1,720,968 research outputs found
Htlv-1 infection and pathogenesis: New insights from cellular and animal models
Full text linkSince the discovery of the human T-cell leukemia virus-1 (HTLV-1), cellular and animal models have provided invaluable contributions in the knowledge of viral infection, transmission and progression of HTLV-associated diseases. HTLV-1 is the causative agent of the aggressive adult T-cell leukemia/lymphoma and inflammatory diseases such as the HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). Cell models contribute to defining the role of HTLV proteins, as well as the mechanisms of cell-to-cell transmission of the virus. Otherwise, selected and engineered animal models are currently applied to recapitulate in vivo the HTLV-1 associated pathogenesis and to verify the effectiveness of viral therapy and host immune response. Here we review the current cell models for studying virus–host interaction, cellular restriction factors and cell pathway deregulation mediated by HTLV products. We recapitulate the most effective animal models applied to investigate the pathogenesis of HTLV-1-associated diseases such as transgenic and humanized mice, rabbit and monkey models. Finally, we summarize the studies on STLV and BLV, two closely related HTLV-1 viruses in animals. The most recent anticancer and HAM/TSP therapies are also discussed in view of the most reliable experimental models that may accelerate the translation from the experimental findings to effective therapies in infected patients
Unveiling the hidden treasury: Ciita-driven mhc class ii expression in tumor cells to dig up the relevant repertoire of tumor antigens for optimal stimulation of tumor specific cd4+ t helper cells
Full text linkDespite the recent enthusiasm generated by novel immunotherapeutic approaches against cancer based on immune checkpoint inhibitors, it becomes increasingly clear that single immune-based strategies are not sufficient to defeat the various forms and types of tumors. Within this frame, novel vaccination strategies that are based on optimal stimulation of the key cell governing adaptive immunity, the CD4+ T helper cell, will certainly help in constructing more efficient treatments. In this review, we will focus on this aspect, mainly describing our past and recent contributions that, starting with a rather unorthodox approach, have ended up with the proposition of a new idea for making available an unprecedented extended repertoire of tumor antigens, both in quantitative and qualitative terms, to tumor-specific CD4+ T helper cells. Our approach is based on rendering the very same tumor cells antigen presenting cells for their own tumor antigens by gene transfer of CIITA, the major transcriptional coordinator of MHC class II expression discovered in our laboratory. CIITA-driven MHC class II-expressing tumor cells optimally stimulate in vivo tumor specific MHC class II-restricted CD4 T cells generating specific and long lasting protective immunity against the tumor. We will discuss the mechanism underlying protection and elaborate not only on the applicability of this approach for novel vaccination strategies amenable to clinical setting, but also on the consequence of our discoveries on sedimented immunological dogmas that are related to antigen presentation
Tumor recognition and acquisition of protecting adaptive anti-tumor immune response in vivo against CIITA-driven MHC class II expressing Oral Squamous Cell Carcinoma Cells
No full textRestriction factors in human retrovirus infections and the unprecedented case of CIITA as link of intrinsic and adaptive immunity against HTLV-1
No full textBackground Immunity against pathogens evolved through complex mechanisms that only for sake of simplicity are defined as innate immunity and adaptive immunity. Indeed innate and adaptive immunity are strongly intertwined each other during evolution. The complexity is further increased by intrinsic mechanisms of immunity that rely on the action of intracellular molecules defined as restriction factors (RFs) that, particularly in virus infections, counteract the action of pathogen gene products acting at different steps of virus life cycle. Main body and conclusion Here we provide an overview on the nature and the mode of action of restriction factors involved in retrovirus infection, particularly Human T Leukemia/Lymphoma Virus 1 (HTLV-1) infection. As it has been extensively studied by our group, special emphasis is given to the involvement of the MHC class II transactivator CIITA discovered in our laboratory as regulator of adaptive immunity and subsequently as restriction factor against HIV-1 and HTLV-1, a unique example of dual function linking adaptive and intrinsic immunity during evolution. We describe the multiple molecular mechanisms through which CIITA exerts its restriction on retroviruses. Of relevance, we review the unprecedented findings pointing to a concerted action of several restriction factors such as CIITA, TRIM22 and TRIM19/PML in synergizing against retroviral replication. Finally, as CIITA profoundly affects HTLV-1 replication by interacting and inhibiting the function of HTLV-1 Tax-1 molecule, the major viral product associated to the virus oncogenicity, we also put forward the hypothesis of CIITA as counteractor of HTLV-1-mediated cancer initiation
Tumor recognition and acquisition of protecting adaptive anti-tumor immune response in vivo against CIITA-driven MHC class II expressing Oral Squamous Cell Carcinoma Cells
No full textBackground: We have previously demonstrated that cells from MHC class II-negative solid tumors can function as surrogate Antigen Presenting Cells (APCs) for their own tumor antigens, provided they optimally express MHC class II (MHC-II) molecules as a function of genetic transfer of the MHC class II transactivator CIITA. CIITA positive tumors became potent stimulators of a protective adaptive antitumor immune response, triggered by CD4+ T helper (Th) cells and mediated by both Th cells and tumor specific CD8+ cytolytic (CTL). Here we extend our approach to Oral Squamous Cell Carcinoma (OSCC), the most common malignant neoplasm of the oral cavity for which, despite advances in detection and standard therapeutic approaches, the prognosis is poor due to a high rate of locoregional recurrence and development of distant metastasis.
