Meme Kanseri Modelinde Myeloid Kökenli Hücrelerin Immün Kompartmanlardaki Dağılımının Anti-Tümör Yanıtlara Yansıması

Myeloid cells of peripheral blood, bone marrow and spleens from NMU induced mammary tumor bearing Sprague-Dawley rats were examined in this study. Myeloid derived suppressor cells (MDSCs) in tumor bearing rats are defined with CD11b/c+ HIS48+ immunophenotype. As this definition addresses both granulocytic and monocytic populations, we separated neutrophils from monocytic populations according to Rp-1 expression and classified monocytes into two sub groups regarding the HIS48 positivity. The RP-1+ neutrophil amounts increased prominently in peripheral blood and spleens of mammary tumor bearing Sprague Dawley rats. Rp-1+ neutrophils also suppressed the antigen specific CD4+ T cell proliferations. These neutrophils were the dominant suppressor populations and corresponded to the granulocytic-MDSCs. Reactive oxygen species (ROS), nitric oxide (NO) productions and TGF-β synthesis were found to be responsible for the suppressive effect of these neutrophils. Additionally, HIS48+ monocytes of tumor hosts had lower MHC class II expression, higher nitric oxide and TGF-β productions than HIS48- monocytes resembling the monocytic-MDSCs of mice. Here we report Rp-1 antibody as a specific marker to distinguish rat PMNMDSCs. Additionally, we identified two functionally different monocyte subsets based on HIS48 staining. Granulocytic subset of tumor bearing rat MDSCs were defined as Rp-1+ HIS48+ neutrophils. Two functionally and morphologically different subsets of RP-1- rat monocytes were discriminated by HIS48 staining.Bu çalışmada, Nitroso Metil Üre (NMU) aracılı meme kanseri oluşturulmuş Sprague Dawley sıçanların periferik kan, kemik iliği ve dalak dokularında bulunan myeloid kökenli hücreler incelenmiştir. Rp-1 ekspresyonu ile sıçan myeloid hücrelerinin nötrofil ve monosit popülasyonları ilk defa birbirlerinden ayırt edilmiştir. Ayrıca HIS48 ekspresyonuna göre iki farklı sıçan monosit alt grubu olduğu tespit edilmiştir. Meme tümörü taşıyan sıçanların periferik kan ve dalaklarında anlamlı oranda Rp-1+ nötrofil birikimi gösterilmiştir. Tümörlü hayvanlarda sayıları artan bu Rp-1 + nötrofillerin, antijene özgü CD4+ T hücre proliferasyonunu baskıladığı gösterilerek myeloid kökenli baskılayıcı hücre (MDSC) karakterinde oldukları gösterilmiştir. Tümörlü sıçanlarda MDSC'ler, CD11b/c+, HIS48+ immünfenotipi ile tanımlanmaktadır. Bu tanım hem granülositik hem de monositik popülasyonları kapsamaktadır. Bu çalışmada, sıçan granülositik MDSC alt grubu Rp-1+ myeloid hücreler olarak ilk defa tanımlanmıştır. Yapılan işlevsel analizlerde; sıçan granülositik myeloid kökenli baskılayıcı hücrelerinin (MDSC'ler) reaktif oksijen türevleri (ROS), nitrik oksit (NO) ve TGF-β sentezleyerek baskılayıcılık fonksiyonu gösterdiği tespit edilmiştir. Tümörlü hayvanlarda klasik tipteki HIS48+ monosit popülasyonlarının MHC II ekspresyonlarında azalma görülmüştür. Tümörlü hayvan dalağında bulunan ve yüksek ROS ve NO üretimi ile TGF-β sentezine de sahip olan HIS48+ monositler, sıçan monositik MDSC'lerini teşkil ederler

Injectable biomimetic hydrogels as tools for efficient T Cell expansion and delivery

