RESUMO
Mycobacterium lepraemurium infection of mice produces a chronic lethal disease that is characterized by massive accumulation of macrophages throughout the mononuclear-phagocyte system. We studied the influence of M. lepraemurium infection on the composition and function of the hematopoietic system. Medullary erythropoiesis was virtually abolished, as reflected by a small number of erythroid elements and a decrease in the number and frequency of erythroid progenitors in the bone marrow, together with reduced uptake of 59Fe into bone marrow hemin. On the other hand, erythropoiesis was observed in the spleen, as demonstrated by a large number of erythroid cells, a sixfold increase of 59Fe uptake, and a pronounced increase in the number of erythroid progenitors. A considerable increase of monocyte progenitors was observed in the spleen, and a more modest increase was observed in the bone marrow. This increase may be accounted for, at least in part, by greatly increased levels of macrophage-colony-stimulating factor in the serum of infected mice. Thus, M. lepraemurium infection produces important changes in the hematopoietic system, during the course of which the spleen becomes the major hematopoietic organ.
Assuntos
Hematopoese , Células-Tronco Hematopoéticas/fisiopatologia , Infecções por Mycobacterium/fisiopatologia , Animais , Medula Óssea/microbiologia , Fatores Estimuladores de Colônias/sangue , Eritropoese , Ferro/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos CBA , Infecções por Mycobacterium/microbiologia , Mycobacterium lepraemurium , Baço/microbiologiaAssuntos
Medula Óssea/patologia , Células-Tronco Hematopoéticas/fisiopatologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Síndromes Mielodisplásicas/patologia , Movimento Celular , Ensaio de Unidades Formadoras de Colônias , Granulócitos , Hematopoese , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Macrófagos , Síndromes Mielodisplásicas/sangueRESUMO
The development of autoimmune diabetes in the nonobese diabetic (NOD) mouse is controlled by at least three recessive loci, including one linked to the MHC. To determine whether any of these genetic loci exert their effects via the immune system, radiation bone marrow chimeras were constructed in which (NOD X B10)F1-irradiated recipients were reconstituted with NOD bone marrow cells. Unmanipulated (NOD X B10)F1 mice, or irradiated F1 mice reconstituted with F1 or B10 bone marrow, did not display insulitis or diabetes. In contrast, insulitis was observed in a majority of the NOD----F1 chimeras and diabetes developed in 21% of the mice. These data demonstrate that expression of the diabetic phenotype in the NOD mouse is dependent on NOD-derived hematopoietic stem cells. Diabetogenic genes in the NOD mouse do not appear to function at the level of the insulin-producing beta cells since NOD----F1 chimeras not only developed insulitis and diabetes but also rejected beta cells within pancreas transplants from newborn B10 mice. These data suggest that the beta cells of the NOD mouse do not express a unique antigenic determinant that is the target of the autoimmune response.
Assuntos
Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 1/genética , Células-Tronco Hematopoéticas/fisiopatologia , Pancreatite/genética , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Medula Óssea/fisiopatologia , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 1/imunologia , Ilhotas Pancreáticas/patologia , Camundongos , Transplante de Pâncreas , Pancreatite/imunologia , Pancreatite/patologia , Quimera por RadiaçãoAssuntos
Síndrome da Imunodeficiência Adquirida/complicações , Agranulocitose/complicações , Leucopenia/complicações , Neutropenia/complicações , Trombocitopenia/complicações , Síndrome da Imunodeficiência Adquirida/fisiopatologia , Biópsia , Medula Óssea/patologia , Adesão Celular , Divisão Celular , Células-Tronco Hematopoéticas/patologia , Células-Tronco Hematopoéticas/fisiopatologia , HumanosRESUMO
In order to investigate the mechanism of polycythemia in chronic obstructive pulmonary disease (COPD), serum and urinary levels of erythropoietin and medullary erythroid progenitors were studied in 21 patients; nine were nonpolycythemic (hematocrit, 39 +/- 4 percent; red blood cell [RBC] mass, 28 +/- 5 ml/kg; forced expiratory volume in one second [FEV1], 0.6 +/- 0.1 L), and 12 patients were polycythemic (hematocrit, 52 +/- 7 percent; RBC mass, 46 +/- 7 ml/kg; FEV1, 0.9 +/- 0.3 L). Hypoxia was severe in both groups, with mean arterial oxygen pressure of 47 mm Hg. The following parameters of tissue oxygenation were not significantly different between the two groups: arterial and mixed-venous oxygen saturations; cardiac output; oxygen utilization coefficient; 2, 3-diphosphoglycerate, and carboxyhemoglobin level. The level of erythropoietin was measured by bioassay in vitro. The level was increased in the serum of 85 percent (18) and in the urine of 38 percent (8) of the patients. There was no significant difference between the nonpolycythemic and polycythemic groups. Without exogenous erythropoietin, none of the subjects showed spontaneous colonies of erythroid progenitors. The addition of one unit of erythropoietin induced a similar normal proliferation of erythroid progenitors in both groups. The absence of adaptative polycythemia in the nonpolycythemic group with severe hypoxia was seemingly related neither to a quantitative deficit of erythropoietin nor to a lack of sensitivity of erythroid progenitors to its action.
