RESUMO
Maternal-fetal immune-tolerance occurs throughout the whole gestational trimester, thus a mother can accept a genetically distinct fetus without immunological aggressive behavior. HLA-G, one of the non-classical HLA class I molecules, is restricted-expression at extravillous trophoblast. It can concordantly interact with various kinds of receptors mounted on maternally immune cells residing in the uterus (e.g. CD4+ T cells, CD8+ T cells, natural killer cells, macrophages, and dendritic cells) for maintaining immune homeostasis of the maternal-fetus interface. HLA-G is widely regarded as the pivotal protective factor for successful pregnancies. In the past 20 years, researches associated with HLA-G have been continually published. Indeed, HLA-G plays a mysterious role in the mechanism of maternal-fetal immune-tolerance. It can also be ectopically expressed on tumor cells, infected sites and other pathologic microenvironments to confer a significant local tolerance. Understanding the characteristics of HLA-G in immunologic tolerance is not only beneficial for pathological pregnancy, but also helpful to the therapy of other immune-related diseases, such as organ transplant rejection, tumor migration, and autoimmune disease. In this review, we describe the biological properties of HLA-G, then summarize our understanding of the mechanisms of fetomaternal immunologic tolerance and the difference from transplant tolerance. Furthermore, we will discuss how HLA-G contributes to the tolerogenic microenvironment during pregnancy. Finally, we hope to find some new aspects of HLA-G in fundamental research or clinical application for the future.
Assuntos
Feto/imunologia , Antígenos HLA-G/imunologia , Privilégio Imunológico/imunologia , Animais , Feminino , Humanos , GravidezRESUMO
Macrophages are functionally plastic and can thus play different roles in various microenvironments. Testis is an immune privileged organ, and testicular macrophages (TMs) show special immunosuppressive phenotype and low response to various inflammatory stimuli. However, the underlying mechanism to maintain the immunosuppressive function of TMs remains unclear. S100A9, a small molecular Ca2+ binding protein, is associated with the immunosuppressive function of macrophages. However, no related research is available about S100A9 in mouse testis. In the present study, we explored the role of S100A9 in TMs. We found that S100A9 was expressed in TMs from postnatal to adulthood and contributed to maintaining the immunosuppressive phenotype of TMs, which is associated with the activation of PI3K/Akt pathway. S100A9 treatment promotes the polarization of bone marrow-derived macrophages from M0 to M2 in vitro. S100A9 was significantly increased in TMs following UPEC-infection and elevated S100A9 contributed to maintain the M2 polarization of TMs. Treatment with S100A9 and PI3K inhibitor decreased the proportion of M2-type TMs in control and UPEC-infected mouse. Our findings reveal a crucial role of S100A9 in maintaining the immunosuppressive function of TMs through the activation of PI3K/Akt pathway, and provide a reference for further understanding the mechanism of immunosuppressive function of TMs.
Assuntos
Calgranulina B/imunologia , Privilégio Imunológico/imunologia , Macrófagos/imunologia , Fosfatidilinositol 3-Quinases/imunologia , Proteínas Proto-Oncogênicas c-akt/imunologia , Testículo/imunologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/imunologiaRESUMO
Cancer stem cells (CSCs) are broadly considered immature, multipotent, tumorigenic cells within the tumor mass, endowed with the ability to self-renew and escape immune control. All these features contribute to place CSCs at the pinnacle of tumor aggressiveness and (immune) therapy resistance. The immune privileged status of CSCs is induced and preserved by various mechanisms that directly affect them (e.g., the downregulation of the major histocompatibility complex class I) and indirectly are induced in the host immune cells (e.g., activation of immune suppressive cells). Therefore, deeper insights into the immuno-biology of CSCs are essential in our pursuit to find new therapeutic opportunities that eradicate cancer (stem) cells. Here, we review and discuss the ability of CSCs to evade the innate and adaptive immune system, as we offer a view of the immunotherapeutic strategies adopted to potentiate and address specific subsets of (engineered) immune cells against CSCs.
