RESUMO
A model of post-diagnosis chronic myeloid leukemia (CML) dynamics across treatment cessations is applied here to pre-diagnosis scenarios of A-bomb survivors. The main result is that perturbing two parameters of a two-state simplification of this model captures the essence of two A-bomb survivor mysteries: (1) in those exposed to > 1 Sv in Hiroshima, four of six female onsets arose as a cluster in 1969-1974, well after 5-10-year latencies expected and observed in two of six female- and nine of ten male cases (about one background case was expected in this high-dose cohort); and (2) no Nagasaki adult cases exposed to > 0.2 Sv were observed though about nine were expected (~ 1.5 background + ~ 7.5 radiation-induced). Overall, it is concluded that: (1) whole-body radiation co-creates malignant and benign BCR-ABL clones; (2) benign clones are more likely to act as anti-CML vaccines in females than in males; (3) the Hong Kong flu of 1968 (and H3N2 seasonal flu thereafter) exhausted anti-CML immunity, thereby releasing radiation-induced clones latent in high-dose Hiroshima females; and (4) benign cells of 1-2 are CD4+ as human T-cell leukemia-lymphoma virus-1 endemic to Nagasaki but not Hiroshima expands numbers of such cells. The next goal is to see if these conclusions can be substantiated using banked A-bomb survivor blood samples.
Assuntos
Sobreviventes de Bombas Atômicas , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Induzida por Radiação/diagnóstico , Modelos Biológicos , Linfócitos T CD4-Positivos/imunologia , Feminino , Humanos , Vírus da Influenza A Subtipo H3N2 , Influenza Humana/imunologia , Japão/epidemiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Leucemia Induzida por Radiação/imunologia , Masculino , Células-Tronco Neoplásicas/imunologiaRESUMO
Adult C57BL/6 mice exposed to fractionated irradiation or inoculated with the radiation leukemia virus (RadLV), develop high incidence (80-100%) of lymphatic leukemias within 3-6 mo. RadLV-induced lymphomas can elicit cytotoxic responses in vitro in lymphocytes of preimmunized syngeneic mice, a reaction that is dependent on the expression of membrane-associated viral antigenicity. As soon as 5 d after RadLV inoculation, and during the entire leukemogenic process, suppressor T cells are detectable in the spleen that are capable of specifically abrogating generation of syngeneic anti-tumor cytotoxic cells in vitro. Mice exposed to fractionated x irradiation do not develop suppressor cells and their splenocytes may be stimulated in vitro to generate cytotoxicity toward RadLV-induced leukemias. These findings suggest that although RadLV has been isolated from radiation-induced leukemias, x-ray- and RadLV-induced leukemogenesis do not seem to involve a common viral etiology, and that induction of suppressor cells during RadLV leukemogenesis may be essential for tumor progression.
Assuntos
Citotoxicidade Imunológica , Tolerância Imunológica , Leucemia Experimental/imunologia , Leucemia Induzida por Radiação/imunologia , Linfócitos T/imunologia , Animais , Relação Dose-Resposta à Radiação , Feminino , Vírus da Leucemia Murina/imunologia , Linfoma/imunologia , Camundongos , Linfócitos T Reguladores/imunologiaRESUMO
BALB/c radiation leukemia RL male 1 is an immunogenic tumor. We established bulk and cloned cytotoxic T lymphocyte (CTL) lines from regressor (BALB/c x C57BL/6)F1 (CB6F1) spleen cells that recognized RL male 1 specifically. We then obtained antigen peptide recognized by CTL from RL male 1 by acid extraction. Analysis of the acid extract by reversed-phase high performance liquid chromatography (HPLC) on a semipreparative C18 column revealed that fractions eluted in 23 min (peak a) and 26 min (peak b) showed sensitization activity on the P815 target for specific CTL. On further purification of these fractions by HPLC and direct sequencing by Edman degradation, we identified the CTL-recognizing RL male 1 peptide pRL1a (IPGLPLSL) in peak a and its possible precursor peptide pRL1b (SIIPGLPLSL) in peak b. Sequence homology indicated that these peptides were derived from the 5' untranslated region of c-akt oncogene.
