RESUMO
Objective: To examine the mid - and long-term outcomes of surgical treatment of brachiocephalic Takayasu arteritis. Methods: This is a retrospective case series study. The clinical data of 39 patients,which had been diagnosed as brachiocephalic Takayasu arteritis (244 cases),who underwent surgical treatment,were analyzed between July 2012 to November 2022 at Department of Endoluminal Vascular Surgery, the First Affiliated Hospital of Zhengzhou University. There were 5 males and 34 females, aged (37.9±14.0)years (range:13 to 71 years). Despite medical treatment, the patients suffered severe ischemic symptoms continually and then underwent surgical interventions. Among them, 20 patients underwent endovascular procedures, 11 underwent open surgical procedures, and 8 underwent hybrid procedures. Patients were followed up through outpatient visits at 1, 3, 6 months after surgery and once every year later. Follow-up was conducted until November 2022. Operation status, postoperative complications and re-intervention of patients were recorded and the Kaplan-Meier survival curves were used to analyze postoperative vascular patency rates. Results: All 39 surgeries were successful, with no intraoperative death or serious complications. The follow-up period was (48.8±38.2) months(range:1 to 123 months). Thirty-three patients experienced symptom relief after surgery, and 6 patients required secondary surgical interventions. The patency rates for the endovascular treatment group at 1-, 3-, 5-, and 10-year were 95.0%, 75.2%, 60.2%, and 60.2%, respectively, while the patency rates for open surgery were all 90.9%. In the hybrid surgery group, the patency rates at 1-, 3-, 5-, and 8-year were all 87.5%. Conclusion: For patients with brachiocephalic Takayasu arteritis, choice of an appropriate blood flow revascularization intervention should be based on the patient's condition,and the mid-and long-term outcomes are satisfactory.
Assuntos
Procedimentos Endovasculares , Arterite de Takayasu , Masculino , Feminino , Humanos , Arterite de Takayasu/cirurgia , Arterite de Takayasu/complicações , Arterite de Takayasu/diagnóstico , Estudos Retrospectivos , Resultado do Tratamento , Procedimentos Endovasculares/métodos , Isquemia , Grau de Desobstrução VascularRESUMO
The pathophysiology of human chronic pancreatitis is not well understood and difficult to follow on a molecular basis. Therefore, we used a rat model [Wistar-Bonn/Kobori (WBN/Kob)] that exhibits spontaneous chronic inflammation and fibrosis in the pancreas. Using microarrays we compared gene expression patterns in the pancreas during development of inflammation and fibrosis of WBN/Kob rats with age-matched healthy Wistar rats. The extracellular matrix protein SPARC (secreted protein, acidic, and rich in cysteines) and other transcripts of inflammatory genes were quantified by real-time PCR, and some were localized by immunohistochemistry. When pancreatic inflammation becomes obvious at the age of 16 wk, several hundred genes are increased between 3- and 50-fold in WBN/Kob rats compared with healthy Wistar rats. Proteins produced by acinar cells and characteristic for inflammation, e.g., pancreatitis-associated protein, are highly upregulated. Other proteins, derived from infiltrating inflammatory cells and from activated stellate cells (fibrosis) such as collagens and fibronectins are also significantly upregulated. SPARC was localized to acinar cells where it increased in the vicinity of inflammatory foci. However, acinar expression of SPARC was lost during destruction of acinar cells. In human pancreatic specimens with chronic pancreatitis, SPARC exhibited a similar expression profile. During chronic inflammation and fibrosis in the WBN/Kob rat, inflammatory genes, growth factors, and structural genes exhibit a high increase of expression. A temporal profile including pre- and postinflammatory phases indicates a concurrent activation of inflammatory and fibrotic changes. Inflammation dependent expression of SPARC appears to be lost during acinar-to-duct metaplasia both in rat and human pancreas.