Assuntos
Privilégio Imunológico/imunologia , Neoplasias/imunologia , Células-Tronco Neoplásicas/imunologia , Evasão Tumoral/imunologia , Imunidade Adaptativa/imunologia , Animais , Humanos , Imunidade Inata/imunologiaRESUMO
The success of pregnancy relies on the fine adjustment of the maternal immune system to tolerate the allogeneic fetus. Trophoblasts carrying paternal antigens are the only fetal-derived cells that come into direct contact with the maternal immune cells at the maternal-fetal interface. The crosstalk between trophoblasts and decidual immune cells (DICs) via cell-cell direct interaction and soluble factors such as chemokines and cytokines is a core event contributing to the unique immunotolerant microenvironment. Abnormal trophoblasts-DICs crosstalk can lead to dysregulated immune situations, which is well known to be a potential cause of a series of pregnancy complications including recurrent spontaneous abortion (RSA), which is the most common one. Immunotherapy has been applied to RSA. However, its development has been far less rapid or mature than that of cancer immunotherapy. Elucidating the mechanism of maternal-fetal immune tolerance, the theoretical basis for RSA immunotherapy, not only helps to understand the establishment and maintenance of normal pregnancy but also provides new therapeutic strategies and promotes the progress of immunotherapy against pregnancy-related diseases caused by disrupted immunotolerance. In this review, we focus on recent progress in the maternal-fetal immune tolerance mediated by trophoblasts-DICs crosstalk and clinical application of immunotherapy in RSA. Advancement in this area will further accelerate the basic research and clinical transformation of reproductive immunity and tumor immunity.
Assuntos
Decídua/imunologia , Privilégio Imunológico/imunologia , Trofoblastos/imunologia , Aborto Habitual/imunologia , Aborto Habitual/terapia , Animais , Feminino , Humanos , Imunoterapia/métodos , GravidezRESUMO
The skin forms a barrier that prevents dehydration and keeps us safe from pathogens. To ensure proper function, the skin possesses a myriad of stem cell populations that are essential for maintenance and repair upon damage. In order to protect, the skin is also an active immunological site, with abundant resident immune cells and strong recruitment of even more immune cells during wounding or infection. Such active and strong immunity makes the skin susceptible to a diverse spectrum of autoimmune diseases, such as vitiligo and alopecia areata. Conversely, despite constant immune surveillance, the skin is also a tissue where frequent malignancies occur, which suggests that immune evasion must also take place. Skin stem cells play a crucial role during both regeneration and tumorigenesis. How immune cells, and in particular T cells, interact with skin stem cells and the implications this crosstalk has in skin disease (both autoimmunity and cancer) is not fully understood. Uncovering the mechanisms governing immune-stem cells interactions in the skin is critical for the development of new therapeutic strategies to safeguard susceptible cells during autoimmunity and, conversely, to improve cancer immunotherapy. Here, I will discuss how distinct skin stem cell populations are attacked by, or conversely, cloaked from immune cells, and the implications their differences have in autoimmunity and cancer.
Assuntos
Autoimunidade/imunologia , Privilégio Imunológico/imunologia , Neoplasias Cutâneas/imunologia , Pele/imunologia , Células-Tronco/imunologia , Linfócitos T/imunologia , HumanosRESUMO
The eye is provided with immune protection against pathogens in a manner that greatly reduces the threat of inflammation-induced vision loss. Immune-mediated inflammation and allograft rejection are greatly reduced in the eye, a phenomenon called 'immune privilege'. Corneal tissue has inherent immune privilege properties with underlying three mechanisms: (1) anatomical, cellular, and molecular barriers in the cornea; (2) an immunosuppressive microenvironment; and (3) tolerance related to regulatory T cells and anterior chamber-associated immune deviation. This review describes the molecular mechanisms of the immunosuppressive microenvironment and regulatory T cells in the cornea that have been elucidated from animal models of ocular inflammation, especially those involving corneal transplantation, it also provides an update on immune checkpoint molecules in corneal and systemic immune regulation, and its relevance for dry eye associated with checkpoint inhibitor therapy.
