Neuropatías asociadas a anticuerpos anti-GM1. Anti-GM1 antibodies associated neuropathies.

Durante varios años estudiamos los anticuerpos presentes en pacientes con neuropatías e individuos normales. Recientemente hemos implementado un modelo animal de neuropatía inducido por inmunización con GM1, y nos proponemos confirmar en este modelo las observaciones realizadas en pacientes. Se caracterizará la respuesta inmune humoral durante la inducción de la enfermedad, y la posible existencia de un mecanismo regulatorio mediado por anticuerpos bloqueantes de anticuerpos anti-GM1. Además, el modelo nos permitirá ensayar diferentes estrategias terapéutica tales como plasmaféresis específica, bloqueo de anticuerpos por antígenos solubles e inducción de anticuerpos bloqueantes.

Regulación de la actividad funcional tiroidea e interacción con mediadores de la respuesta inmune. Regulation of thyroid functional activity and interaction with mediators of immune response.

TEMA I. MECANISMOS NO CLÁSICOS EN EL CONTROL DE LA BIOSÍNTESIS DE HORMONAS TIROIDEAS. El objetivo general de este aspecto del proyecto es el estudio de los mecanismos bioquímicos y moleculares que regulan la hormonogénesis tiroidea en diferentes condiciones funcionales. En proyectos anteriores hemos demostrado que la endotoxina bacteriana lipopolisacárido (LPS) y el oxido nítrico (NO) inducen modificaciones en la biosíntesis de hormonas tiroideas. En base a estos resultados se propone investigar el mecanismo responsable de la estimulación de la captación de ioduro y la expresión de NIS ejercida por LPS y los factores que regulan la producción de NO en la célula tiroidea. Por otra parte se investigarán posibles factores hormonales reguladores de la absorción de ioduro a nivel intestinal y su relación con el eje hipófiso-tiroideo, así como los mecanismos involucrados en la expresión de NIS en enterocitos. Como extensión con aplicación clínica y en base a la experiencia del grupo en el estudio de proteínas que participan en la biosíntesis hormonal tiroidea, se realizará una pesquisa de posibles mutaciones en el transportador de ioduro en pacientes con Hipotiroidismo congénito.TEMA II. ESTUDIO DEL EFECTO DE LAS HORMONAS TIROIDEAS EN LA INICIACIÓN DE LA RESPUESTA INMUNE EN RATÓN. INTERACCIÓN CON GLUCOCORTICOIDES. En nuestro grupo demostramos recientemente un efecto novel de las hormonas tiroideas sobre la maduración/función de células presentadoras de antígenos especializadas: células dendríticas (DC), derivadas de médula ósea de ratón. En este proyecto se propone: 1) profundizar el mecanismo molecular involucrado en el efecto de triiodotironina (T3) sobre DC: rol del receptor de T3-señalamiento intracelular; capacidad de DC tratadas con T3 de estimular la citotoxicidad antígeno-específica; estrategia de vacunación en el tratamiento antitumoral. Por su parte, también previamente demostramos la característica de los glucocorticoides (GC) de interaccionar con el mecanismo de acción de las hormonas tiroideas en la expresión final de los efectos T3-específicos. Considerando el uso terapéutico de los GC en diversos estados clínico-patológicos inmunes, se propone: 2) Estudio del efecto de dexametasona (GC de síntesis) sobre el mecanismo de acción de T3 a nivel de DC.

Thyroid hormone modulation of early neocortical network development

Magdeburg, Univ., Fak. für Naturwiss., Diss., 2012

EVI antibodies in patients with Chagas' disease: relationship with anti-Trypanosoma cruzi immunoglobulins and effects of specific treatment

Antibodies against heart vascular structures and striated muscle cells interstitium (EVI antibodies) persist in Chagas' disease patients who had been cured by specific treatment as demonstrated by negative xenodiagnosis, conventional serology (CS) and complement mediated lysis (CoML). On the other hand, EVI antibodies are either present or absent in treated patients presenting positive CS but negative CoML. Since CoML detects antibodies associated to resistance, EVI antibodies are not likely to participate in the control of T. cruzi infections although they might be induced by cross-reacting antigens of heart cells and the parasite. They are neither necessarily related to antibodies responsible for CS. Absorption with T. cruzi and heart tissue confirms the suggestion that EVI antibodies are induced by a number of antigenic determinants, most from heart structures with a minor participation of T. cruzi antigens.

Differential effects of two anti-apo-cytochrome c-specific monoclonal antibodies on the function of apo-cytochrome c-specific murine T cell clones.

A murine monoclonal antibody (SJL 2-4) specific for the antigen apo-cytochrome c was shown to inhibit both antigen-induced proliferation and lymphokine secretion by an apo-cytochrome c-specific BALB/c helper T cell clone. The inhibition was specific because additional apo-cytochrome c-specific T cell clones were not inhibited by the same monoclonal antibody. Time course studies of the inhibition indicated that the initial 8 hr of contact between T cell clones and antigen-presenting cells were critical for activation of the T cell clones. Inhibition of T cell functions by antigen-specific antibodies appeared to correlate with the antibody-antigen binding constant because a second monoclonal antibody (Cyt-1-59), with identical specificity but with a lower affinity constant for apo-cytochrome c, had very little inhibitory effect on the proliferation or lymphokine secretion of apo-cytochrome c-specific T cell clones.

Use of limitations of radiolabeled anti-CEA antibodies and their fragments for photoscanning detection of human colorectal carcinomas.

Fifty-three patients with histologically proven carcinoma were injected with highly purified [131I]-labeled goat antibodies or fragments of antibodies against carcinoembryonic antigen (CEA). Each patient was tested by external photoscanning 4, 24, 36 and 48 h after injection. In 22 patients (16 of 38 injected with intact antibodies, 5 of 13 with F(ab')2 fragments and 1 of 2 with Fab' fragments), an increased concentration of 131I radioactivity corresponding to the previously known tumor location was detected by photoscanning 36-48 h after injection. Blood pool and secreted radioactivity was determined in all patients by injecting 15 min before scanning, [99mTc]-labeled normal serum albumin and free 99mTc04-. The computerized subtraction of 99mTc from 131I radioactivity enhanced the definition of tumor localization in the 22 positive patients. However, in spite of the computerized subtraction, interpretation of the scans remained doubtful for 12 patients and was entirely negative for 19 additional patients. In order to provide a more objective evaluation for the specificity of the tumor localization of antibodies, 14 patients scheduled for tumor resection were injected simultaneously with [131I]-labeled antibodies or fragments and with [125I]-labeled normal goat IgG or fragments. After surgery, the radioactivity of the two isotopes present either in tumor or adjacent normal tissues was measured in a dual channel scintillation counter. The results showed that the antibodies or their fragments were 2-4 times more concentrated in the tumor than in the normal tissues. In addition, it was shown that the injected antibodies formed immune complexes with circulating CEA and that the amount of immune complexes detectable in serum was roughly proportional to the level of circulating CEA.