Assuntos
Antígenos de Neoplasias/análise , Leucemia Induzida por Radiação/imunologia , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas/genética , Proto-Oncogenes , Linfócitos T Citotóxicos/imunologia , Sequência de Aminoácidos , Animais , Antígenos de Neoplasias/genética , Cromatografia Líquida de Alta Pressão , Citotoxicidade Imunológica , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Dados de Sequência Molecular , Proteínas Proto-Oncogênicas c-aktRESUMO
Anomalous appearance of TL (thymus-leukemia) antigens is a characteristic feature of radiation-induced leukemias of C57bl/6 mice. We now report that thymocytes of irradiated C57BL/6 mice express TL antigens long before the development of overt leukemia. Thus, TL is a marker for preleukemic changes occurring during radiation leukemogenesis. Low levels of murine leukemia virus (MuLV)-related antigens are also detected on preleukemic thymocytes. Comparative tests on individual mice show no direct correlation between TL and MuLV antigen expression.
Assuntos
Antígenos de Neoplasias/análise , Leucemia Induzida por Radiação/imunologia , Neoplasias do Timo/imunologia , Animais , Antígenos Virais/análise , Soro Antilinfocitário/análise , Antígenos de Histocompatibilidade/análise , Vírus da Leucemia Murina/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T/imunologiaRESUMO
Resistance to neoplasia caused by radiation-induced leukemia virus (RadLV) is mediated by gene(s) in the H-2D region of the major histocompatibility complex. The previous observation that rapid increases in cellular synthesis and cell-surface expression of H-2 antigens are detectable immediately after virus inoculation has suggested that altered expression of H-2 antigens may play a significant role in the mechanism(s) of host defense to virus infection. This concept is supported by the following observations. First, cell-mediated immunity against RadLV transformed or infected cells can be detected with ease when H-2-positive target cells are used in the cell-mediated lympholysis (CML) assay. (Although RadLV transformed cells obtained from overtly leukemic animals and maintained in tissue culture are H-2 negative, these cells can regain their H-2 phenotype by in vivo passage in normal animals. The H-2-negative cells are poor targets in a CML assay.) Second, resistant mice develop greater numbers of effectors when infected with RadLV than do susceptible mice. Third, injection of normal (uninfected) thymocytes into syngeneic recipients of resistant or susceptible H-2 type does not stimulate a CML response. However, injection of RadLV infected thymocytes from resistant mice produces a vigorous CMI response, and such thymocytes elicit the strongest response at a time when both H-2 and viral antigen expression is elevated. By contrast, injection of infected thymocytes from susceptible mice, which express viral antigens, but low levels of H-2 antigens, does not stimulate a CML reaction. These findings may explain the easier induction of leukemia found by many investigators when virus is inoculated into neonatal mice and the preferential thymus tropism of some oncogenic type-C RNA virus. Cells expressing very low levels of H-2, such as thymocytes, may serve as permissive targets for virus infection because they lack an important component (H-2 antigens) of the dual or altered recognition signal required to trigger a defensive host immune response.
Assuntos
Antígenos H-2 , Células Matadoras Naturais/imunologia , Vírus da Leucemia Murina/imunologia , Leucemia Experimental/imunologia , Animais , Citotoxicidade Imunológica , Antígenos H-2/genética , Imunidade Inata , Leucemia Experimental/genética , Leucemia Experimental/microbiologia , Leucemia Induzida por Radiação/imunologia , Camundongos , Baço/imunologia , Linfócitos T/imunologia , Linfócitos T/microbiologiaRESUMO
The humoral immune response against endogenous ecotropic murine leukemia viruses (MuLV) was examined in irradiated and control C57BL/6 mice. Control mice developed antibodies against MuLV slowly throughout life. In contrast, within 2-3 mo after irradiation 90% of irradiated C57BL/6 mice had developed detectable antibodies against MuLV. The characteristics of this immune response, however, were identical in control and irradiated mice in terms of peak titers, specificity for endogenous ecotropic MuLV, and reactivity against the ecotropic viruses' glycoprotein (gp71). Moreover, the rate of appearance of antibodies against MuLV in irradiated mice and the peak titers were generally not affected by age at irradiation, dose of irradiation (two, three, or four treatments of 175 R), or bone marrow reconstitution. Although the ability of irradiation to accelerate the appearance of antibody in a population of C57BL/6 mice suggested activation of endogenous ecotropic MuLV, there was no apparent correlation between the appearance of this immune response or its persistence and the development of lymphoma. Thus, the incidence of lymphoma was comparable in mice that: (a) developed no immune response; (b) developed an immune response only transiently after irradiation; or (c) developed an immune response which persisted until death from lymphoma. Moreover, experimental conditions that alter the ability of irradiation to induce leukemia, such as age, dose, or bone marrow reconstitution did so without significantly altering either the rate of appearance of a humoral immune response to MuLV or its peak titers. The results, therefore, fail to demonstrate any seroepidemological relationship between endogenous ecotropic MuLV and radiation-induced leukemia.