Assuntos
Córnea/imunologia , Síndromes do Olho Seco/imunologia , Privilégio Imunológico/imunologia , Sistema Imunitário , Animais , Câmara Anterior/imunologia , Antígeno B7-H1/metabolismo , Transplante de Córnea , Proteína Ligante Fas/metabolismo , Rejeição de Enxerto/imunologia , Humanos , Tolerância Imunológica , Fatores Imunológicos , Imunossupressores/uso terapêutico , Inflamação , Ligantes , Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Receptor fas/metabolismoRESUMO
In mammals, the uterine mucosal immune system simultaneously recognizes and reacts to most bacteria as well as allogenic sperm mainly through the Toll-like receptors (TLR)2/4 signaling pathway. Here, we characterized the impact of pathogen-derived TLR2/4 ligands (peptidoglycan (PGN)/lipopolysaccharide (LPS)) on the immune crosstalk of sperm with the bovine endometrial epithelium. The real-time PCR analysis showed that the presence of low levels of PGN, but not LPS, blocked the sperm-induced inflammatory responses in bovine endometrial epithelial cells (BEECs) in vitro. Immunoblotting analysis revealed that PGN prevented the sperm-induced phosphorylation of JNK in BEECs. Activation or blockade of the TLR2 system in the endometrial epithelium verified that TLR2 signaling acts as a commonly-shared pathway for PGN and sperm recognition. The impairment of endometrial sperm recognition, induced by PGN, subsequently inhibited sperm phagocytosis by polymorphonuclear neutrophils (PMNs). Moreover, using an ex vivo endometrial explant that more closely resembles those in vivo conditions, showed that sperm provoked a mild and reversible endometrial tissue injury and triggered PMN recruitment into uterine glands, while PGN inhibited these events. Of note, PGN markedly increased the sperm attachment to uterine glands, and relatively so in the surface epithelium. However, addition of the anti-CD44 antibody into a PGN-sperm-explant co-culture completely blocked sperm attachment into glands and surface epithelia, indicating that the CD44 adhesion molecule is involved in the PGN-triggered sperm attachment to the endometrial epithelium. Together, these findings demonstrate that, the presence of PGN residues disrupts sperm immune recognition and prevents the physiological inflammation induced by sperm in the endometrial epithelium via the MyD88-dependent pathway of TLR2 signaling, possibly leading to impairment of uterine clearance and subsequent embryo receptivity.
Assuntos
Endométrio/imunologia , Privilégio Imunológico/imunologia , Peptidoglicano/imunologia , Espermatozoides/imunologia , Receptor 2 Toll-Like/imunologia , Animais , Bovinos , Feminino , Imunidade nas Mucosas/imunologia , Lipopolissacarídeos/imunologia , Masculino , GravidezRESUMO
BACKGROUND: Cancer stem cells (CSCs) have innate abilities to resist even the harshest of therapies. To eradicate CSCs, parallels can be drawn from signalling modules that orchestrate pluripotency. Notch-Hedgehog hyperactivation are seen in CSCs, yet, not much is known about their conserved roles in tumour progression across cancers. METHODS: Employing a comparative approach involving 21 cancers, we uncovered clinically-relevant, pan-cancer drivers of Notch and Hedgehog. GISTIC datasets were used to evaluate copy number alterations. Receiver operating characteristic and Cox regression were employed for survival analyses. RESULTS: We identified a Notch-Hedgehog signature of 13 genes exhibiting high frequencies of somatic amplifications leading to transcript overexpression. The signature successfully predicted patients at risk of death in five cancers (n = 2278): glioma (P < 0.0001), clear cell renal cell (P = 0.0022), papillary renal cell (P = 0.00099), liver (P = 0.014) and stomach (P = 0.011). The signature was independent of other clinicopathological parameters and offered an additional resolution to stratify similarly-staged tumours. High-risk patients exhibited features of stemness and had more hypoxic tumours, suggesting that hypoxia may influence CSC behaviour. Notch-Hedgehog+ CSCs had an immune privileged phenotype associated with increased regulatory T cell function. CONCLUSION: This study will set the stage for exploring adjuvant therapy targeting the Notch-Hedgehog axis to help optimise therapeutic regimes leading to successful CSC elimination.