Assuntos
Eritropoetina/sangue , Células-Tronco Hematopoéticas/fisiopatologia , Pneumopatias Obstrutivas/complicações , Policitemia/sangue , Idoso , Pressão Sanguínea , Eritropoetina/urina , Feminino , Hematócrito , Humanos , Pneumopatias Obstrutivas/sangue , Pneumopatias Obstrutivas/fisiopatologia , Pneumopatias Obstrutivas/urina , Masculino , Pessoa de Meia-Idade , Oxigênio/sangue , Policitemia/etiologia , Policitemia/fisiopatologia , Policitemia/urina , Artéria Pulmonar/fisiopatologiaRESUMO
The present study was undertaken to investigate the hemopoietic cell from which malignant change evolves in juvenile dyshemopoiesis with monosomy 7. Two male patients, aged 18 and 5 months, were studied using progenitor assays combined with cytogenetics. Both had hepatosplenomegaly, cytopenias and a cellular marrow. The karyotype in direct marrow was 45,XY-7/47,XY,+8/46,XY in patient 1 and 45,XY,-7/46,XY in patient 2. Patient 1 received chemotherapy but developed acute nonlymphocytic leukemia after 17 months and died 20 months after diagnosis. During this time marrow metaphases with 45,XY,-7 increased to 100% (25/25). Patient 2 received an allogeneic marrow transplant 4 months after diagnosis which did not engraft. In both patients progenitors of both small (CFU-E) and large (BFU-E) erythroid colonies were present at normal frequencies. However, the colonies produced were small and poorly hemoglobinized with some erythropoietin-independent maturation. Progenitors of large granulocyte/macrophage colonies (CFU-GM) were present at an elevated frequency in the marrow of patient 1 and in the blood all progenitor classes were markedly increased. Cytogenetic analysis of colonies from this patient showed BFU-E to be 45,XY,-7 or 47,XY,+8 and CFU-GM to be 45,XY,-7 or 47,XY,+8 or 46,XY. In patient 2, most BFU-E were 45,XY,-7, although a few were 46,XY. These data indicate that malignant change in this disease involves hemopoietic stem cells capable of erythroid and in at least some cases, myeloid differentiation.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 7 , Células-Tronco Hematopoéticas/patologia , Monossomia , Síndromes Mielodisplásicas/genética , Doença Aguda , Medula Óssea/patologia , Medula Óssea/fisiopatologia , Ensaio de Unidades Formadoras de Colônias , Células-Tronco Hematopoéticas/fisiopatologia , Humanos , Lactente , Cariotipagem , Leucemia/etiologia , Masculino , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/patologiaRESUMO
Tumor nodules composed of fibroblasts, large undifferentiated cells, granulocytes, and small lymphocytes develop in the spleens of adult DBA/2 mice infected with the myeloproliferative sarcoma virus (MPSV). They spread thereafter in the organism, and at the terminal stage of the disease they are especially numerous on the peritoneal membrane. The present study, performed on those tumor nodules to avoid contamination by exogenous hematopoietic cells, demonstrated that they were sites of granulopoiesis, which may have occurred via the local differentiation of granulomacrophage precursor cells (GM-CFC) and perhaps also from pluripotent hematopoietic stem cells, since these two populations were present in the tumor nodules (25 +/- 11 and 13 +/- 10, respectively, per 5-10(5) cells). Almost all (88%) those GM-CFC were able to clone in vitro without added colony-stimulating factor. A comparative study with the Moloney murine sarcoma virus-induced tumor indicated that the local production of hematopoiesis-stimulating factors was not sufficient to allow such ectopic granulopoiesis. These results imply the presence of a specific hematopoietic microenvironment in the MPSV-induced tumor nodules.