Assuntos
Regulação da Expressão Gênica/fisiologia , Osteonectina/metabolismo , Pancreatite Crônica/metabolismo , Animais , Primers do DNA/genética , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Análise de Sequência com Séries de Oligonucleotídeos , Pancreatite Crônica/complicações , Proteínas Associadas a Pancreatite , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
A diffusion cloud chamber has been used to qualitatively study some dynamic properties of liquid drops by suspending them in an electric field at the plane of saturation (p/ps = 1, where p is the actual partial pressure of the vapor at a given elevation and ps is the equilibrium pressure at that temperature characteristic of that elevation). By varying the strength of the electric field, it is possible to change the size of the suspended droplets and even, if desired, to isolate a single drop.
RESUMO
Arachnoiditis ossificans is a rare type of chronic arachnoiditis characterised by the presence of calcification or ossification of the spinal arachnoid. There are a few reports of this condition in Japanese and western populations but no case has been reported in a Chinese population before. We describe a 35-year-old woman with typical findings of arachnoiditis ossificans. A brief review of the literature is also presented.
Assuntos
Aracnoidite/patologia , Adulto , Aracnoidite/diagnóstico , Feminino , Humanos , Ossificação HeterotópicaRESUMO
Spinal infection caused by Mycobacterium avium complex (MAC) is rarely seen in people who do not have acquired immune deficiency syndrome. We report such a case in a 60-year-old man who underwent anterior spinal fusion after treatment with antibiotics had failed. The presentation of MAC spinal infection is different from that seen in MAC lung infection, with more than half presenting with urgent or semi-urgent neurological deficits. Younger patients who are not immunocompromised can also be infected. It should be considered as a differential diagnosis in patients with tuberculosis of the spine. The use of antibiotics should be based on the cultured organism's sensitivity results. Indications for surgery are progressive bony destruction, abscess formation, and neurological compression.
Assuntos
Complexo Mycobacterium avium , Infecção por Mycobacterium avium-intracellulare/diagnóstico , Espondilite/diagnóstico , Espondilite/microbiologia , Humanos , Masculino , Pessoa de Meia-Idade , Infecção por Mycobacterium avium-intracellulare/etiologia , Infecção por Mycobacterium avium-intracellulare/terapia , Fusão Vertebral , Espondilite/cirurgiaRESUMO
A 15-month-old boy presented with a 2-day history of a wry neck (bent to the left side) with no definite trauma. He had bilateral upper limb weakness and was afebrile, conscious, and stable. There was no spontaneous movement in both upper limbs. Magnetic resonance imaging of the cervical and thoracic spine demonstrated an extensive spontaneous spinal epidural haematoma from C3 to T8. 23 hours after admission, the patient underwent an emergency right-sided C3 to T8 hemi-laminectomy and haematoma evacuation. The patent's strength gradually recovered and he attained full power 3 weeks after operation. Spontaneous spinal epidural haematoma is a rare disease in children. A high index of suspicion is essential for its effective management as the interval to operation is the most important prognostic factor.
Assuntos
Hematoma Epidural Espinal/complicações , Torcicolo/etiologia , Diagnóstico Diferencial , Hematoma Epidural Espinal/diagnóstico , Hematoma Epidural Espinal/cirurgia , Humanos , Lactente , Laminectomia , Imageamento por Ressonância Magnética , Masculino , Tomografia Computadorizada por Raios XRESUMO
Subchondral insufficiency fracture of the femoral head is a recently recognised entity. There are a few cases reported in Japanese and Caucasian patients but none in the Hong Kong population. The condition typically occurs in elderly females with osteoporosis. Acute hip pain is the usual presentation. The patient may have concomitant insufficiency fractures elsewhere. Magnetic resonance imaging is usually required to make the diagnosis. The prognosis of the condition is unknown. Reported complications include rapid collapse of the femoral head and coxopathy. Joint replacement should be considered if conservative management fails.
