T- and B-cell responses to multivalent prime-boost DNA and viral vectored vaccine combinations against hepatitis C virus in non-human primates.

Immune responses against multiple epitopes are required for the prevention of hepatitis C virus (HCV) infection, and the progression to phase I trials of candidates may be guided by comparative immunogenicity studies in non-human primates. Four vectors, DNA, SFV, human serotype 5 adenovirus (HuAd5) and Modified Vaccinia Ankara (MVA) poxvirus, all expressing hepatitis C virus Core, E1, E2 and NS3, were combined in three prime-boost regimen, and their ability to elicit immune responses against HCV antigens in rhesus macaques was explored and compared. All combinations induced specific T-cell immune responses, including high IFN-γ production. The group immunized with the SFV+MVA regimen elicited higher E2-specific responses as compared with the two other modalities, while animals receiving HuAd5 injections elicited lower IL-4 responses as compared with those receiving MVA. The IFN-γ responses to NS3 were remarkably similar between groups. Only the adenovirus induced envelope-specific antibody responses, but these failed to show neutralizing activity. Therefore, the two novel regimens failed to induce superior responses as compared with already existing HCV vaccine candidates. Differences were found in response to envelope proteins, but the relevance of these remain uncertain given the surprisingly poor correlation with immunogenicity data in chimpanzees, underlining the difficulty to predict efficacy from immunology studies.

[The immunotherapy potential of agonistic anti-CD137 (4-1BB) monoclonal antibodies for malignancies and chronic viral diseases]. / El potencial de la inmunomodulación con anticuerpos monoclonales anti-CD137 (4-1BB) para terapia de enfermedades malignas e infecciones virales crónicas.

Pharmacological intervention on the immune system to achieve more intense lymphocyte responses has potential application in tumour immunology and in the treatment of chronic viral diseases. Immunostimulating monoclonal antibodies are defined as a new family of drugs that augment cellular immune responses. They interact as artificial ligands with functional proteins of the immune system, either activating or inhibiting their functions. There are humanized monoclonal antibodies directed to the inhibitory receptor CD152 (CTLA-4) that are being tested in clinical trials with evidence of antitumoural activity. As a drawback, anti-CTLA-4 monoclonal antibodies induce severe autoimmunity reactions in a fraction of the patients. Anti-CD137 monoclonal antibodies have the ability to induce potent immune responses mainly mediated by cytotoxic lymphocytes with the result of frequent complete tumour eradications in mice. Comparative studies in experimental models indicate that the antitumour activity of anti-CD137 monoclonal antibodies is superior to that of anti-CD152. CD137 (4-1BB) is a leukocyte differentiation antigen selectively expressed on the surface of activated T and NK lymphocytes, as well as on dendritic cells. Monoclonal antibodies acting as artificial stimulatory ligands of this receptor (anti-CD137 agonist antibodies) enhance cellular antitumoural and antiviral immunity in a variety of mouse models. Paradoxically, anti-CD137 monoclonal antibodies are therapeutic or preventive in the course of model autoimmune diseases in mice. In light of these experimental results, a number of research groups have humanized antibodies against human CD137 and early clinical trials are about to start.

[Predictive score of success adapted to our environment to improve results of extracorporeal lithotripsy]. / Sistema predictivo de éxito adaptado a nuestro medio para mejorar los resultados de la Litotricia Extracorpórea.

OBJECTIVE: To present a predictive tool of success of ESWL adapted to our environment. METHODS: We performed a retrospective, descriptive and analytical study of patients with renal and upper ureteral stones whom underwent ESWL with DUET MAGNA lithotripter between January 2014 and March 2015. We included 114 patients in whom demographics and CT scan characteristics were studied. Multivariate analysis by logistic regression was performed to establish independent predictors of success in ESWL. A ROC curve was used to determine success cut-off values of ESWL in each significant variable. The score was established based on the numbers of variables under the cut-off value in each patient. In every one of these categories, percentage of stone free was determined. Finally, the area under the curve of our ESWL treatment success score was made. RESULTS: Of 114 patients studied, 58 (51%) were stone free. After multivariate study, independent predictors of success with ESWL were tomographic density of lithiasis (UH), body mass index (BMI) and stone diameter (mm). Ideal cut off points of treatment success in each one of the score parameters were: density of lithiasis 900 UH, BMI 27 and lithiasis diameter 11 mm. Percentage of stone free was 31.8% for score 0, 37.1% for score 1, 57.5% for score 2 and 88.3% for score 3. Area under the curve for the score was 0.723 (p<0.001). CONCLUSIONS: This score could represent a predictive tool in our environment to predict ESWL results. Utilization of this score could limit the use of this therapy only to patients with favorable profile (score2-3) improving in this way cost-effectiveness of this procedure.