Assuntos
Células-Tronco Hematopoéticas/fisiopatologia , Transtornos Mieloproliferativos/fisiopatologia , Neoplasias Peritoneais/fisiopatologia , Infecções Tumorais por Vírus/fisiopatologia , Animais , Anticorpos Monoclonais , Divisão Celular , Ensaio de Unidades Formadoras de Colônias , Meios de Cultura , Fibroblastos/fisiopatologia , Hematopoese , Látex , Macrófagos/fisiopatologia , Camundongos , Camundongos Endogâmicos DBA , Microscopia Eletrônica , Vírus do Sarcoma Murino de Moloney , Células-Tronco Neoplásicas/fisiopatologia , FagocitoseRESUMO
To determine the quantitative effects of iron deficiency on erythropoiesis and to assess the response of erythroid progenitors to sustained anemia, we developed quantitative assays for various hematopoietic progenitors in the adult, Sprague-Dawley rat including erythroid colony- and burst-forming cells (CFU-E and BFU-E), granulocyte/macrophage colony-forming cells (CFU-GM), and megakaryocytic colony-forming cells (CFU-Meg). CFU-E were cultured in methylcellulose and grew best in the presence of fetal calf serum. CFU-GM, BFU-E, and CFU-Meg grew better in normal rat plasma and required the presence of pokeweed mitogen-stimulated rat spleen cell conditioned medium. The numbers of progenitors and nucleated erythroblasts in total marrow were estimated by the ratios of radioactivity in the humerus to the total skeleton as determined by radioiron dilution. The numbers of progenitors and erythroblasts in the spleen were measured by simple dilution. Sustained anemia was brought about through chronic iron deficiency. The response to iron deficiency anemia (IDA) was monitored by the numbers of the various progenitors and their cell cycle characteristics as measured by the tritiated thymidine suicide technique. With IDA, the number of CFU-F in the body (marrow plus spleen) was increased to 3.5 times control, whereas the numbers of BFU-E and CFU-GM were unchanged. There was no difference in the percentage of CFU-E, BFU-E, and CFU-GM in DNA synthesis (68%, 19.4%, and 18.8%, respectively). With iron therapy of IDA, CFU-E numbers in marrow began to decrease by day 1 and fell in a manner reciprocal to changes in the hematocrit. Marrow and spleen erythroblasts, 1.7 times control in IDA, increased further to 3.9 times control by the fourth day after iron administration. There was no change in BFU-E or CFU-GM numbers in response to iron repletion, although the fraction of progenitors increased in the spleen. Thus, IDA does not limit the increase in CFU-E seen with anemia, but does restrict erythroid maturation. Furthermore, the increase in CFU-E and the state of chronic anemia occur without detectable changes in the number of cell cycle state of the more primitive BFU-E.
Assuntos
Anemia Hipocrômica/fisiopatologia , Hematopoese , Células-Tronco Hematopoéticas/fisiopatologia , Animais , Transfusão de Sangue , Medula Óssea/patologia , Contagem de Células , Replicação do DNA , Eritroblastos/fisiopatologia , Eritropoese/efeitos dos fármacos , Transfusão Total , Hematopoese/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Ferro/administração & dosagem , Ferro/farmacologia , Masculino , Policitemia/etiologia , Policitemia/fisiopatologia , Ratos , Ratos Endogâmicos , Baço/patologiaRESUMO
An impaired erythropoietic response to anemia has been noted in human patients with malaria and in rodents experimentally infected with Plasmodium berghei. We have attempted to characterize the erythropoietic response in mice with a fatal P berghei infection, with particular emphasis on changes in marrow hematopoietic stem cells. Mice infected with P berghei had dramatic decreases in bone marrow cellularity, erythroblasts, BFU-E, and CFU-E as early as 24 hours postinfection and before there was any change in hematocrit. With development of anemia, marrows became erythropoietic with some expansion of the CFU-E compartment, but the BFU-E pool remained depleted and reticulocyte response was inadequate. There was no significant change in CFU-S from marrows of malaria-infected mice one day after infection. The lethality of malaria infection may take three weeks to be revealed, but it may be determined within hours of the infection by the irreparable changes in marrow erythroid stem cells.