Assuntos
Anticorpos Antivirais/biossíntese , Formação de Anticorpos/efeitos da radiação , Vírus da Leucemia Murina , Leucemia Induzida por Radiação , Linfoma/etiologia , Camundongos Endogâmicos C57BL/microbiologia , Vírus AKR da Leucemia Murina/imunologia , Fatores Etários , Animais , Epitopos , Vírus da Leucemia Murina de Friend/imunologia , Vírus da Leucemia Murina/imunologia , Leucemia Induzida por Radiação/etiologia , Leucemia Induzida por Radiação/imunologia , Camundongos , Camundongos Endogâmicos C57BL/imunologia , Timoma/etiologia , Neoplasias do Timo/etiologiaRESUMO
Thymus leukemia (TL) alloantigenic activity was solubilized by papain proteolytic digestion from intact RADA1 tumor cells. If the cells were labeled with amino acids and fucose, the TL alloantigen could be isolated as a doubly labeled glycoprotein fragment by indirect precipitation from the papain digest. This TL glycoprotein fragment was approximately the same mol wt as the papain-digested H-2.4 alloantigen fragment as judged by chromatography on Sephadex G-150 in sodium dodecyl sulfate. The carbohydrate chain of the TL glycoprotein obtained by exhaustive pronase digestion behaved as a glycopeptide of approximately 4,500 mol wt, as compared with the glycopeptide of the H-2.4 alloantigen that had a mol wt of about 3,500. Thus, the TL alloantigen can be solubilized by papain digestion as a glycoprotein fragment similar in mol wt to the H-2 alloantigen glycoprotein fragment. The carbohydrate chain of the TL glycoprotein is larger than the H-2 carbohydrate chain.
Assuntos
Antígenos de Neoplasias/análise , Leucemia Experimental/imunologia , Papaína/farmacologia , Timo/imunologia , Aminoácidos , Animais , Anticorpos Anti-Idiotípicos , Complexo Antígeno-Anticorpo , Antígenos de Neoplasias/isolamento & purificação , Isótopos de Carbono , Membrana Celular/imunologia , Cromatografia em Gel , Meios de Cultura , Testes Imunológicos de Citotoxicidade , Fucose , Glicopeptídeos/análise , Glicoproteínas/análise , Soros Imunes , Isoantígenos/análise , Isoantígenos/isolamento & purificação , Marcação por Isótopo , Leucemia Induzida por Radiação/imunologia , Camundongos , Peso Molecular , Solubilidade , TrítioRESUMO
The generation of an in vitro major histocompatibility complex class I specific response of CD4-CD8- T cell receptor (TCR) alpha beta cytotoxic T lymphocytes (CTL) and their allogeneic tumor rejection were investigated. Inocula of BALBRL male 1 were rejected in C57BL/6 (B6) mice treated with minimum essential medium (MEM) (control), anti-L3T4 (CD4) monoclonal antibody (mAb) or anti-Lyt-2.2 (CD8) mAb and CTL against the tumor were generated in vitro. No rejection and no induction of CTL were observed in B6 mice treated with anti-L3T4 (CD4) plus anti-Lyt-2.2 (CD8) mAb. CTL with the classical Thy-1+ CD3+CD4-CD8+ TCR alpha beta phenotype were generated in mixed lymphocyte tumor cell culture (MLTC) spleen cells from B6 mice treated with MEM (control) or anti-L3T4 (CD4) mAb, whereas CTL with an unusual Thy-1+CD3+CD4-CD8- TCR alpha beta phenotype were generated in MLTC spleen cells from anti-Lyt-2.2 (CD8) mAb-treated B6 mice. Both types of CTL were reactive with both H-2Kd and Dd (Ld) class I antigen. These findings suggest that when CD4+ cells were blocked by anti-L3T4 (CD4) mAb, CD8+ CTL mediated rejection, and when CD8+ cells were blocked by anti-Lyt-2.2 (CD8) mAb, CD4+ cells were capable of mediating rejection, although less efficiently than CD8+ cells, by inducing CD4-CD8- TCR alpha beta CTL. The finding that adoptive transfer of CD4 and CD8-depleted MLTC spleen cells, obtained from anti-Lyt-2.2 (CD8) mAb-treated B6 mice that had rejected BALBRL male 1, resulted in rejection of BALBRL male 1 inoculated into B6 nu/nu mice confirmed the above notion. CTL clones with the CD4-CD8- TCR alpha beta phenotype specific for Ld were established.
