RESUMEN
Anti-Müllerian hormone receptor, type II (AMHR2), is a differentiation protein expressed in 90% of primary epithelial ovarian carcinomas (EOCs), the most deadly gynecologic malignancy. We propose that AMHR2 may serve as a useful target for vaccination against EOC. To this end, we generated the recombinant 399-amino acid cytoplasmic domain of mouse AMHR2 (AMHR2-CD) and tested its efficacy as a vaccine target in inhibiting growth of the ID8 transplantable EOC cell line in C57BL/6 mice and in preventing growth of autochthonous EOCs that occur spontaneously in transgenic mice. We found that AMHR2-CD immunization of C57BL/6 females induced a prominent antigen-specific proinflammatory CD4+ T cell response that resulted in a mild transient autoimmune oophoritis that resolved rapidly with no detectable lingering adverse effects on ovarian function. AMHR2-CD vaccination significantly inhibited ID8 tumor growth when administered either prophylactically or therapeutically, and protection against EOC growth was passively transferred into naive recipients with AMHR2-CD-primed CD4+ T cells but not with primed B cells. In addition, prophylactic AMHR2-CD vaccination of TgMISIIR-TAg transgenic mice significantly inhibited growth of autochthonous EOCs and provided a 41.7% increase in mean overall survival. We conclude that AMHR2-CD vaccination provides effective immunotherapy of EOC with relatively benign autoimmune complications.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Vacunas contra el Cáncer/administración & dosificación , Carcinoma/inmunología , Ooforitis/prevención & control , Neoplasias Ováricas/inmunología , Receptores de Péptidos/metabolismo , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Proteínas Recombinantes/administración & dosificación , Traslado Adoptivo , Animales , Linfocitos T CD4-Positivos/trasplante , Vacunas contra el Cáncer/efectos adversos , Carcinoma/genética , Carcinoma/prevención & control , Procesos de Crecimiento Celular , Línea Celular Tumoral , Células Cultivadas , Células Epiteliales/fisiología , Femenino , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Terapia Molecular Dirigida , Trasplante de Neoplasias , Ooforitis/etiología , Neoplasias Ováricas/genética , Neoplasias Ováricas/prevención & control , Ingeniería de Proteínas , Estructura Terciaria de Proteína/genética , Receptores de Péptidos/genética , Receptores de Factores de Crecimiento Transformadores beta/genéticaRESUMEN
High numbers of proinflammatory cells (PMNLs), which are carried by the blood to ischemic tissue during reperfusion, are considered responsible for inducing the inflammatory response that occurs in ischemia-reperfusion (I/R) injury. Our objective was to determine the controlled reperfusion (CR) interval duration (CRID) that would minimize the injury caused by the PMNLs that infiltrate ischemic tissue. Animal groups were divided into the following groups: Sham group, ovarian I/R group (OIR), and ovarian ischemia controlled-reperfusion groups OICR-1, OICR-2, OICR-3, OICR-4, OICR-5, OICR-6, which had their ovarian artery opened and then closed for 10, 8, 6, 4, 2, or 1 s, respectively. The results show that the COX-2 activity and the gene expression decreased while the COX-1 activity and the gene expression were found to be increased in parallel to the shortening of the period in CRID. From the histopathological examinations, the findings of hemorrhage, edema, congested vascular structures, degenerated cells, and migration and adhesion of PMNLs were scaled as follows: Sham group < OICR-6 < OICR-5 < OICR-4 < OICR-3 < OICR-2 < OICR-1. The results from the histopathological assessments were consistent with the molecular and biochemical findings. In conclusion, our findings suggest that increased COX-2 activity plays a role in I/R injury of the rat ovary, and that controlled reperfusion for 3, 2, or 1 s following 2 h of ischemia may attenuate the effects of I/R injury.