Assuntos
Células-Tronco Hematopoéticas/fisiopatologia , Malária/sangue , Animais , Células da Medula Óssea , Eritropoese , Eritropoetina/sangue , Feminino , Hematócrito , Camundongos , Camundongos Endogâmicos C57BL , Plasmodium berghei , Reticulócitos , Baço/citologiaRESUMO
Aplastic anemia is a disorder characterized by marrow aplasia and pancytopenia. The pathogenetic mechanisms that lead to bone marrow aplasia have been intensively studied. Data obtained from these studies suggest that aplastic anemia is a heterogeneous disorder with regards to pathogenesis. Bone marrow aplasia may result from a number of abnormalities including qualitative or quantitative abnormalities of hematopoietic stem cells, abnormal interaction between bone marrow accessory cells (lymphocytes and macrophages) and hematopoietic stem cells, cytotoxic humoral inhibitors of hematopoiesis, and abnormalities of the bone marrow microenvironment. A number of new therapeutic options have improved the survival of patients with aplastic anemia. Allogeneic bone marrow transplantation has actually resulted in the cure of patients. Unfortunately, only a minority of patients have a suitable bone marrow donor and alternate modes of therapy have been sought. Encouraging results have been reported from several centers concerning the use of antilymphocyte serum in patients with aplastic anemia. Certainty of the ultimate long-term benefit of this type of immunosuppressive therapy is not possible until careful, randomized, prospective studies of its use are completed.
Assuntos
Anemia Aplástica/etiologia , Fatores Etários , Anemia Aplástica/epidemiologia , Anemia Aplástica/patologia , Anemia Aplástica/fisiopatologia , Doenças Autoimunes/complicações , Medula Óssea/fisiopatologia , Comunicação Celular , Diferenciação Celular , Meio Ambiente , Eritropoese , Regulação da Expressão Gênica , Genes Reguladores , Hematopoese , Células-Tronco Hematopoéticas/fisiopatologia , Humanos , Infecções/complicaçõesAssuntos
Granulócitos/fisiologia , Células-Tronco Hematopoéticas/fisiopatologia , Lactoferrina/deficiência , Lactoglobulinas/deficiência , Leucemia Linfoide/fisiopatologia , Leucemia Mieloide Aguda/fisiopatologia , Peroxidase/deficiência , Peroxidases/deficiência , Criança , Humanos , Lactoferrina/sangue , Peroxidase/sangue , Valores de ReferênciaRESUMO
Bone marrow derived mononuclear phagocytes (BMDMP) differentiated in vitro from bone marrows of YAC-lymphoma bearing mice and Corynebacterium parvum (CP)-inflamed mice shown to differ in several functional parameters from those derived from bone marrows of control mice. The former 2 BMDMP populations expressed: (a) an increased level of acid phosphatase activity; (b) an increased degree of zymosan-induced chemiluminescence reaction; (c) a lower sensitivity of the proliferative capacity to prostaglandin E2 (PGE2), as compared to the BMDMP population from normal mice. These data suggest that YAC-lymphoma bearing in A/J mice induces similarly to inflammatory stimuli changes in the functional capacity of bone marrow mononuclear phagocyte precursor cells.
Assuntos
Hematopoese , Células-Tronco Hematopoéticas/fisiopatologia , Linfoma/fisiopatologia , Fagócitos/fisiologia , Fosfatase Ácida/metabolismo , Animais , Divisão Celular/efeitos dos fármacos , Dinoprostona , Hematopoese/efeitos dos fármacos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Inflamação/fisiopatologia , Medições Luminescentes , Masculino , Camundongos , Camundongos Endogâmicos , Neoplasias Experimentais/fisiopatologia , Fagócitos/efeitos dos fármacos , Fagócitos/enzimologia , Propionibacterium acnes , Prostaglandinas E/farmacologia , Zimosan/farmacologiaRESUMO
We studied myeloid progenitor cells (CFUc) from peripheral blood mononuclear leukocytes (MNL) of normals and patients with severe aplastic anaemia (AA). Baseline CFUc averaged 4.4 +/- 1.5 (range 0--17)/10(6) MNL in fifteen normals and 0 +/- 1/10(6) MNL in six patients with severe AA (P less than 0.05). To assess CFUc proliferative capacity, 10(7) MNL were put into liquid culture in Marbrook chambers with colony-stimulating activity and sub-cultured in agar at intervals up to 10 days. CFUc from normal MNL increased from 44 +/- 15/chamber at Day 0 to 156 +/- 33/chamber at peak value (P less than 0.02). In contrast, CFUc from AA MNL remained undetectable throughout the period of liquid culture (AA peak v. normal peak; P less than 0.001). These results indicate a marked decrease in circulating CFUc in patients with severe AA, and a profound abnormality in CFUc proliferation in vitro. This abnormality could be due to defective replication of CFUc, a lack of feed-in from more primitive precursors, or both.