Assuntos
Antígenos de Diferenciação de Linfócitos T/imunologia , Antígenos CD4/imunologia , Genes MHC Classe I , Rejeição de Enxerto , Leucemia Experimental/imunologia , Leucemia Induzida por Radiação/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Anticorpos Monoclonais , Northern Blotting , Antígenos CD8 , Antígenos de Histocompatibilidade Classe I/análise , Imunoterapia Adotiva , Camundongos , Camundongos Endogâmicos , Transplante de Neoplasias , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/isolamento & purificação , Baço/imunologiaRESUMO
Antigenic modulation (the loss of TL antigens from TL+ cells exposed to TL antibody in the absence of lytic complement) has been demonstrated in vitro. An ascites leukemia, phenotype TL.1,2,3, which modulates rapidly and completely when incubated with TL antiserum in vitro, was selected for further study of the phenomenon. Over a wide range of TL antibody concentrations modulation at 37 degrees C was detectable within 10 min and was complete within approximately 1 hr. The cells were initially sensitized to C' by their contact with antibody, thereafter losing this sensitivity to C' lysis together with their sensitivity to TL antibody and C' in the cytotoxic test. The capacity of the cells to undergo modulation was abolished by actinomycin D and by iodoacetamide, and by reducing the temperature of incubation to 0 degrees C. Thus modulation apparently is an active cellular process. Antigens TL. 1,2, and 3 are all modulated by anti-TL.1,3 serum and by anti-TL.3 serum. This modulation affects all three TL components together, even when antibody to one or two of them is lacking. aAnti-TL.2 serum does not induce modulation and in fact impairs modulation by the other TL antibodies. The influence of the TL phenotype of cells upon the demonstrable content of H-2 (D region) isoantigen, first shown in cells modulated in vivo, has been observed with cells modulated in vitro. Cells undergoing modulation show a progressive increase in H-2 (D region) antigen over a period of 4 hr, with no change in H-2 antigens of the K region. Restoration of the TL+ phenotype of modulated cells after removal of antibody is less rapid than TL+ --> TL- modulation and may require several cell divisions.
Assuntos
Reações Antígeno-Anticorpo , Antígenos , Leucemia Experimental/imunologia , Timo/imunologia , Amidas/farmacologia , Animais , Reações Antígeno-Anticorpo/efeitos dos fármacos , Dactinomicina/farmacologia , Soros Imunes , Técnicas In Vitro , Isoantígenos/fisiologia , Leucemia Induzida por Radiação/imunologia , Camundongos , Transplante de Neoplasias , Ácidos Nucleicos/biossíntese , Fenótipo , Biossíntese de Proteínas , Temperatura , Timidina/metabolismo , Trítio , Uridina/metabolismo , Valina/metabolismoRESUMO
The review summarizes and analyzes the data of world scientific literature and the results of the own research con- cerning one of the main non-targeted effects of ionizing radiation - the radiation induced bystander effect (RIBE) - the ability of irradiated target cells to induce secondary biological changes in non-irradiated receptor cells. The his- tory of studies of this phenomenon is presented - it described under various names since 1905, began to study from the end of the twentieth century when named as RIBE and caused particular interest in the scientific community during recent decades. It is shown that the development of biological science and the improvement of research methods allowed to get new in-depth data on the development of RIBE not only at the level of the whole organism, but even at the genome level. The review highlights the key points of numerous RIBE investigations including mod- eling; methodological approaches to studying; classification; features of interaction between irradiated and intact cells; the role of the immune system, oxidative stress, cytogenetic disorders, changes in gene expression in the mechanism of development of RIBE; rescue effect, abscopal effect, persistence, modification, medical effects. It is emphasized that despite the considerable amount of research concerning the bystander response as the universal phenomenon and RIBE as one of its manifestations, there are still enough «white spots¼ in determining the mech- anisms of the RIBE formation and assessing the possible consequences of its development for human health.