Methods: Syngeneic C57BL/6 mice were injected subcutaneously (s.c.) with either parental Mouse Oral Cancer 2 parental (MOC2pc) or MOC2-CIITA tumor cells and tumor growth was checked at least twice a week, using a manual caliper. Mice which have rejected MOC2-CIITA tumor cells were challenged s.c. with MOC2pc. The size for the tumor was measured weekly as described above. For Adoptive Cells Transfer (ACT) experiments, mice were injected s.c. MOC2 cells plus total naïve splenocytes, or total immune splenocytes, or immune CD4+ or CD8+ lymphocytes previously isolated from spleens of mice vaccinated with MOC2-CIITA tumor cells and challenged with MOC2pc that showed no tumor growth.
Results: CIITA-driven MHC-II+ MOC2 tumor cells were rejected or strongly retarded in their growth in vivo. When challenged with MOCpc, these animals strongly delayed tumor growth, indicating the acquisition of an anamnestic response. ACT experiments showed that total spleen cells from tumor protected mice, as well as CD8+ and, more importantly, CD4+ spleen cells significantly protected from MOC2pc tumor take, demonstrating the ability of CIITA-transfected tumor cells to stimulate an adaptive immunity based on the triggering of tumor specific Th and CTL cells.
Conclusions: These results validate our vaccination approach also in OSCC emphasizing the importance of the expression of MHC-II molecules driven by CIITA, to render tumor cells surrogate APC for their own tumor antigens in vivo and thus open the way to characterize the specific antigenic peptides valuable for possible novel formulations of anti-tumor vaccines
A Truncated Isoform of Cyclin T1 Could Contribute to the Non-Permissive HIV-1 Phenotype of U937 Promonocytic Cells
Full text linkThe different susceptibility to HIV-1 infection in U937 cells-permissive (Plus) or nonpermissive (Minus)-is linked to the expression in Minus cells of interferon (IFN)-gamma inducible antiviral factors such as tripartite motif-containing protein 22 (TRIM22) and class II transactivator (CIITA). CIITA interacts with Cyclin T1, a key component of the Positive-Transcription Elongation Factor b (P-TEFb) complex needed for the efficient transcription of HIV-1 upon interaction with the viral transactivator Tat. TRIM22 interacts with CIITA, recruiting it into nuclear bodies together with Cyclin T1. A 50 kDa Cyclin T1 was found only in Minus cells, alongside the canonical 80 kDa protein. The expression of this truncated form remained unaffected by proteasome inhibitors but was reduced by IFN gamma treatment. Unlike the nuclear full-length protein, truncated Cyclin T1 was also present in the cytoplasm, and this subcellular localization correlated with its capacity to inhibit Tat-mediated HIV-1 transcription. The 50 kDa Cyclin T1 in Minus cells likely contributes to their non-permissive phenotype by acting as a dominant negative factor, disrupting P-TEFb complex formation and function. Its reduction upon IFN gamma treatment suggests a regulatory loop by which its inhibitory role on HIV-1 replication is then exerted by the IFN gamma-induced CIITA, which binds to the canonical Cyclin T1, displacing it from the P-TEFb complex
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
The NLR member CIITA: Master controller of adaptive and intrinsic immunity and unexpected tool in cancer immunotherapy
Full text linkHuman nucleotide-binding oligomerization domain (NOD)-like receptors (NLR) include a large family of proteins that have important functions in basic physio-pathological processes like inflammation, cell death and regulation of transcription of key molecules for the homeostasis of the immune system. They are all characterized by a common backbone structure (the STAND ATPase module consisting in a nucleotide-binding domain (NBD), an helical domain 1 (HD1) and a winged helix domain (WHD), used by both prokaryotes and eukaryotes as defense mechanism. In this review, we will focus on the MHC class II transactivator (CIITA), the master regulator of MHC class II (MHC-II) gene expression and the founding member of NLR. Although a consistent part of the described NLR family components is often recalled as innate or intrinsic immune sensors, CIITA in fact occupies a special place as a unique example of regulator of both intrinsic and adaptive immunity. The description of the discovery of CIITA and the genetic and molecular characterization of its expression will be followed by the most recent studies that have unveiled this dual role of CIITA, key molecule in intrinsic immunity as restriction factor for human retroviruses and precious tool to induce the expression of MHC-II molecules in cancer cells, rendering them potent surrogate antigen presenting cells (APC) for their own tumor antigens
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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