Assuntos
Anemia Aplástica/sangue , Células-Tronco Hematopoéticas/fisiopatologia , Monócitos/fisiopatologia , Adulto , Divisão Celular , Células Cultivadas , HumanosRESUMO
A quantitative assessment was made of the myogenic capability in vitro of muscle cells from dystrophic (129 Rej dy/dy) and normal mice from birth to 5 months old. Seeding efficiency was increased in dystrophic cells from neonatal and 1-week-old mice compared to age-matched controls. The extent of myogenesis in cultures from neonatal and 1-week-old dystrophic mice did not differ from controls. Muscle colony formation in cultures established from 5-month-old dystrophic mice was reduced by 80% compared with normal cultures. Normal and dystrophic cultures established from 5-month-old mice contained equal numbers of fibroblast colonies. The results suggest that decreased myogenesis in cultures from 5-month-old dystrophic mice is due to a relative absence of myogenic cells rather than a numerical dilution of the cultures by fibroblasts. This may be due to population of nonviable satellite cells or to necrosis of dystrophic myotubes in vitro.
Assuntos
Envelhecimento , Músculos/fisiologia , Distrofia Muscular Animal/fisiopatologia , Regeneração , Animais , Divisão Celular , Sobrevivência Celular , Células Cultivadas , Extremidades/anatomia & histologia , Fibroblastos/fisiopatologia , Crescimento , Células-Tronco Hematopoéticas/fisiopatologia , Camundongos , Músculos/patologiaAssuntos
Células-Tronco Hematopoéticas/fisiologia , Anemia Aplástica/fisiopatologia , Anemia Aplástica/cirurgia , Animais , Medula Óssea/fisiologia , Transplante de Medula Óssea , Transformação Celular Neoplásica/patologia , Fatores Estimuladores de Colônias , Feminino , Células-Tronco Hematopoéticas/fisiopatologia , Humanos , Técnicas In Vitro , Leucemia Mieloide/fisiopatologia , Leucemia Mieloide/cirurgia , Camundongos , Baço/fisiologiaAssuntos
Transplante de Medula Óssea , Animais , Ensaios Clínicos como Assunto , Ensaio de Unidades Formadoras de Colônias , Hematopoese , Células-Tronco Hematopoéticas/fisiologia , Células-Tronco Hematopoéticas/fisiopatologia , Humanos , Leucemia Linfoide/cirurgia , Leucemia Mieloide/cirurgia , Linfoma/cirurgia , Camundongos , Baço/fisiologiaAssuntos
Anemia Aplástica/complicações , Hepatite B/complicações , Adulto , Medula Óssea/fisiopatologia , Feminino , Células-Tronco Hematopoéticas/fisiopatologia , Hepatite B/imunologia , Antígenos de Superfície da Hepatite B/análise , Vírus da Hepatite B/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
Prompted by previous reports that in certain patients with aplastic anemia, cell-mediated autoimmune suppression of myeloid stem cell proliferation may be demonstrable in vitro, we studied the effects of bone marrow lymphocytes from 18 patients with myeloid aplasia on the proliferation of committed granulocytic-monocytic progenitor cells (CFU-C). When assayed in soft agar cultures, marrow suspensions from 10 patients with aplastic anemia contained significantly fewer viable CFU-C than similar cell preparations from control subjects. To deplete marrow cell suspensions of lymphocytes, we employed rabbit anti-human thymocyte serum (ATS), which after multiple adsorptions exhibited marked cytotoxicity for human B and T lymphocytes but had negligible effect on normal CFU-C proliferation. Preincubation of marrow samples from 12 patients with ATS and complement resulted in no inhibition or enhancement of CFU-C growth. In further experiments, marrow cells from 8 patients were incubated with marrow from control subjects prior to CFU-C culture. No suppression of donor CFU-C proliferation was observed in any of these studies, and in 4 cocultures, mixture of the 2 marrow suspensions resulted in stimulation of CFU-C growth. Using these assays, we detected no evidence of cell-mediated inhibition of CFU-C proliferation in any of the 18 patients that we evaluated. Our data support the conclusion that in the majority of patients with aplastic anemia, an absolute deficiency of hemopoietic stem cells is present within the marrow that does not appear to be effected or sustained by suppressor lymphocytes. Whether the reduction of viable stem cells is the cause or the consequence of the process that leads to marrow failure remains unknown.