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https://www.readbyqxmd.com/read/28062921/targeted-deletion-of-traf2-allows-immunosuppression-free-islet-allograft-survival-in-mice
#1
Jeanette E Villanueva, Stacey N Walters, Mitsuru Saito, Elisabeth K Malle, Nathan W Zammit, Katherine A Watson, Robert Brink, Nicole L La Gruta, Stephen I Alexander, Shane T Grey
AIMS/HYPOTHESIS: Administration of anti-CD40 ligand (CD40L) antibodies has been reported to allow long-term islet allograft survival in non-human primates without the need for exogenous immunosuppression. However, the use of anti-CD40L antibodies was associated with thromboembolic complications. Targeting downstream intracellular components shared between CD40 and other TNF family co-stimulatory molecules could bypass these complications. TNF receptor associated factor 2 (TRAF2) integrates multiple TNF receptor family signalling pathways that are critical for T cell activation and may be a central node of alloimmune responses...
January 6, 2017: Diabetologia
https://www.readbyqxmd.com/read/28061947/b-lymphocytes-forming-follicle-like-structures-in-the-lung-tissue-of-tuberculosis-infected-mice-dynamics-phenotypes-and-functional-activity
#2
Irina Linge, Alexander Dyatlov, Elena Kondratieva, Vadim Avdienko, Alexander Apt, Tatiana Kondratieva
During tuberculosis (TB) infection, B cells form follicles in close vicinity of lung granuloma. We assessed the dynamics of follicle formation, surface phenotypes and functional activity of lung B cells during TB course in genetically susceptible mice. The follicles appeared early post infection and peaked at weeks 7-8. Lung B cells resembled classical B2 cells (CD19(+)IgMloIgD(hi)CD1d(-)CD21/35(int)CD5(-)CD11b(-)CD43(-)), but differed from them by the absence of B2 marker CD23. Lung B-cells constitutively expressed MHC II molecules, presented mycobacterial antigens to immune CD4(+) T-cells and produced high amounts of IL-6 and IL-11, but no classical type 1 (TNF-α, IFN-γ), or anti-inflammatory (IL-10, TGF-β) cytokines...
January 2017: Tuberculosis
https://www.readbyqxmd.com/read/28060313/generation-of-human-monocyte-derived-dendritic-cells-from-whole-blood
#3
Wilfried Posch, Cornelia Lass-Flörl, Doris Wilflingseder
Dendritic cells (DCs) recognize foreign structures of different pathogens, such as viruses, bacteria, and fungi, via a variety of pattern recognition receptors (PRRs) expressed on their cell surface and thereby activate and regulate immunity. The major function of DCs is the induction of adaptive immunity in the lymph nodes by presenting antigens via MHC I and MHC II molecules to naïve T lymphocytes. Therefore, DCs have to migrate from the periphery to the lymph nodes after the recognition of pathogens at the sites of infection...
December 24, 2016: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28057216/histone-acetylation-and-the-regulation-of-major-histocompatibility-class-ii-gene-expression
#4
K Suzuki, Y Luo
Major histocompatibility complex (MHC) class II molecules are essential for processing and presenting exogenous pathogen antigens to activate CD4(+) T cells. Given their central role in adaptive immune responses, MHC class II genes are tightly regulated in a tissue- and activation-specific manner. The regulation of MHC class II gene expression involves various transcription factors that interact with conserved proximal cis-acting regulatory promoter elements, as well as MHC class II transactivator that interacts with a variety of chromatin remodeling machineries...
2017: Advances in Protein Chemistry and Structural Biology
https://www.readbyqxmd.com/read/28057175/pour-comprendre-l%C3%A2-activation-lymphocytaire-t
#5
Jeanne Galaine, Yann Godet, Olivier Adotévi
T cells activation is a finely regulated process to establish an effective anti-infectious or antitumor immune response while avoiding harmful autoimmune reactions. Although T cells are considered to be the main protagonists of the antitumor immune response, they act in interaction with other immune cells. The meeting of naive T cells with dendritic cells induces their differentiation into effector cells following the recognition of the peptide-MHC complex by the T cell receptor. The interaction of costimulatory molecules present on the surface of T cells with their ligand (s) expressed by mature dendritic cells contribute to the optimal T cell activation and to the formation of the immunological synapse...