\u3cp\u3eBiomaterial-based scaffolds are promising tools for controlled immunomodulation. They can be applied as three dimensional (3D) culture systems in vitro, whereas in vivo they may be used to dictate cellular localization and exert spatiotemporal control over cues presented to the immune system. As such, scaffolds can be exploited to enhance the efficacy of cancer immunotherapies such as adoptive T cell transfer, in which localization and persistence of tumor-specific T cells dictates treatment outcome. Biomimetic polyisocyanopeptide (PIC) hydrogels are polymeric scaffolds with beneficial characteristics as they display reversible thermally-induced gelation at temperatures above 16°C, which allows for their minimally invasive delivery via injection. Moreover, incorporation of azide-terminated monomers introduces functional handles that can be exploited to include immune cell-modulating cues. Here, we explore the potential of synthetic PIC hydrogels to promote the in vitro expansion and in vivo local delivery of pre-activated T cells. We found that PIC hydrogels support the survival and vigorous expansion of pre-stimulated T cells in vitro even at high cell densities, highlighting their potential as 3D culture systems for efficient expansion of T cells for their adoptive transfer. In particular, the reversible thermo-sensitive behavior of the PIC scaffolds favors straightforward recovery of cells. PIC hydrogels that were injected subcutaneously gelated instantly in vivo, after which a confined 3D structure was formed that remained localized for at least 4 weeks. Importantly, we noticed no signs of inflammation, indicating that PIC hydrogels are non-immunogenic. Cells co-delivered with PIC polymers were encapsulated within the scaffold in vivo. Cells egressed gradually from the PIC gel and migrated into distant organs. This confirms that PIC hydrogels can be used to locally deliver cells within a supportive environment. These results demonstrate that PIC hydrogels are highly promising for both the in vitro expansion and in vivo delivery of pre-activated T cells. Covalent attachment of biomolecules onto azide-functionalized PIC polymers provides the opportunity to steer the phenotype, survival or functional response of the adoptively transferred cells. As such, PIC hydrogels can be used as valuable tools to improve current adoptive T cell therapy strategies.\u3c/p\u3

Nanovaccine administration route is critical to obtain pertinent iNKt cell help for robust anti-tumor T and B cell responses

Nanovaccines, co-delivering antigen and invariant natural killer T (iNKT) cell agonists, proved to be very effective in inducing anti-tumor T cell responses due to their exceptional helper function. However, it is known that iNKT cells are not equally present in all lymphoid organs and nanoparticles do not get evenly distributed to all immune compartments. In this study, we evaluated the effect of the vaccination route on iNKT cell help to T and B cell responses for the first time in an antigen and agonist co-delivery setting. Intravenous administration of PLGA nanoparticles was mainly targeting liver and spleen where iNKT1 cells are abundant and induced the highest serum IFN-y levels, T cell cytotoxicity, and Th-1 type antibody responses. In comparison, after subcutaneous or intranodal injections, nanoparticles mostly drained or remained in regional lymph nodes where iNKT17 cells were abundant. After subcutaneous and intranodal injections, antigen-specific IgG2 c production was hampered and IFN-y production, as well as cytotoxic T cell responses, depended on sporadic systemic drainage. Therapeutic anti-tumor experiments also demonstrated a clear advantage of intravenous injection over intranodal or subcutaneous vaccinations. Moreover, tumor control could be further improved by PD-1 immune checkpoint blockade after intravenous vaccination, but not by intranodal vaccination. Anti PD-1 antibody combination mainly exerts its effect by prolonging the cytotoxicity of T cells. Nanovaccines also demonstrated synergism with anti-4-1BB agonistic antibody treatment in controlling tumor growth. We conclude that nanovaccines containing iNKT cell agonists shall be preferentially administered intravenously, to optimally reach cellular partners for inducing effective anti-tumor immune responses

Injectable biomimetic hydrogels as tools for efficient T Cell expansion and delivery