Assuntos
Cabeça do Fêmur/lesões , Fraturas Espontâneas/diagnóstico , Osteoporose/complicações , Idoso , Diagnóstico Diferencial , Feminino , Necrose da Cabeça do Fêmur/diagnóstico , Humanos , Imageamento por Ressonância MagnéticaRESUMO
PURPOSE: To evaluate the neurological recovery and fusion rate of patients with myelopathy who were treated with anterior corpectomy and anterior cervical plating. METHODS: The results of 17 cervical myelopathy patients who underwent decompression and anterior cervical plating were retrospectively reviewed at a mean follow-up of 2 years. RESULTS: By Kurokawa score, 82.4% of patients showed excellent-to-good results. The fusion rates of 2-level and 3-level anterior cervical corpectomy, and of anterior plate fixation were 100%. There were no implant- or graft-related complications. Transient dysphagia in 9 (52.9%) patients resolved after a mean of 3 months (range, 1-9 months). CONCLUSION: The use of anterior cervical plating after anterior corpectomy and fusion with autologous bone graft greatly enhances arthrodesis. The improved fusion rate and low complication rate associated with anterior cervical plating may justify its use in the treatment of cervical spondylotic myelopathy.
Assuntos
Placas Ósseas , Vértebras Cervicais/cirurgia , Doenças Neurodegenerativas/cirurgia , Compressão da Medula Espinal/cirurgia , Fusão Vertebral/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Transplante Ósseo , Vértebras Cervicais/diagnóstico por imagem , Descompressão Cirúrgica , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/diagnóstico por imagem , Radiografia , Recuperação de Função Fisiológica , Estudos Retrospectivos , Compressão da Medula Espinal/diagnóstico por imagem , Fusão Vertebral/instrumentação , Resultado do TratamentoRESUMO
The mechanism of alpha-chymotrypsin action has been probed by extending studies of native chymotrypsin to immobilized chymotrypsin, where the organic content of the solution can be raised to much higher levels and thus one can explicitly look at the role of water. When one does this, one finds that water only appears in the deacylation reaction. The premise that one can go from native chymotrypsin (souble) to immobilized chymotrypsin (insoluble) has been tested by several criteria. It has been found in many instances that the two are identical: in absolute rate, in pKa. They are, however, not identical to one another in binding, due to differences in diffusion, which is to be expected. Thus, mechanistically immobilized and native chymotrypsin are identical to one another and the use of immobilized chymotrypsin can be used to specify the mechanism even more: it must proceed through two tetrahedral intermediates and two acyl-enzyme intermediates.
Assuntos
Quimotripsina/metabolismo , Enzimas Imobilizadas/metabolismo , Dioxanos , Vidro , Concentração de Íons de Hidrogênio , Cinética , SefaroseRESUMO
OBJECTIVE: To study the incidence of microbial contamination at the bone bank of the United Christian Hospital. DESIGN. Retrospective study. SETTING: Regional hospital, Hong Kong. PATIENTS: A total of 151 patients (33 men and 118 women) who underwent hip arthroplasty surgery and from whom femoral head allografts were retrieved between January 1994 and March 2000; and 81 patients in whom allografts were implanted. MAIN OUTCOME MEASURES: Bone biopsies were taken from the femoral head and used to detect any microbial contamination that might have occurred during removal and after storage. The rates of infection among recipients and donors were also assessed. RESULTS: Of the 151 allografts, 94 non-contaminated allografts were implanted by the end of the study. Fourteen (9.3%) heads showed positive culture results after retrieval and were discarded. Four (4.3%) of the 94 stored allografts that were implanted tested positive for microbial growth, but the recipients of these allografts did not develop any clinical infection. Three (3.2%) had wound infections after implantation of the stored allografts although the grafts had previously been tested negative for any microbial contamination. CONCLUSION: Our centre has a low allograft contamination rate. The wound infection rate among recipients was also low. The culture of a bone biopsy sample is a reliable method to detect contamination of bone grafts. However, the contamination rate among stored allografts should prompt orthopaedics departments to review allograft handling procedures, so as to minimise the chance of contamination.
