfócitos B/transplante , Feminino , Humanos , Imunização Passiva , Depleção Linfocítica , Masculino , Período Pós-Operatório , Linfócitos T/imunologiaRESUMO
After conventional bone marrow transplantation serum IgG, IgM and IgA levels fall from pre-transplant levels and may not return to normal for 3-12 months. In contrast IgE may rise to supranormal levels, an event that may be associated with graft-versus-host disease. We have investigated the recovery of immunoglobulin isotypes in the recipients of allogeneic marrows depleted of T-cells to prevent graft-versus-host disease. We find that pre-transplant IgG, IgM and IgA levels are maintained throughout the post-transplant period but that there is a short-lived rise in IgE about 3 weeks after transplantation: this rise occurs in the absence of clinically detectable graft-versus-host disease. We conclude that specific T-cell depletion does not impair and may actually enhance the functional recovery of B cells after allogeneic BMT.
Assuntos
Transplante de Medula Óssea , Imunoglobulinas/análise , Linfócitos T , Adolescente , Adulto , Separação Celular , Criança , Humanos , Imunoglobulina A/análise , Imunoglobulina E/análise , Imunoglobulina G/análise , Imunoglobulina M/análise , Pessoa de Meia-Idade , Fatores de TempoRESUMO
After marrow transplantation, major histocompatibility complex (MHC)-unrestricted natural killer (NK) lymphocytes are among the first cells to appear in the circulation. After T-cell-depleted bone marrow transplantation (TD-BMT), these cells have an activated pattern of target cell killing; they also secrete lymphokines including gamma-interferon (gamma-IFN), interleukin-2 (IL-2), and tumor necrosis factor (TNF) and may have a significant role as a primary defense against viral reactivation and in the elimination of residual host malignancy. We studied 43 patients with hematologic malignancy, treated by allogeneic TD-BMT, autologous nondepleted BMT, or chemotherapy alone to investigate (a) the mechanisms underlying the generation of these activated killer cells, (b) the range of conditions under which they are produced, and (c) their surface phenotype. We showed that gamma-IFN-secreting activated killer cells with the capacity to kill MHC-nonidentical NK-resistant targets are generated 4 to 6 weeks after either allogeneic TD-BMT or autologous BMT but do not appear after treatment with chemotherapy. Production therefore is not owing to T-cell depletion per se or to host donor alloreactivity, nor is it caused by stimulation by alloantigens contained in blood product support since no significant difference exists between allograft and chemotherapy patients in the number of units of blood platelet support given in the posttreatment period. Because most patients had no evidence of stimulation from virus reactivation/infection, the phenomenon of activation therefore appears to represent posttransplant immune disregulation following repopulation of the host immune system with lymphoid subsets derived exclusively from blood and marrow. Activated killing is predominantly mediated by the CD16+ CD3- subset, but substantial activity remains in the CD16- CD3+ cell fraction. Monoclonal antibodies (MoAbs) that block interaction with class-I MHC molecules at the level of target cell (W6/32 anti-HLA class I) or effector cell (CD8) do not inhibit killing by CD16- CD3+ cells. Activated killer cells may contribute to the lower risk of relapse after marrow transplantation as compared with intensive chemotherapy.