Biomaterial-based scaffolds are promising tools for controlled immunomodulation. They can be applied as three dimensional (3D) culture systems in vitro, whereas in vivo they may be used to dictate cellular localization and exert spatiotemporal control over cues presented to the immune system. As such, scaffolds can be exploited to enhance the efficacy of cancer immunotherapies such as adoptive T cell transfer, in which localization and persistence of tumor-specific T cells dictates treatment outcome. Biomimetic polyisocyanopeptide (PIC) hydrogels are polymeric scaffolds with beneficial characteristics as they display reversible thermally-induced gelation at temperatures above 16°C, which allows for their minimally invasive delivery via injection. Moreover, incorporation of azide-terminated monomers introduces functional handles that can be exploited to include immune cell-modulating cues. Here, we explore the potential of synthetic PIC hydrogels to promote the in vitro expansion and in vivo local delivery of pre-activated T cells. We found that PIC hydrogels support the survival and vigorous expansion of pre-stimulated T cells in vitro even at high cell densities, highlighting their potential as 3D culture systems for efficient expansion of T cells for their adoptive transfer. In particular, the reversible thermo-sensitive behavior of the PIC scaffolds favors straightforward recovery of cells. PIC hydrogels that were injected subcutaneously gelated instantly in vivo, after which a confined 3D structure was formed that remained localized for at least 4 weeks. Importantly, we noticed no signs of inflammation, indicating that PIC hydrogels are non-immunogenic. Cells co-delivered with PIC polymers were encapsulated within the scaffold in vivo. Cells egressed gradually from the PIC gel and migrated into distant organs. This confirms that PIC hydrogels can be used to locally deliver cells within a supportive environment. These results demonstrate that PIC hydrogels are highly promising for both the in vitro expansion and in vivo delivery of pre-activated T cells. Covalent attachment of biomolecules onto azide-functionalized PIC polymers provides the opportunity to steer the phenotype, survival or functional response of the adoptively transferred cells. As such, PIC hydrogels can be used as valuable tools to improve current adoptive T cell therapy strategies

PLGA Nanoparticles Co-encapsulating NY-ESO-1 Peptides and IMM60 Induce Robust CD8 and CD4 T Cell and B Cell Responses

International audienceTumor-specific neoantigens can be highly immunogenic, but their identification for each patient and the production of personalized cancer vaccines can be time-consuming and prohibitively expensive. In contrast, tumor-associated antigens are widely expressed and suitable as an off the shelf immunotherapy. Here, we developed a PLGA-based nanoparticle vaccine that contains both the immunogenic cancer germline antigen NY-ESO-1 and an α-GalCer analog IMM60, as a novel iNKT cell agonist and dendritic cell transactivator. Three peptide sequences (85–111, 117–143, and 157–165) derived from immunodominant regions of NY-ESO-1 were selected. These peptides have a wide HLA coverage and were efficiently processed and presented by dendritic cells via various HLA subtypes. Co-delivery of IMM60 enhanced CD4 and CD8 T cell responses and antibody levels against NY-ESO-1 in vivo . Moreover, the nanoparticles have negligible systemic toxicity in high doses, and they could be produced according to GMP guidelines. Together, we demonstrated the feasibility of producing a PLGA-based nanovaccine containing immunogenic peptides and an iNKT cell agonist, that is activating DCs to induce antigen-specific T cell responses

Institutionalization of History in the Ottoman Empire

This article examines the process within which history was institutionalized in the Ottoman Empire. Institutional space for history had begun to be constructed within the context of interstate rivalry during the mid-nineteenth century. History had the task of "proving" the fact that the Turks had been from the very beginning a part of the "Western civilization." The essential period for the institutionalization history was that of the regime of the Committee of Union and Progress in 1908-18, providing historians to emphasize the role of the "people" in history along with large structures of geography and "civilizations." Once professional institutions were established and various history journals began to be published in this context, historians also began to pay due attention to the professional standards of the discipline. Despite the exclusionary tendencies of the Turkish official history, institutionalization during a revolutionary period functioned as a significant counter-tendency as institutions are path-dependent