RESUMO
Immunosuppressive drugs make possible the acceptance of organ allografts among individuals with differences in Major Histocompatibility Antigens (HLA). Transplantation of vital organs prolongs the survival of patients with terminal diseases, and this procedure has become a routine practice in the clinic, mainly because of advances in immunosuppressive therapy. Some immunosuppressive drugs, such as glucocorticosteroids and azathioprine, have been used for the past 30 years. More recently, newly discovered agents with a better ratio of efficacy to toxicity have been added to the armamentarium of anti-rejection therapies. Progress in understanding T cell activation in response to alloantigens has contributed to the development of new and more selective strategies to control the immune response and prevent acute rejection. The use of drugs in combination, with or without monoclonal antibodies, has also improved the efficacy and reduced the toxicity of immunosuppressive therapies. The new agents include drugs that interfere with calcineurin, inhibitors of de novo purine biosynthesis, kinase inhibitors, as well as monoclonal antibodies that block activation signals on the surface of T cells or co-stimulatory signals between T cells and antigen-presenting cells. In this review the modes of action of commonly used immunosuppressive drugs are described. Successful new strategies are also being developed to establish tolerance to allografts in rodents and non-human primates. The progress in these approaches, although still in the experimental stages, offers promising alternatives for these patients in the future. Treatment protocols using combinations of drugs with antibodies that might produce tolerance in humans are also discussed.
Assuntos
Tolerância Imunológica , Terapia de Imunossupressão/tendências , Imunossupressores/farmacologia , Humanos , Ativação Linfocitária , Transplante de Órgãos , Linfócitos T/imunologia , Imunologia de Transplantes , Transplante HomólogoRESUMO
Immunosuppressive drugs make possible the acceptance of organ allografts among individuals with differences in Major Histocompatibility Antigens (HLA). Transplantation of vital organs prolongs the survival of patients with terminal diseases, and this procedure has become a routine practice in the clinic, mainly because of advances in immunosuppressive therapy. Some immunosuppressive drugs, such as glucocorticosteroids and azathioprine, have been used for the past 30 years. More recently, newly discovered agents with a better ratio of efficacy to toxicity have been added to the armamentarium of anti-rejection therapies. Progress in understanding T cell activation in response to alloantigens has contributed to the development of new and more selective strategies to control the immune response and prevent acute rejection. The use of drugs in combination, with or without monoclonal antibodies, has also improved the efficacy and reduced the toxicity of immunosuppressive therapies. The new agents include drugs that interfere with calcineurin, inhibitors of de novo purine biosynthesis, kinase inhibitors, as well as monoclonal antibodies that block activation signals on the surface of T cells or co-stimulatory signals between T cells and antigen-presenting cells. In this review the modes of action of commonly used immunosuppressive drugs are described. Successful new strategies are also being developed to establish tolerance to allografts in rodents and non-human primates. The progress in these approaches, although still in the experimental stages, offers promising alternatives for these patients in the future. Treatment protocols using combinations of drugs with antibodies that might produce tolerance in humans are also discussed.
Assuntos
Humanos , Terapia de Imunossupressão/tendências , Tolerância Imunológica , Imunossupressores/farmacologia , Transplante Homólogo , Imunologia de Transplantes , Ativação Linfocitária , Linfócitos T/imunologia , Transplante de ÓrgãosRESUMO
Immunosuppressive drugs make possible the acceptance of organ allografts among individuals with differences in Major Histocompatibility Antigens (HLA). Transplantation of vital organs prolongs the survival of patients with terminal diseases, and this procedure has become a routine practice in the clinic, mainly because of advances in immunosuppressive therapy. Some immunosuppressive drugs, such as glucocorticosteroids and azathioprine, have been used for the past 30 years. More recently, newly discovered agents with a better ratio of efficacy to toxicity have been added to the armamentarium of anti-rejection therapies. Progress in understanding T cell activation in response to alloantigens has contributed to the development of new and more selective strategies to control the immune response and prevent acute rejection. The use of drugs in combination, with or without monoclonal antibodies, has also improved the efficacy and reduced the toxicity of immunosuppressive therapies. The new agents include drugs that interfere with calcineurin, inhibitors of de novo purine biosynthesis, kinase inhibitors, as well as monoclonal antibodies that block activation signals on the surface of T cells or co-stimulatory signals between T cells and antigen-presenting cells. In this review the modes of action of commonly used immunosuppressive drugs are described. Successful new strategies are also being developed to establish tolerance to allografts in rodents and non-human primates. The progress in these approaches, although still in the experimental stages, offers promising alternatives for these patients in the future. Treatment protocols using combinations of drugs with antibodies that might produce tolerance in humans are also discussed.
Assuntos
Insulina/farmacologia , Interleucina-1/biossíntese , Interleucina-6/biossíntese , Lipopolissacarídeos/farmacologia , Monócitos/metabolismo , Bioensaio , Ensaio de Imunoadsorção Enzimática , Humanos , Técnicas In Vitro , Monócitos/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Timidina/metabolismoRESUMO
Cultured splenic mononuclear adherent cells (SMAc) from normal BALB/c mice as well as those from mice bearing 10-day sarcoma 180 (S180), exhibited a marked increase in Escherichia coli lipopolysaccharide-stimulated interleukin-1 (IL-1) production, when compared to spontaneous values. On days 20 and 30 following S180 challenge, a decrease in this effect on IL-1 production in treated and untreated SMAc was observed. Concomitantly with the alterations in the regulation of IL-1 production during tumor growth, an increase in the levels of prostaglandin E2 and serum immune complexes could be detected. These data suggest that the immunosuppression associated with later stages of tumor development may be due to direct effects on monocytes, by means of a down-regulation of IL-1 production.