Asunto(s)
Regulación Enzimológica de la Expresión Génica , Infiltración Neutrófila , Neutrófilos/inmunología , Ooforitis/prevención & control , Ovario/irrigación sanguínea , Daño por Reperfusión/prevención & control , Reperfusión , Animales , Adhesión Celular , Ciclooxigenasa 1/genética , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Edema/etiología , Edema/prevención & control , Femenino , Hemorragia/etiología , Hemorragia/prevención & control , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Neutrófilos/metabolismo , Neutrófilos/patología , Ooforitis/inmunología , Ooforitis/metabolismo , Ooforitis/patología , Ovario/inmunología , Ovario/metabolismo , Ovario/patología , Ratas Wistar , Daño por Reperfusión/inmunología , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Factores de TiempoRESUMEN
Contraceptive vaccines can be designed to inhibit (i) production of the gametes (sperm and oocyte), (ii) functions of gametes leading to block in fertilization, and (iii) the gamete outcome (pregnancy). The zona pellucida (ZP) glycoproteins have been proposed as candidates for developing contraceptive vaccines by virtue of their critical role in fertilization. Immunization of non-human primates with either native or recombinant ZP proteins leads to curtailment of fertility, which however is invariably associated with ovarian pathology. To avoid oophoritis, immunogens corresponding to mapped B cell epitopes of ZP proteins that are devoid of 'oophoritogenic' T cell epitopes have been proposed. However, ways to overcome the observed oophoritis associated with the ZP-based contraceptive vaccines are yet to be fully defined. This is essential if their use for control of human fertility is to be considered. Nonetheless, contraceptive vaccines based on ZP proteins have shown very promising results in controlling wildlife population such as wild horses, white-tailed deers, elephants, marsupials, grey seals and dogs, where long term infertility or even permanent sterility is desirable.
Asunto(s)
Fertilización/efectos de los fármacos , Gametogénesis/efectos de los fármacos , Ovario/efectos de los fármacos , Vacunas Anticonceptivas/administración & dosificación , Zona Pelúcida/inmunología , Animales , Antígenos/inmunología , Antígenos/metabolismo , Mapeo Epitopo , Epítopos de Linfocito B/inmunología , Epítopos de Linfocito B/metabolismo , Femenino , Humanos , Ooforitis/etiología , Ooforitis/prevención & control , Ovario/inmunología , Ovario/patología , Regulación de la Población , Embarazo , Primates , Vacunas Anticonceptivas/efectos adversos , Vacunas Anticonceptivas/inmunología , Zona Pelúcida/metabolismoRESUMEN
Autoimmune oophoritis develops in some patients despite evidence of impaired cellular immunity. Here, using the murine postthymectomy model of autoimmune oophoritis, we investigate the hypothesis that neonatal thymectomy induces autoimmune oophoritis by disrupting the normal postnatal balance of T helper cell regulation. Stimulated CD4+ splenic lymphocytes from adult mice sham-operated as neonates produced the expected T helper type 1 (Th1) predominant response normally seen in adult mice (low levels of interleukin-4 and high levels of interferon gamma). In contrast, cells from adult mice thymectomized as neonates produced an inappropriate neonatal-like Th2-predominant response (high levels of interleukin-4 and low levels of interferon-gamma). Manipulations that restored the postnatal shift to an adult Th1-dominant pattern ameliorated the autoimmune oophoritis. Thus, neonatal thymectomy abrogates the postnatal shift to a Th1-dominant pattern, and the resulting persistent neonatal-like Th2-dominant response is tightly associated with the development of postthymectomy autoimmune oophoritis. These results (i) suggest that the postnatal shift to the normal adult Th1/Th2 balance is established by a thymus-dependent process and (ii) raise the possibility that specific genetic defects, as yet to be determined, might mimic the effect of neonatal thymectomy in this model, impair the development of normal Th1/Th2 balance, and be a cause autoimmunity. These results hold implications for the pathogenesis and possibly for the therapy of autoimmune polyglandular failure in humans.