Assuntos
Efeito Espectador/efeitos da radiação , Leucemia Induzida por Radiação/patologia , Modelos Biológicos , Neoplasias Induzidas por Radiação/patologia , Radiação Ionizante , Animais , Apoptose/imunologia , Apoptose/efeitos da radiação , Efeito Espectador/genética , Efeito Espectador/imunologia , Citocinas/biossíntese , Instabilidade Genômica/imunologia , Instabilidade Genômica/efeitos da radiação , Humanos , Leucemia Induzida por Radiação/genética , Leucemia Induzida por Radiação/imunologia , Neoplasias Induzidas por Radiação/genética , Neoplasias Induzidas por Radiação/imunologiaRESUMO
We have previously shown that the RLakt antigen was predominantly recognized by CD8 cytotoxic T lymphocytes (CTL) in RL male 1-bearing or -rejected syngeneic BALB/c mice. CD8 CTL were directed to the octamer pRL1a peptide IPGLPLSL of which recognition was H-2L(d)-restricted. In this study, we identified a CD4 T-cell epitope peptide in the tumor rejection antigen RLakt on BALB/c radiation-leukemia RL male 1. Analyses of the recognition of a bulk CD4 T-cell line using several recombinant RLakt proteins suggested the presence of multiple CD4 T-cell epitopes in the molecule. However, cloning from a bulk CD4 T-cell line resulted in only two clones from 200 wells seeded at three cells per well, and those two CD4 T-cell clones recognized the same epitope peptide in RLakt. The epitope peptide was 14-mer p12-25, AYREETLSIIPGLP, and its recognition was H-2IA(d)-restricted. This sequence overlapped with the CD8 T-cell epitope pRL1a in its N-terminal 5 amino acid residues. The relationship of the epitope to the pRL1a peptide predominantly recognized by CD8 CTL suggests that the 14-mer epitope is predominantly recognized by CD4 T-cells.
Assuntos
Antígenos de Neoplasias/imunologia , Linfócitos T CD4-Positivos/imunologia , Epitopos de Linfócito T , Leucemia Induzida por Radiação/imunologia , Animais , Linhagem Celular , Feminino , Antígenos de Histocompatibilidade Classe II/imunologia , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Linfócitos T Reguladores/imunologiaRESUMO
Acute leukaemia is a consequence of malignant transformation of a haematopoetic progenitor cell. Molecular studies have revealed a prenatal origin of many childhood leukaemias. According to current models, a preleukaemic stem cell clone is generated by a first mutation in utero which, in a minority of children, progresses to leukaemia after receiving further postnatal genetic hits. The nature of pre- and postnatal events involved in leukaemogenesis in children is not well understood. Although genetic predisposition and specific environmental exposures may account for individual cases, the bulk of childhood leukaemia cannot be explained by any of these factors. The higher incidence of the most common leukaemia subtype in affluent societies, as well as the age peak between 2-5 y, suggest a contributory role of socioeconomic factors. An abnormal immune response during delayed exposure to common infections provides a plausible mechanism for malignant progression of preleukaemic clones in a subgroup of children. As highlighted in this review, a common cause for all types and subtypes of childhood leukaemia is highly unlikely. Deeper insights into the pathogenesis of childhood leukaemia will rely on large-scale and combined epidemiological and biomolecular studies.