November 2016: Bulletin du Cancer
https://www.readbyqxmd.com/read/28051183/hiv-1-env-associates-with-hla-c-free-chains-at-the-cell-membrane-modulating-viral-infectivity
#6
Michela Serena, Francesca Parolini, Priscilla Biswas, Francesca Sironi, Almudena Blanco Miranda, Elisa Zoratti, Maria Teresa Scupoli, Serena Ziglio, Agustin Valenzuela-Fernandez, Davide Gibellini, Maria Grazia Romanelli, Antonio Siccardi, Mauro Malnati, Alberto Beretta, Donato Zipeto
HLA-C has been demonstrated to associate with HIV-1 envelope glycoprotein (Env). Virions lacking HLA-C have reduced infectivity and increased susceptibility to neutralizing antibodies. Like all others MHC-I molecules, HLA-C requires β2-microglobulin (β2m) for appropriate folding and expression on the cell membrane but this association is weaker, thus generating HLA-C free-chains on the cell surface. In this study, we deepen the understanding of HLA-C and Env association by showing that HIV-1 specifically increases the amount of HLA-C free chains, not bound to β2m, on the membrane of infected cells...
January 4, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28040582/folate-deficiency-affects-dendritic-cell-function-and-subsequent-t-helper-cell-differentiation
#7
Chi-Heng Wu, Tzu-Chien Huang, Bi-Fong Lin
Insufficient folate status may be related to the increasing prevalence of immune- or inflammation-related chronic diseases. To investigate the effects of folate on immune regulation, we examined the impact of folate deficiency (FD) on dendritic cell (DC) maturation and function and, thus, T helper (Th) cells differentiation. First, bone marrow-derived DCs (BMDCs) were generated from BALB/c mice bone marrow cells cultured in folate-containing (F-BMDCs) or folate-deficient (FD-BMDCs) medium. FD-BMDC displayed more immature phenotype including reduced levels of major histocompatibility complex class II (MHC II), co-stimulatory molecules and characteristic of higher endocytic activity...
November 20, 2016: Journal of Nutritional Biochemistry
https://www.readbyqxmd.com/read/28018349/allorecognition-by-t-lymphocytes-and-allograft-rejection
#8
REVIEW
Jose Marino, Joshua Paster, Gilles Benichou
Recognition of donor antigens by recipient T cells in secondary lymphoid organs initiates the adaptive inflammatory immune response leading to the rejection of allogeneic transplants. Allospecific T cells become activated through interaction of their T cell receptors with intact allogeneic major histocompatibility complex (MHC) molecules on donor cells (direct pathway) and/or donor peptides presented by self-MHC molecules on recipient antigen-presenting cells (APCs) (indirect pathway). In addition, recent studies show that alloreactive T cells can also be stimulated through recognition of allogeneic MHC molecules displayed on recipient APCs (MHC cross-dressing) after their transfer via cell-cell contact or through extracellular vesicles (semi-direct pathway)...
2016: Frontiers in Immunology
https://www.readbyqxmd.com/read/28011995/delivery-of-foreign-cytotoxic-t-lymphocyte-epitopes-to-tumor-tissues-for-effective-antitumor-immunotherapy-against-pre-established-solid-tumors-in-mice
#9
Herbert W Kavunja, Shuyao Lang, Suttipun Sungsuwan, Zhaojun Yin, Xuefei Huang
Cytotoxic T lymphocyte (CTL) can have remarkable abilities to kill tumor cells. However, the establishment of successful CTL-based anticancer therapy has met with many challenges. Within tumor cells, there exist subpopulations with low or no expression of the targeted antigen (termed as antigen-loss variants). In addition, tumor cells can downregulate the levels of major histocompatibility complex class I (MHC-I) molecules on cell surface due to immune pressure. As a result, some tumor cells can escape the immune pressure bestowed by CTLs, resulting in treatment failure...
December 23, 2016: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/28011506/distant-bystander-effect-of-reic-dkk3-gene-therapy-through-immune-system-stimulation-in-thoracic-malignancies
#10
Ken Suzawa, Kazuhiko Shien, Huang Peng, Masakiyo Sakaguchi, Masami Watanabe, Shinsuke Hashida, Yuho Maki, Hiromasa Yamamoto, Shuta Tomida, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Yasutomo Nasu, Hiromi Kumon, Shinichiro Miyoshi, Shinichi Toyooka
BACKGROUND: Reduced expression in immortalized cell (REIC)/Dickkoph-3 (DKK3) is a tumor-suppressor gene, and its overexpression by adenovirus vector (Ad-REIC) exhibits a remarkable therapeutic effect on various human cancer types through a mechanism triggered by endoplasmic reticulum stress. MATERIALS AND METHODS: We examined the direct anti-tumor effect of Ad-REIC gene therapy on lung cancer and malignant mesothelioma cell lines in vitro, and the distant bystander effect using immunocompetent mouse allograft models with bilateral flank tumors...