Assuntos
Cabeça do Fêmur/microbiologia , Cabeça do Fêmur/transplante , Antibacterianos/uso terapêutico , Bactérias/efeitos dos fármacos , Bactérias/isolamento & purificação , Bancos de Ossos/normas , Feminino , Hong Kong , Hospitais , Humanos , Masculino , Estudos Retrospectivos , Transplante HomólogoRESUMO
The superior dislocation of the patella with interlocking osteophytes is a rare condition. A review of the English literature revealed only 12 reported cases. The purpose of reviewing these case reports is to highlight the unusual presentation and the injury mechanism in 2 of our patients, and to present our treatment algorithm. Closed reduction with manipulation of the patella, with or without anaesthesia, was performed without difficulty. We recommend an intermediate step of trying a regional nerve block before proceeding to general anaesthesia. Our patients had full range-of-motion after reduction and they were symptom-free after 3 years of follow-up. There were no recurrent dislocations in our patients.
Assuntos
Luxação Patelar/cirurgia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Luxação Patelar/diagnóstico por imagem , Radiografia , Amplitude de Movimento ArticularRESUMO
Human hybridoma cell lines secreting IgG specific for the major allergen in the pollen of short ragweed, Amb a I, were established from patients who had been receiving antigen injections for immunotherapy. Recombinant Ig genes were then constructed by cloning the heavy and light chain variable region genes of the human hybridoma cell line and joining them to the human alpha or kappa constant region genes in mammalian expression vectors. Amb a I-specific IgA was expressed in two mouse myeloma cell lines, NS0 and Sp2/0. In both systems, transfected alpha and kappa chains were assembled into IgA monomers or into dimers covalently linked by the endogenous murine J chains. We propose that recombinant IgA monoclonal antibodies specific for airborne allergens may be applied to the mucosal surface of the nasal linings or of the lower airway of sensitized individuals to inhibit the entry of allergenic molecules across the mucosal epithelium and, therefore, to prevent the development of allergic responses.
Assuntos
Alérgenos/imunologia , Antígenos/uso terapêutico , Imunoglobulina A/imunologia , Imunoterapia , Pólen/imunologia , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais , Especificidade de Anticorpos , Sequência de Bases , Linhagem Celular , Estudos de Viabilidade , Humanos , Hipersensibilidade/terapia , Camundongos , Dados de Sequência Molecular , Ligação Proteica , Proteínas Recombinantes/isolamento & purificaçãoRESUMO
OBJECTIVE: To determine characteristics of classical and partial deletions of the Y chromosome azoospermia factor (AZF) region transmitted from father to son by natural fertilization. METHODS: Patients from northeastern China with primary male infertility (n = 10) and their fathers were investigated. Healthy fertile men and women were recruited as positive and negative controls, respectively. The Y chromosome microdeletions were detected by polymerase chain reaction. Serum concentrations of reproductive hormones were determined by electrochemiluminescence immunoassay and enzyme-linked immunosorbent assay. RESULTS: Expansions of microdeletions were observed in seven fatherson pairs; de novo microdeletions were found in the remaining three fatherson pairs. The Y chromosome microdeletions were larger in sons than in their fathers. Patients with infertility had significantly higher levels of follicle stimulating hormone and lower levels of inhibin B than fertile men. CONCLUSIONS: The Y chromosome microdeletions were transmitted from father to son via natural transmission. These microdeletions may expand during transmission or arise de novo, possibly resulting in reduced fertility.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Y , Técnicas de Transferência de Genes , Adulto , Sequência de Bases , Estudos de Casos e Controles , China , Primers do DNA , Ensaio de Imunoadsorção Enzimática , Feminino , Hormônios/sangue , Humanos , Infertilidade Masculina/genética , Cariotipagem , Masculino , Reação em Cadeia da PolimeraseAssuntos