Assuntos
Surtos de Doenças/estatística & dados numéricos , Leucemia/epidemiologia , Leucemia/imunologia , Modelos Biológicos , Medição de Risco , Adolescente , Causalidade , Criança , Pré-Escolar , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Incidência , Lactente , Recém-Nascido , Leucemia Induzida por Radiação/epidemiologia , Leucemia Induzida por Radiação/imunologia , Masculino , Fatores de Risco , Fatores SocioeconômicosRESUMO
Spleen cells from untreated young male and female C57BL/6 and C58 mice and of male C3H/He mice showed cytotoxic activity in vitro against BALB/c X-radiation-induced leukemia RL male 1 cells by 51Cr-releasing lymphocyte-mediated cytoxicity (LMC) tests, but old mice of these strains lacked LMC activity. In contrast, spleen cells from male and female AKR, BALB/c, and DBA/2 mice, and from female C3H/He mice had no appreciable LMC activity. The proportion of active cells in spleens from young (C57BL/6 times BALB/c)F1 or reciprocal hybrid mice was higher in females than in males. The specificity of the LMC reaction of RL male 1 cells, determined by LMC inhibition assays, was somewhat different from that of previously reported serologic X.1 tests. Thus the antigen detected by LMC has been tentatively designated X.1'. The main effector cells in this system were uncharacterized cells not adherent to glass surfaces or nylon-wool columns. These findings in RL male 1 leukemia extend the evidence for the presence of naturally occurring LMC. With the single unexplained exception of strain C3H/He, the LMC activity against RL male 1 cells, exhibited by untreated mice of various strains, corresponded with a previous classification of mouse strains immunologically as X.1 responders or as X.1 nonresponders according to their ability to reject X.1-positive leukemia cells.
Assuntos
Leucemia Experimental/imunologia , Fatores Etários , Animais , Testes Imunológicos de Citotoxicidade , Rejeição de Enxerto , Técnicas In Vitro , Leucemia Induzida por Radiação/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Fatores Sexuais , Baço/citologiaRESUMO
Two T-cell lines (XR11-4T and XR11-5T), established from radiation-induced, murine lymphoblastic lymphomas, were examined for the expression of class I major histocompatibility complex antigen and tumor induction. These cell lines expressed class I private determinants, H-2.9 and H-2.26, but not the monomorphic determinant defined by monoclonal antibody M1/42. Both cell lines produced tumors in syngeneic and allogeneic hosts. The monomorphic determinant could be demonstrated on both cell lines following growth in allogeneic (BALB/c mice) but not in syngeneic (RFM mice) hosts. The re-expressed determinant present on cells following growth in allogeneic mice was not of host origin. Thus, tumorigenic x irradiation may differentially affect the expression of class I major histocompatibility complex determinants.
Assuntos
Epitopos/imunologia , Genes MHC Classe I/imunologia , Leucemia Linfoide/imunologia , Leucemia Induzida por Radiação/imunologia , Linfoma não Hodgkin/imunologia , Animais , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos , Transplante de Neoplasias , Imunologia de Transplantes , Células Tumorais Cultivadas/imunologiaRESUMO
The relationship of the leukemogenic and natural killer (NK)-suppressive effects of fractionated doses of gamma-radiation in mice was studied. A/J mice were relatively resistant; CBA/J, BALB/c, and C57BL/6 were susceptible to both the NK-suppressive and leukemogenic effects, and young (1 mo old) C57BL/6 mice were more susceptible than were 2- and 3-month-old C57BL/6 mice to both effects. Age-dependent susceptibility to radiation-induced leukemogenesis also was observed in C57BL/6 (bg/bg) (beige) mice. No differences in incidence and latent period of lymphoma development were found between C57BL/6 (+/+) and beige mice. Bone marrow cells (BMC) from normal C57BL/6 donors reconstituted the NK reactivity of irradiated C57BL/6 (+/+) or beige recipients and inhibited leukemogenesis. Although BMC of beige donors did not reconstitute the NK reactivity of irradiated C57BL/6 (+/+) or beige recipients, these cells were as efficient for antileukemic protection as were BMC from C57BL/6 (+/+) mice. The bone marrow of irradiated mice contained preleukemia cells that produced leukemias when transplanted iv into recipients preirradiated with 400 R. Inoculation (iv) of spleen cells (SpC) from syngeneic nude mice plus preleukemia bone marrow cells (PBMC) were able to inhibit leukemia formation in the 400 R-irradiated recipients. SpC from beige mice, normal C57BL/6 (+/+) mice, or C57BL/6 (+/+) mice treated with anti-asialo GM1 serum had no influence on the development of leukemia after their transplantation with PBMC.