Assuntos
Neoplasias/genética , Células-Tronco Neoplásicas/metabolismo , Linfócitos T Reguladores/imunologia , Evasão Tumoral/genética , Hipóxia Tumoral/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/imunologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/imunologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/imunologia , Variações do Número de Cópias de DNA , Bases de Dados Genéticas , Progressão da Doença , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/imunologia , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Glioma/genética , Glioma/imunologia , Proteínas Hedgehog/genética , Humanos , Privilégio Imunológico/imunologia , Neoplasias Renais/genética , Neoplasias Renais/imunologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Masculino , Neoplasias/imunologia , Células-Tronco Neoplásicas/imunologia , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC , Receptores Notch/genética , Transdução de Sinais , Neoplasias Gástricas/genética , Neoplasias Gástricas/imunologiaRESUMO
It has been hypothesized that anterior chamber-associated immune deviation (ACAID) to neural antigens induced prior to central nervous system injury can inhibit self-reactivity and lessen secondary degeneration. This work evaluated the effect of ACAID induced to three neural tissue-derived extracts (whole extract, cytosolic extract, CE; or organelle-membrane extract) prior to optic nerve injury on retinal ganglion cell (RGC) survival. The results show that only ACAID to the CE increased RGC survival at 7 and14 days post-injury (dpi). This effect was achieved by retinal polarization towards an anti-inflammatory profile, driven by regulatory T cells and M2-type macrophages at 7 dpi.
Assuntos
Câmara Anterior/imunologia , Autoantígenos/imunologia , Privilégio Imunológico/imunologia , Traumatismos do Nervo Óptico/imunologia , Retina/imunologia , Animais , Autoimunidade , Citosol/imunologia , Feminino , Hipersensibilidade Tardia/imunologia , Macrófagos/imunologia , Compressão Nervosa , Fatores de Crescimento Neural/biossíntese , Fatores de Crescimento Neural/genética , Ratos , Ratos Wistar , Células Ganglionares da Retina/imunologia , Linfócitos T Reguladores/imunologiaRESUMO
Despite their abilities to elicit immune responses, both syngeneic tumors and the half-mismatched placenta grow in the host, unlike a tissue allograft that is aggressively rejected. This is because of local and systemic factors that contribute to the immunologic privilege of tumors and the placenta. Checkpoint blockade immunotherapies subvert this privilege, with spectacularly beneficial outcomes in subsets of patients with certain types of cancer. A challenge for the community of scientists and clinicians is to replicate these successes in pregnant patients with cancer, without harm to the placenta. Here we compare and contrast the immunology of cancers and the placenta, and suggest that immunotherapy for pregnant patients with cancer may be a reasonable option, but that this should be explored systematically.
Assuntos
Privilégio Imunológico/imunologia , Imunoterapia/métodos , Neoplasias/terapia , Placenta/imunologia , Complicações Neoplásicas na Gravidez/terapia , Feminino , Antígenos HLA/imunologia , Humanos , Neoplasias/imunologia , Neoplasias/metabolismo , Placenta/metabolismo , Gravidez , Complicações Neoplásicas na Gravidez/imunologia , Complicações Neoplásicas na Gravidez/metabolismo , Linfócitos T/imunologiaRESUMO
Glioblastoma is a highly aggressive neoplasm with an extremely poor prognosis. Despite maximal gross resection and chemoradiotherapy, these grade IV astrocytomas consistently recur. Glioblastoma cells exhibit numerous pathogenic mechanisms to decrease tumor immunogenicity while promoting gliomagenesis, which manifests clinically as a median survival of less than 2 years and few long-term survivors. Recent clinical trials of vaccine-based immunotherapeutics against glioblastoma have demonstrated encouraging results in prolonging progression-free survival and overall survival. Several vaccine-based treatments have been trialed, such as peptide and heat-shock proteins, dendritic cell-based vaccines, and viral-based immunotherapy. In this literature review, we discuss the immunobiology of glioblastoma, significant current and completed vaccine-based immunotherapy clinical trials, and broad clinical challenges and future directions of glioblastoma vaccine-based immunotherapeutics.