Anticorpos Monoclonais , Genes , Regiões Constantes de Imunoglobulina/genética , Região Variável de Imunoglobulina/genética , Imunoglobulinas/genética , Complexo Antígeno-Anticorpo , Antígenos de Neoplasias/imunologia , Antígenos de Superfície/imunologia , Quimera , Clonagem Molecular , Neoplasias do Colo/imunologia , Humanos , Neoplasias Retais/imunologiaRESUMO
INTRODUCTION: Therapeutic strategies to treat chronic pancreatitis (CP) are very limited. Other chronic inflammatory diseases can be successfully suppressed by selective cyclooxygenase 2 (COX-2) inhibitors. As COX-2 is elevated in CP, we attempted to inhibit COX-2 activity in an animal model of CP (WBN/Kob rat). We then analysed the effect of COX-2 inhibition on macrophages, important mediators of chronic inflammation. METHODS: Male WBN/Kob rats were continuously fed the COX-2 inhibitor rofecoxib, starting at the age of seven weeks. Animals were sacrificed 2, 5, 9, 17, 29, 41, and 47 weeks later. In some animals, treatment was discontinued after 17 weeks, and animals were observed for another 24 weeks. RESULTS: Compared with the spontaneous development of inflammatory injury and fibrosis in WBN/Kob control rats, animals treated with rofecoxib exhibited a significant reduction and delay (p<0.0001) in inflammation. Collagen and transforming growth factor beta synthesis were significantly reduced. Similarly, prostaglandin E(2) levels were markedly lower, indicating strong inhibition of COX-2 activity (p<0.003). If treatment was discontinued at 24 weeks of age, all parameters of inflammation strongly increased comparable with that in untreated rats. The correlation of initial infiltration with subsequent fibrosis led us to determine the effect of rofecoxib on macrophage migration. In chemotaxis experiments, macrophages became insensitive to the chemoattractant fMLP in the presence of rofecoxib. CONCLUSION: In the WBN/Kob rat, chronic inflammatory changes and subsequent fibrosis can be inhibited by rofecoxib. Initial events include infiltration of macrophages. Cell culture experiments indicate that migration of macrophages is COX-2 dependent.
Assuntos
Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Lactonas/uso terapêutico , Macrófagos/efeitos dos fármacos , Pâncreas/patologia , Pancreatite Crônica/prevenção & controle , Sulfonas/uso terapêutico , Animais , Movimento Celular/efeitos dos fármacos , Fatores Quimiotáticos/biossíntese , Fatores Quimiotáticos/genética , Ciclo-Oxigenase 1/biossíntese , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 2/biossíntese , Ciclo-Oxigenase 2/genética , Citocinas/biossíntese , Citocinas/genética , Dinoprostona/metabolismo , Modelos Animais de Doenças , Esquema de Medicação , Fibrose , Macrófagos/fisiologia , Masculino , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Pâncreas/metabolismo , Pancreatite Crônica/patologia , Reação em Cadeia da Polimerase/métodos , RNA Mensageiro/genética , Ratos , Ratos Endogâmicos , Ratos WistarRESUMO
We have cloned and mapped the sequences extending 38 kb 3' of the c-myc gene. This region is found to be highly repetitive in nature and hybridizes extensively with a BLUR 8 Alu probe. Unique sequence probes derived from this region were used to map the chromosomal breakpoints of a number of lymphoma cell lines with t(2;8) or t(8;22) translocations. In five of the cell lines (PA682, LY67, LY47, LY66 and LY91), the immunoglobulin light chain locus translocates into a region which is greater than 47 kb downstream of c-myc. For one of the cell lines, JI, the location of the breakpoint on the 8q+ chromosome was found to be 25-32 kb 3' of c-myc. The breakpoint for the BL2 cell line had been previously mapped at 10 kb 3' of the c-myc oncogene. Analyses of steady-state levels of c-myc mRNA in cell lines with chromosomal breakpoints ranging from 10 kb to greater than 47 kb 3' of c-myc range from 0.5 to 10X the levels in lymphoblast controls. The different levels of c-myc transcripts is not a direct function of the distance between the c-myc gene and the translocated immunoglobulin light chain locus.