Assuntos
Complexo Antígeno-Anticorpo/sangue , Interleucina-1/biossíntese , Sarcoma 180/patologia , Sarcoma 180/fisiopatologia , Animais , Adesão Celular/fisiologia , Divisão Celular/fisiologia , Dinoprostona/metabolismo , Escherichia coli , Estudos de Avaliação como Assunto , Feminino , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Monócitos/citologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Transplante de Neoplasias , Sarcoma 180/sangue , Baço/citologia , Baço/efeitos dos fármacos , Baço/metabolismoRESUMO
Receptors for insulin and insulin-like growth factor-1 (IGF-1) have been demonstrated on activated T-lymphocytes. The question is whether receptors for insulin or IGF-1 have any function in these cells. In this study we demonstrate that the concentration of IGF-1 in commercial samples of fetal calf serum is about 70 times that of insulin. Moreover, antibodies binding IGF-1 reduce responses of human peripheral blood mononuclear cells to PHA by about 50%, whereas antibodies to insulin have no demonstrable effect. These observations suggest that binding of IGF-1 to specific receptors contributes to the proliferative responses of activated T-lymphocytes.
Assuntos
Fator de Crescimento Insulin-Like I/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Fito-Hemaglutininas/farmacologia , Somatomedinas/farmacologia , Linfócitos T/efeitos dos fármacos , Animais , Anticorpos/imunologia , Bovinos/sangue , Divisão Celular/efeitos dos fármacos , Sangue Fetal/fisiologia , Humanos , Fator de Crescimento Insulin-Like I/imunologia , Fator de Crescimento Insulin-Like I/isolamento & purificação , Receptores de Superfície Celular/fisiologia , Receptores de Somatomedina , Proteínas Recombinantes/farmacologia , Estimulação Química , Linfócitos T/citologiaRESUMO
Mediante la identificacion de diferentes poblaciones de linfocitos perifericos, se realizo un estudio comparativo entre 32 pacientes con neoplasias solidas malignas de distinto origen, sin tratamiento oncologico previo y 17 controles sanos. Para su evaluacion se utilizaron las tecnicas de formacion de rosetas espontaneas con globulos rojos de carnero (rosetas E) para linfocitos T, de rosetas EAC para celulas con receptor para el complemento, y de inmunofluorescencia directa para linfocitos con Ig de superficie. Ademas, se valoro el numero total de leococitos y el porcentaje de linfocitos antes y despues del tratamiento antineoplasico instituido. Los valores correspondientes al % de rosetas E, no mostraron diferencias entre los distintos grupos de enfermos ni con relacion a los controles normales. Con respecto al % de rosetas EAC no se observaron diferencias entre los testigos y los distintos grupos de enfermos estudiados, aunque si pudieran advertirse entre los pacientes con adenocarcinomas y los portadores de melanomas (p < 0.05). Los resultados obtenidos en el estudio de celulas con Ig de superficie, mostraron diferencias entre los enfermos con adenocarcinomas y los testigos sanos, y con el grupo de Ca epidermoide. El % de linfocitos antes y despues del tratamiento, fue similar en los enfermos con melanomas, adenocarcinomas y carcinomas epidermoides, pero disminuyo sensiblemente en el grupo con cancer de pulmon, estimandose que ese porcentaje durante la enfermedad, estaba en relacion directa con el periodo de sobrevida de los pacientes
Assuntos
Neoplasias Pulmonares , LinfócitosRESUMO
Mediante la identificacion de diferentes poblaciones de linfocitos perifericos, se realizo un estudio comparativo entre 32 pacientes con neoplasias solidas malignas de distinto origen, sin tratamiento oncologico previo y 17 controles sanos. Para su evaluacion se utilizaron las tecnicas de formacion de rosetas espontaneas con globulos rojos de carnero (rosetas E) para linfocitos T, de rosetas EAC para celulas con receptor para el complemento, y de inmunofluorescencia directa para linfocitos con Ig de superficie. Ademas, se valoro el numero total de leococitos y el porcentaje de linfocitos antes y despues del tratamiento antineoplasico instituido. Los valores correspondientes al % de rosetas E, no mostraron diferencias entre los distintos grupos de enfermos ni con relacion a los controles normales. Con respecto al % de rosetas EAC no se observaron diferencias entre los testigos y los distintos grupos de enfermos estudiados, aunque si pudieran advertirse entre los pacientes con adenocarcinomas y los portadores de melanomas (p < 0.05). Los resultados obtenidos en el estudio de celulas con Ig de superficie, mostraron diferencias entre los enfermos con adenocarcinomas y los testigos sanos, y con el grupo de Ca epidermoide. El % de linfocitos antes y despues del tratamiento, fue similar en los enfermos con melanomas, adenocarcinomas y carcinomas epidermoides, pero disminuyo sensiblemente en el grupo con cancer de pulmon, estimandose que ese porcentaje durante la enfermedad, estaba en relacion directa con el periodo de sobrevida de los pacientes