RESUMEN
IL-7 plays many essential roles in human health and disease. Congenital deficiencies in IL-7 signaling result in profound immunodeficiency, polymorphisms in IL7Rα modulate susceptibility to autoimmune disease, and acquired somatic activating mutations in IL7Rα contribute to neoplastic transformation in B cell and T cell leukemia. In response to lymphopenia, IL-7 accumulates to supranormal levels, which alters T cell homeostasis by augmenting T cell reactivity toward self and cognate antigens. This physiologic response is now routinely exploited to improve the efficacy of adoptive cell therapies for cancer. Clinical trials of recombinant IL-7 have demonstrated safety and potent immunorestorative effects, and current studies are investigating whether rhIL-7 therapy can improve outcomes in chronic viral infection and in the context of cancer immunotherapies. Building upon the large fund of knowledge regarding the basic biology of IL-7, this review will discuss the many and varied roles of IL-7 in human health and disease.
Asunto(s)
Interleucina-7/inmunología , Animales , Autoinmunidad , Diferenciación Celular , Homeostasis , Humanos , Linfocitos/citología , Linfocitos/inmunología , Receptores de Interleucina-7/inmunologíaRESUMEN
To begin to understand the contributions of maternal obesity and over-nutrition to human development and the early origins of obesity, we utilized a non-human primate model to investigate the effects of maternal high-fat feeding and obesity on breast milk, maternal and fetal plasma fatty acid composition and fetal hepatic development. While the high-fat diet (HFD) contained equivalent levels of n-3 fatty acids (FA's) and higher levels of n-6 FA's than the control diet (CTR), we found significant decreases in docosahexaenoic acid (DHA) and total n-3 FA's in HFD maternal and fetal plasma. Furthermore, the HFD fetal plasma n-6:n-3 ratio was elevated and was significantly correlated to the maternal plasma n-6:n-3 ratio and maternal hyperinsulinemia. Hepatic apoptosis was also increased in the HFD fetal liver. Switching HFD females to a CTR diet during a subsequent pregnancy normalized fetal DHA, n-3 FA's and fetal hepatic apoptosis to CTR levels. Breast milk from HFD dams contained lower levels of eicosopentanoic acid (EPA) and DHA and lower levels of total protein than CTR breast milk. This study links chronic maternal consumption of a HFD with fetal hepatic apoptosis and suggests that a potentially pathological maternal fatty acid milieu is replicated in the developing fetal circulation in the nonhuman primate.
Asunto(s)
Apoptosis/efectos de los fármacos , Grasas de la Dieta/efectos adversos , Ácidos Grasos Omega-3/sangre , Feto/efectos de los fármacos , Hígado/efectos de los fármacos , Fenómenos Fisiologicos Nutricionales Maternos , Animales , Apoptosis/fisiología , Dieta Aterogénica , Ácidos Grasos Omega-3/análisis , Ácidos Grasos Omega-3/metabolismo , Femenino , Sangre Fetal/química , Sangre Fetal/metabolismo , Feto/metabolismo , Feto/patología , Humanos , Hígado/embriología , Hígado/patología , Embarazo , Efectos Tardíos de la Exposición Prenatal/patología , Primates , Distribución AleatoriaRESUMEN
Cytokines that signal through the common-gamma chain are potent growth factors for T cells and natural killer cells. Interleukin (IL)-2, the gammac prototype, can mediate antitumor effects as a single agent or in the context of multimodality regimens but is limited by side effects and a propensity for expansion of regulatory T cells. IL-7, IL-15, and IL-21 each possess properties that can be exploited in the context of immunotherapy for cancer. Each has been demonstrated to mediate potent vaccine adjuvant effects in tumor models, and each can enhance the effectiveness of adoptive immunotherapies. Although the overlap among the agents is significant, IL-7 is uniquely immunorestorative and preferentially augments reactivity of naive populations, IL-15 potently augments reactivity of CD8 memory cells and natural killer cells, and IL-21 preferentially expands the inflammatory Th17 subset and may limit terminal differentiation of effector CD8 cells. Clinical trials of IL-7 and IL-21 have already been completed and, so far, demonstrate safety and biologic activity of these agents. Clinical trials of IL-15 are expected soon. Ultimately, these agents are expected to be most effective in the context of multimodal immunotherapy regimens, and careful clinical trial design will be needed to efficiently identify the proper doses, regimens, and settings in which to exploit their biologic properties for therapeutic gain.
Asunto(s)
Citocinas/inmunología , Citocinas/uso terapéutico , Inmunoterapia/métodos , Neoplasias/inmunología , Neoplasias/terapia , Animales , HumanosRESUMEN
Essential survival signals within hematopoietic stem cell (HSC) and thymic niches are mediated by receptor tyrosine kinases, which can be reversibly inhibited using clinically available drugs. We studied whether sunitinib, a multityrosine kinase inhibitor that inhibits KIT, enhances engraftment after bone marrow transplantation (BMT) in mice. Sunitinib diminished hematopoietic progenitor cell numbers, and sunitinib enhanced marrow, peripheral myeloid, and lymphoid engraftment after BMT in Rag1(-/-) mice. Sunitinib augmented HSC engraftment because recipients displayed increased myeloid and lymphoid engraftment and because sunitinib-treated recipients of purified HSCs showed enhanced engraftment of secondary hosts. However, sunitinib preferentially augmented T-cell engraftment with lesser effects on myeloid and HSC engraftment. Consistent with this, sunitinib preferentially depleted the early thymic progenitor subset in the thymus. Sunitinib did not increase engraftment in mice with deficient KIT signaling, and the pattern of more potent effects on T cell compared with HSC engraftment observed in sunitinib-treated hosts was also observed after BMT into KIT(W/Wv) mice. These results implicate KIT as a critical modulator of thymic niches. We conclude that transient, pharmacologic inhibition of KIT enhances accessibility of marrow and thymic niches, and provides a novel, noncytotoxic approach to accomplish engraftment after stem cell transplantation.