Assuntos
Células Matadoras Naturais/imunologia , Leucemia Induzida por Radiação/etiologia , Envelhecimento/efeitos da radiação , Animais , Medula Óssea/efeitos da radiação , Transplante de Medula Óssea , Suscetibilidade a Doenças , Relação Dose-Resposta à Radiação , Feminino , Raios gama , Células Matadoras Naturais/efeitos da radiação , Leucemia Induzida por Radiação/imunologia , Camundongos , Camundongos Endogâmicos A , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Baço/efeitos da radiação , Baço/transplante , Irradiação Corporal TotalRESUMO
Most X-irradiation-induced thymomas in C57BL/6 mice are virus-free when assayed by immunofluorescence for the gs antigen (gsa) of murine leukemia virus (MuLV). Virus was induced transiently in bone marrow cells and later appeared in thymus cells. Six to 7 weeks post irradiation, thymocytes and bone marrow cells were MuLV gsa-negative and remained negative for the lifetime of most animals, whether or not they contracted overt leukemia. During the period when MuLV gsa-positive bone marrow cells were found, XC-positive syncytia-producing bone marrow cells were also found. Virus information was expressed, therefore, for a limited duration, long before any signs of leukemia in the animals were evident. MuLV gsa-positive thymocytes taken from mice 4 weeks after X-irradiation were cocultivated with a series of indicator cells. B-tropic virus, in addition to a xenotropic virus, was isolated from these cells. Ecotropic virus was not found in normal mouse thymocytes, in irradiated thymocytes a few days after termination of the X-irradiation sequence, or in most primary thymomas. All thymocytes produced only xenotropic virus in the cocultivation assays. Expression of the ecotropic virus was, therefore, transient, as assayed by immunofluorescence, XC syncytia formation, and virus isolation from MuLV gsa-positive thymus cells.
Assuntos
Vírus da Leucemia Murina/isolamento & purificação , Leucemia Induzida por Radiação/microbiologia , Animais , Antígenos Virais , Medula Óssea/imunologia , Medula Óssea/microbiologia , Células da Medula Óssea , Membrana Celular/imunologia , Feminino , Vírus da Leucemia Murina/imunologia , Vírus da Leucemia Murina/efeitos da radiação , Leucemia Experimental/imunologia , Leucemia Experimental/microbiologia , Leucemia Induzida por Radiação/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T/imunologia , Linfócitos T/microbiologia , Fatores de Tempo , Replicação Viral/efeitos da radiação , Raios XRESUMO
The effect of thiabendazole (TBZ) and dinitrofluorobenzene (DNFB) on radiation-induced leukemogenesis was investigated in the C57BL/6 mouse model. Administration of TBZ-DNFB during, post, or during and post irradiation successfully blocked leukemogenesis, as indicated by the absence of leukemia blast cells in thymus and peripheral blood, as well as prevented thymic lymphoma. TBZ-DNFB treatment prevented the development of leukemia when studies were terminated both after 7 months of last irradiation (disease fully developed) and after 5 months of last irradiation (disease in the process of development). This TBZ-DNFB treatment also resulted in a significant increase in survival.
Assuntos
Dinitrofluorbenzeno/administração & dosagem , Leucemia Induzida por Radiação/induzido quimicamente , Nitrobenzenos/administração & dosagem , Tiabendazol/administração & dosagem , Animais , Dinitrofluorbenzeno/uso terapêutico , Quimioterapia Combinada , Raios gama , Imunoterapia , Leucemia Induzida por Radiação/imunologia , Leucemia Induzida por Radiação/prevenção & controle , Longevidade/efeitos dos fármacos , Linfoma/etiologia , Linfoma/imunologia , Linfoma/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Linfócitos T/efeitos da radiação , Tiabendazol/uso terapêutico , Timo/efeitos dos fármacosRESUMO
The lymphoblastic leukemia ERLD, induced by radiation in a C57BL/6 mouse, was established in culture. Three cell lines, ERLD/Y3, ERLD/T ERLD/Two, have been in culture for nearly three years. Their isolation and growth depended upon the presence of 2-mercaptoethanol, glutamine, and asparagine in the medium. The cell lines, except ERLD/T, possess the TL antigen, a characteristic of ERLD and of other murine leukemia cells in vivo and of normal thymus cells of certain mouse strains, but not of C57BL/6. A distinctive submetacentric marker chromosome is also common to ERLD and the derived cell lines. The successful establishment of ERLD in culture provides a malignant thymocyte-related cell system for studies in nutrition and immunobiology.