Assuntos
Linfoma/genética , Oncogenes , Translocação Genética , Linhagem Celular , Mapeamento Cromossômico , Cromossomos Humanos 1-3 , Cromossomos Humanos 6-12 e X , Clonagem Molecular , Humanos , Hibridização de Ácido Nucleico , Sequências Repetitivas de Ácido NucleicoRESUMO
Congeners of vitamin K have been found to inhibit growth in various rodent and human tumor cells, but the mechanisms of the inhibitory action are still not well understood. To investigate the modes of actions of vitamin K, we used several vitamin K analogs and examined their cytotoxic effect for human glioma cell lines RBR17T and U251. The analogs included vitamin K1 (VK1), vitamin K2 (VK2), vitamin K3 (VK3), and geranylgeraniol (GGO) which form an unsaturated side chain of VK2. Cell viability was estimated by MTT assay. DNA fragmentation was demonstrated by gel electrophoresis and flow cytometry. In order to study the mechanism of apoptosis, we measured the changes of intracellular reactive oxygen intermediates (ROI) and Fas/APO-1 expression by flow cytometry. The results showed: (1) VK2, VK3, and GGO inhibited cell growth; (2) VK3 had a more potent cytotoxic effect than VK2, and VK3 enhanced the cytotoxic effect of antitumor agents (ACNU and IFN-beta) in RBR17T cells; (3) VK2, VK3, and GGO induce apoptosis: (4) VK3 increased the expression of Fas/APO-1 although VK2 and GGO did not increase its expression in glioma cells; (5) VK3 increased the production of intracellular ROI. Catalase and reduced glutathione (GSH) inhibited production of intracellular ROI and antagonized inhibition of cell-growth induced by VK3, but failed to antagonize that of VK2 and GGO. We hypothesize that VK3 induces apoptosis by promoting the generation of intracellular ROI and Fas/APO-1 expression. On the other hand, VK2 and GGO induce apoptosis but most likely by some other unknown pathway.
Assuntos
Apoptose/efeitos dos fármacos , Glioma , Hemostáticos/farmacologia , Vitamina K/análogos & derivados , Vitamina K/farmacologia , Receptor fas/biossíntese , Antifibrinolíticos/farmacologia , Apoptose/fisiologia , Catalase/farmacologia , Divisão Celular/efeitos dos fármacos , Citotoxinas/farmacologia , Fragmentação do DNA/efeitos dos fármacos , Fragmentação do DNA/fisiologia , Diterpenos/farmacologia , Glutationa/farmacologia , Humanos , Peróxidos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Células Tumorais Cultivadas/citologia , Células Tumorais Cultivadas/metabolismo , Vitamina K 1/farmacologia , Vitamina K 2/análogos & derivadosRESUMO
BACKGROUND: Matrix degradation products such as fragmented hyaluronan (HA) display important proinflammatory effects on renal tubular epithelial cells (TECs) and macrophages (MPhis). We hypothesized that HA could up-regulate cyclooxygenase type 2 (COX-2) in these cells and that the subsequent production of thromboxane A2 (TXA2) could play a role in inflammatory renal lesions. METHODS: We used an in vitro approach to examine the expression of COX-1 and COX-2 and the production of TXA2 in response to fragments of HA. COX-2 mRNA, protein, and the resulting TXA2 production were measured in CD44-positive, HA-responsive cells lines of TECs and MPhi. COX-2 mRNA was also measured in vivo in MRL-Faslpr mice and in mice with anti-glomerular basement membrane (anti-GBM) nephritis. RESULTS: In TECs and MPhis, HA increased the steady-state COX-2 mRNA and protein levels markedly, whereas COX-1 mRNA levels did not change. The HA-induced response was comparable to lipopolysaccharide stimulation. In comparison with MPhi, the response was much weaker in TECs. Likewise, the production of TXA2 in response to HA was markedly increased in MPhi, but less in TECs. In TECs and in MPhi, the HA-stimulated TXA2 synthesis was inhibited with the COX-2-selective inhibitors SC58125 (12.5 micromol/L) or celecoxib (0.25 to 5.00 micromol/L). COX-2 mRNA levels were increased in nephritic mice with MRL-Faslpr lupus nephritis and in mice with anti-GBM disease. CONCLUSIONS: HA is a proinflammatory factor that stimulates COX-2 expression and subsequent TXA2 production. Since HA accumulates markedly in renal injury, we speculate that this matrix molecule could therefore play a significant role in thromboxane-mediated immune events in the kidney.