El potencial de la inmunomodulación con anticuerpos monoclonales anti-CD137 (4-1BB) para terapia de enfermedades malignas e infecciones virales crónicas / The immunotherapy potential of agonistic anti-CD137 (4-1BB) monoclonal antibodies for malignancies and chronic viral diseases

La manipulación farmacológica del sistema inmunitario para conseguir respuestas linfocitarias de mayor intensidad tiene aplicación potencial en inmunoterapia tumoral y en el tratamiento de enfermedades virales crónicas. Los anticuerpos monoclonales inmunoestimuladores se definen como una familia de fármacos que aumentan la respuesta inmunitaria al interaccionar como ligandos artificiales con proteínas funcionales del sistema inmunitario, activando o inhibiendo su función. Hay anticuerpos monoclonales humanizados dirigidos frente al receptor inhibidor linfocitario CD152 (CTLA-4) que se están probando en ensayos clínicos con evidencia de actividad antitumoral, aunque con la contrapartida de producir reacciones autoinmunitarias severas. Los anticuerpos anti-CD137 tienen la capacidad de inducir potentes respuestas inmunitarias, mediadas principalmente por linfocitos T citotóxicos, con el resultado de erradicar tumores transplantables de ratón de forma comparativamente superior a los anticuerpos frente a CD152. CD137 (4-1BB) es un antígeno de diferenciación expresado selectivamente en la superficie de linfocitos T y NK activados y sobre células dendríticas. Los anticuerpos monoclonales que actúan como ligandos artificiales estimuladores de este receptor (anticuerpos monoclonales agonistas anti-CD137) potencian la inmunidad celular antitumoral y antiviral en modelos experimentales murinos. Paradójicamente, estos mismos anticuerpos previenen o mejoran el curso de enfermedades autoinmunitarias establecidas en ratones como modelo. A la luz de estos datos experimentales, varios grupos de investigación han procedido a la humanización de anticuerpos dirigidos frente a CD137 humano y se plantea la inminente realización de los primeros ensayos clínicos

Pharmacological intervention on the immune system to achieve more intense lymphocyte responses has potential application in tumour immunology and in the treatment of chronic viral diseases. Immunostimulating monoclonal antibodies are defined as a new family of drugs that augment cellular immune responses. They interact as artificial ligands with functional proteins of the immune system, either activating or inhibiting their functions. There are humanized monoclonal antibodies directed to the inhibitory receptor CD152 (CTLA-4) that are being tested in clinical trials with evidence of antitumoural activity. As a drawback, anti-CTLA-4 monoclonal antibodies induce severe autoimmunity reactions in a fraction of the patients. Anti-CD137 monoclonal antibodies have the ability to induce potent immune responses mainly mediated by cytotoxic lymphocytes with the result of frequent complete tumour eradications in mice. Comparative studies in experimental models indicate that the antitumour activity of anti-CD137 monoclonal antibodies is superior to that of anti-CD152. CD137 (4-1BB) is a leukocyte differentiation antigen selectively expressed on the surface of activated T and NK lymphocytes, as well as on dendritic cells. Monoclonal antibodies acting as artificial stimulatory ligands of this receptor (anti-CD137 agonist antibodies) enhance cellular antitumoural and antiviral immunity in a variety of mouse models. Paradoxically, anti-CD137 monoclonal antibodies are therapeutic or preventive in the course of model autoimmune diseases in mice. In light of these experimental results, a number of research groups have humanized antibodies against human CD137 and early clinical trials are about to start

Respuesta inmunitaria en la infección por el virus de la hepatitis C / Immune response in hepatitis C virus infection

La infección por el virus de la hepatitis C (VHC) se caracteriza por la alta tasa de cronificación viral. Aunque los tratamientos antivirales son eficaces en algunos pacientes, todavía queda un porcentaje alto de ellos que permanece crónicamente infectado. El estudio de los mecanismos del sistema inmunitario involucrados en la eliminación viral es importante tanto para el desarrollo de vacunas como para la comprensión de los fenómenos inmunopatológicos asociados a la infección. Aunque todos los pacientes con infección crónica desarrollan anticuerpos f rente a las proteínas virales, el alto grado de mutación de las regiones reconocidas por anticuerpos neutralizantes hace que la respuesta humoral no sea eficaz. Por otro lado, la eliminación de la infección por VHC tras una hepatitis aguda o tras el tratamiento con IFN- , se asocia con una potente respuesta de los linfocitos T CD4 y CD8, junto con un perfil de citocinas Th1. Sin embargo, la infección crónica viene acompañada con bajas respuestas inmunitarias c e l u l a res, así como un perfil de citocinas de tipo Th2.Además de su alta tasa de mutación, el VHC ha desarrollado mecanismos de interacción con componentes celulare s que desempeñan el normal funcionamiento del sistema inmunitario, permitiendo así la evasión de la respuesta y la cronificación viral. Las futuras vacunas, así como los tratamientos frente al VHC, habrán de tener en cuenta estos factores para conseguir una eliminación eficaz de la infección (AU)