Assuntos
Linhagem Celular , Leucemia Linfoide , Leucemia Induzida por Radiação , Animais , Antígenos de Neoplasias , Asparagina , Aberrações Cromossômicas , Meios de Cultura , Glutamina , Leucemia Experimental/genética , Leucemia Experimental/imunologia , Leucemia Linfoide/genética , Leucemia Linfoide/imunologia , Leucemia Induzida por Radiação/genética , Leucemia Induzida por Radiação/imunologia , Mercaptoetanol , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Radiation leukemia virus-induced leukemia of a male C57BL/6 mouse, B6RV2, is immunogenic to female BALB/c X C57BL/6 F1 mice. In these mice, B6RV2 tumors regressed after initial growth, and after tumor regression the mice were resistant to repeated inocula of up to 10(8) B6RV2 cells. Serum from these mice reacted with B6RV2 in mixed hemadsorption or protein A assays, and absorption analysis indicated that the antigen was restricted to B6RV2; it could not be detected in normal thymocytes or spleen concanavalin A blasts from different inbred strains, nor in 16 C57BL/6 or BALB/c leukemias. Spleen cells from mice in which the tumor had regressed were cytotoxic to B6RV2 after in vitro stimulation with B6RV2, as shown by 51-chromium release assay. This cytotoxicity was eliminated by pretreatment of the cells with anti-Thy-1.2, anti-Lyt-2.2, anti-Lyt-3.2, and complement, indicating that the effector cells were T-cells. The specificity of T-cell killing of B6RV2 was examined by competitive inhibition assays with unlabeled cells; only B6RV2 inhibited killing, while eight other C57BL/6 leukemias did not inhibit. Thus, the antigen on B6RV2 defined serologically and by cytotoxic T-cells is a unique antigen. However, it was not revealed by antibody-blocking test whether the unique determinant defined serologically was related to that recognized by T-cells; B6RV2 antiserum did not block lytic activity in the absence of added complement, irrespective of whether the target cells were untreated or anti-H-2b-treated B6RV2. H-2Kb antisera, but not H-2Db antisera, blocked lysis. This indicated that the H-2Kb molecule was exclusively involved in recognition of B6RV2 by cytotoxic T-cell.
Assuntos
Antígenos de Neoplasias/análise , Vírus da Leucemia Murina/imunologia , Leucemia Induzida por Radiação/microbiologia , Animais , Linhagem Celular , Cruzamentos Genéticos , Citotoxicidade Imunológica , Feminino , Antígenos H-2/análise , Leucemia Induzida por Radiação/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Fatores Sexuais , Linfócitos T/imunologiaRESUMO
Immune regulation has been shown to be involved in the progressive growth of some murine tumors. In this study, we demonstrated that a single in vivo administration of an amount less than 0.125 mg of anti-CD25 interleukin 2 receptor alpha monoclonal antibody (mAb; PC61) caused the regression of tumors that grew progressively in syngeneic mice. The tumors used were five leukemias, a myeloma, and two sarcomas derived from four different inbred mouse strains. Anti-CD25 mAb (PC61) showed an effect in six of the eight tumors. Administration of anti-CD25 mAb (PC61) caused a reduction in the number of CD4+ CD25+ cells in the peripheral lymphoid tissues. The findings suggested that CD4+ CD25+ immunoregulatory cells were involved in the growth of those tumors. Kinetic analysis showed that the administration of anti-CD25 mAb (PC61) later than day 2 after tumor inoculation caused no tumor regression, irrespective of depletion of CD4+ CD25+ immunoregulatory cells. Two leukemias, on which the PC61-treatment had no effect, seemed to be incapable of eliciting effective rejection responses in the recipient mice because of low or no antigenicity.