Assuntos
Ácido Hialurônico/farmacologia , Isoenzimas/metabolismo , Rim/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Tromboxano A2/biossíntese , Animais , Doença Antimembrana Basal Glomerular/metabolismo , Linhagem Celular , Ciclo-Oxigenase 2 , Isoenzimas/genética , Isoenzimas/fisiologia , Rim/citologia , Rim/efeitos dos fármacos , Túbulos Renais/citologia , Túbulos Renais/metabolismo , Nefrite Lúpica/metabolismo , Macrófagos/metabolismo , Camundongos , Prostaglandina-Endoperóxido Sintases/genética , Prostaglandina-Endoperóxido Sintases/fisiologia , RNA Mensageiro/metabolismo , Tromboxano-A Sintase/genéticaRESUMO
Chimeric antibodies were constructed in which the murine variable region of anti-colorectal cancer monoclonal antibody CO17-1A was joined with human gamma 1, gamma 2, gamma 3, and gamma 4 constant regions. Human-mouse chimeric proteins were compared with the parental murine IgG2a antibody CO17-1A for their ability to participate in tumor-cell destruction by human and murine effector cells in antibody-dependent cell-mediated cytotoxicity (ADCC) assays. All of the chimeric antibodies showed different degrees of ADCC with human lymphocytes, monocytes, and granulocytes and with murine macrophages. Monocytes and macrophages were able to utilize the chimeric IgG1 and, to a lesser degree, IgG4 and IgG3 antibodies to lyse tumor-cell targets in ADCC assays. The chimeric IgG1 and IgG4 antibodies were nearly as effective as the parental CO17-1A antibody in inhibiting tumor growth in nude mice. These data indicate that chimeric IgG1 antibody is superior in its antitumor activity.
Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Antineoplásicos/imunologia , Imunoglobulina G/imunologia , Proteínas Recombinantes/imunologia , Animais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Antineoplásicos/uso terapêutico , Especificidade de Anticorpos , Citotoxicidade Celular Dependente de Anticorpos , Humanos , Imunoglobulina G/classificação , Imunoglobulina G/uso terapêutico , Macrófagos/imunologia , Camundongos , Neoplasias Experimentais/terapia , Fagócitos/imunologia , Receptores Fc/classificação , Receptores Fc/imunologia , Especificidade da EspécieRESUMO
A chimeric antibody was constructed in which the murine H- and L-chain variable regions of mAb 17-1A, raised against human colorectal cancer cells, were joined with the human constant mu and kappa regions. Transfection of these constructs into the murine myeloma Sp2/0 resulted in the expression and secretion of a pentameric Ig, designated chimeric 17-1A IgM. The chimeric 17-1A IgM was subsequently compared to a previously described chimeric 17-1A IgG1 for biological activities. Both chimeric mAbs were equally effective (weight basis) in competing against the binding of murine 125I-17-1A to cultures of HT-29 colon carcinoma cells. The calculated association constants for the chimeric 17-1A IgM and IgG1 were 1.63 x 10(8) l/mol and 3.41 x 10(7) l/mol, respectively. Unlike chimeric 17-1A IgG1, the chimeric 17-1A IgM was able to render colon carcinoma target cells susceptible to lysis by both xenogeneic (rabbit) and human complement. The extent of complement-mediated lysis dependent upon chimeric 17-1A IgM was correlated to 17-1A antigen expression on target cells. HT-29 colon carcinoma cells treated with chimeric 17-1A IgM did not directly result in antibody-dependent cellular cytotoxicity by human peripheral blood monocytes. However, chimeric 17-1A IgM greatly enhanced the deposition of C3 on complement-treated HT-29 cells, and concomitant incubation with monocytes resulted in heightened lysis of the tumor cells. The feasibility of enhancing host defense against gastrointestinal malignancies by the administration of this chimeric 17-1A IgM may have certain clinical advantages.