January 2017: Anticancer Research
https://www.readbyqxmd.com/read/27999739/tlr7-based-cancer-immunotherapy-decreases-intratumoral-myeloid-derived-suppressor-cells-and-blocks-their-immunosuppressive-function
#11
Thibaud Spinetti, Lorenzo Spagnuolo, Inès Mottas, Chiara Secondini, Marina Treinies, Curzio Rüegg, Christian Hotz, Carole Bourquin
Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells with the capacity to inhibit immunological responses. During cancer progression, MDSC are recruited to the tumor sites and secondary lymphoid organs, leading to the suppression of the antitumor function of NK and T cells. Here, we show that the TLR7/8 agonist resiquimod (R848) has a direct effect on MDSC populations in tumor-bearing mice. Systemic application of R848 led to a rapid reduction in both intratumoral and circulating MDSC...
2016: Oncoimmunology
https://www.readbyqxmd.com/read/27997080/prevention-of-allograft-rejection-by-use-of-regulatory-t-cells-with-a-mhc-specific-chimeric-antigen-receptor
#12
F Noyan, K Zimmermann, M Hardtke-Wolenski, A Knoefel, E Schulde, R Geffers, M Hust, J Huehn, M Galla, M Morgan, A Jokuszies, M P Manns, E Jaeckel
CD4+CD25highFOXP3+ regulatory T cells (Tregs) are involved in graft-specific tolerance after solid organ transplantation. However, adoptive transfer of polyspecific Tregs alone is insufficient to prevent graft rejection even in rodent models, indicating that graft-specific Tregs are required. We developed a highly specific chimeric antigen receptor that recognizes the HLA molecule A*02 (referred to as A2-CAR). Transduction into nTregs changes the specificity of the nTregs without alteration of their regulatory phenotype and epigenetic stability...
December 20, 2016: American Journal of Transplantation
https://www.readbyqxmd.com/read/27982048/efficient-generation-of-b2m-null-pigs-via-injection-of-zygote-with-talens
#13
Yong Wang, Yinan Du, Xiaoyang Zhou, Lulu Wang, Jian Li, Fengchao Wang, Zhengen Huang, Xingxu Huang, Hong Wei
Donor major histocompatibility complex class I (MHC I) molecules are the main targets of the host immune response after organ allotransplantation. Whether and how MHC I-deficiency of pig donor tissues affects rejection after xenotransplantation has not been assessed. Beta2-microglobulin (B2M) is indispensable for the assembly of MHC I receptors and therefore provides an effective target to disrupt cell surface MHC I expression. Here, we report the one-step generation of mutant pigs with targeted disruptions in B2m by injection of porcine zygotes with B2m exon 2-specific TALENs...
December 16, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27978789/heat-shock-proteins-therapeutic-perspectives-in-inflammatory-disorders
#14
Rekha Khandia, Ashok K Munjal, Hafiz M N Iqbal, Kuldeep Dhama
Heat shock proteins (HSPs) are highly conserved proteins present in all kingdoms of organisms. These are expressed under stress conditions in order to protect the cells from injuries. The stress induced protein denaturation is rectified by refolding and remodelling. These are intracellular proteins but can be present in extracellular fluid like serum of the patients suffering from trauma, autoimmune and inflammatory disorders. Virtually in most inflammatory diseases, immune response towards HSPs is developed...
December 13, 2016: Recent Patents on Inflammation & Allergy Drug Discovery
https://www.readbyqxmd.com/read/27959684/t-cell-transfer-therapy-targeting-mutant-kras-in-cancer
#15
Eric Tran, Paul F Robbins, Yong-Chen Lu, Todd D Prickett, Jared J Gartner, Li Jia, Anna Pasetto, Zhili Zheng, Satyajit Ray, Eric M Groh, Isaac R Kriley, Steven A Rosenberg
We identified a polyclonal CD8+ T-cell response against mutant KRAS G12D in tumor-infiltrating lymphocytes obtained from a patient with metastatic colorectal cancer. We observed objective regression of all seven lung metastases after the infusion of approximately 1.11×10(11) HLA-C*08:02-restricted tumor-infiltrating lymphocytes that were composed of four different T-cell clonotypes that specifically targeted KRAS G12D. However, one of these lesions had progressed on evaluation 9 months after therapy. The lesion was resected and found to have lost the chromosome 6 haplotype encoding the HLA-C*08:02 class I major histocompatibility complex (MHC) molecule...
December 8, 2016: New England Journal of Medicine
https://www.readbyqxmd.com/read/27942611/donor-exosomes-rather-than-passenger-leukocytes-initiate-alloreactive-t-cell-responses-after-transplantation
#16
Jose Marino, Mohamed H Babiker-Mohamed, Patrick Crosby-Bertorini, Joshua T Paster, Christian LeGuern, Sharon Germana, Reza Abdi, Mayuko Uehara, James I Kim, James F Markmann, Georges Tocco, Gilles Benichou
Transplantation of allogeneic organs and tissues represents a lifesaving procedure for a variety of patients affected with end-stage diseases. Although current immunosuppressive therapy prevents early acute rejection, it is associated with nephrotoxicity and increased risks for infection and neoplasia. This stresses the need for selective immune-based therapies relying on manipulation of lymphocyte recognition of donor antigens. The passenger leukocyte theory states that allograft rejection is initiated by recipient T cells recognizing donor major histocompatibility complex (MHC) molecules displayed on graft leukocytes migrating to the host's lymphoid organs...
July 14, 2016: Science Immunology
https://www.readbyqxmd.com/read/27940660/march1-e3-ubiquitin-ligase-dampens-the-innate-inflammatory-response-by-modulating-monocyte-functions-in-mice
#17
Tristan Galbas, Maxime Raymond, Antoine Sabourin, Marie-Claude Bourgeois-Daigneault, Fanny Guimont-Desrochers, Tae Jin Yun, Jean-François Cailhier, Satoshi Ishido, Sylvie Lesage, Cheolho Cheong, Jacques Thibodeau
Ubiquitination was recently identified as a central process in the pathogenesis and development of numerous inflammatory diseases, such as obesity, atherosclerosis, and asthma. Treatment with proteasomal inhibitors led to severe side effects because ubiquitination is heavily involved in a plethora of cellular functions. Thus, new players regulating ubiquitination processes must be identified to improve therapies for inflammatory diseases. In addition to their role in adaptive immunity, endosomal MHC class II (MHCII) molecules were shown to modulate innate immune responses by fine tuning the TLR4 signaling pathway...
December 9, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27917375/recombinant-lipoprotein-rv1016c-derived-from-mycobacterium-tuberculosis-is-a-tlr-2-ligand-that-induces-macrophages-apoptosis-and-inhibits-mhc-ii-antigen-processing
#18
Haibo Su, Shenglin Zhu, Lin Zhu, Wei Huang, Honghai Wang, Zhi Zhang, Ying Xu
TLR2-dependent cellular signaling in Mycobacterium tuberculosis-infected macrophages causes apoptosis and inhibits class II major histocompatibility complex (MHC-II) molecules antigen processing, leading to evasion of surveillance. Mycobacterium tuberculosis (MTB) lipoproteins are an important class of Toll-like receptor (TLR) ligand, and identified as specific components that mediate these effects. In this study, we identified and characterized MTB lipoprotein Rv1016c (lpqT) as a cell wall associated-protein that was exposed on the cell surface and enhanced the survival of recombinants M...
2016: Frontiers in Cellular and Infection Microbiology
https://www.readbyqxmd.com/read/27914923/alloantigen-gene-transfer-to-hepatocytes-promotes-tolerance-to-pancreatic-islet-graft-by-inducing-cd8-regulatory-t-cells
#19
Valentin Le Guen, Jean-Paul Judor, Françoise Boeffard, Vanessa Gauttier, Nicolas Ferry, Jean-Paul Soulillou, Sophie Brouard, Sophie Conchon
BACKGROUND & AIM: Induction of donor-specific immune tolerance is a good alternative to chronic life-long immunosuppression for transplant patients. Donor major histocompatibility complex (MHC) molecules represent the main targets of the allogeneic immune response of transplant recipients. Liver-targeted gene transfer with viral vectors induces tolerance toward the encoded antigen. The aim of this work was to determine whether alloantigen gene transfer to hepatocytes induces tolerance and promotes graft acceptance...
November 30, 2016: Journal of Hepatology
https://www.readbyqxmd.com/read/27907183/activation-of-innate-and-adaptive-immunity-by-a-recombinant-human-cytomegalovirus-strain-expressing-an-nkg2d-ligand
#20
Adriana Tomić, Pavankumar R Varanasi, Mijo Golemac, Suzana Malić, Peggy Riese, Eva M Borst, Eva Mischak-Weissinger, Carlos A Guzmán, Astrid Krmpotić, Stipan Jonjić, Martin Messerle
Development of an effective vaccine against human cytomegalovirus (HCMV) is a need of utmost medical importance. Generally, it is believed that a live attenuated vaccine would best provide protective immunity against this tenacious pathogen. Here, we propose a strategy for an HCMV vaccine that aims at the simultaneous activation of innate and adaptive immune responses. An HCMV strain expressing the host ligand ULBP2 for the NKG2D receptor was found to be susceptible to control by natural killer (NK) cells, and preserved the ability to stimulate HCMV-specific T cells...
December 2016: PLoS Pathogens
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