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CD8 tolerance

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https://www.readbyqxmd.com/read/29127360/a-mouse-model-of-autoimmune-cholangitis-via-syngeneic-bile-duct-protein-immunization
#1
Wen-Tao Ma, Qing-Zhi Liu, Jing-Bo Yang, Yan-Qing Yang, Zhi-Bin Zhao, Hong-Di Ma, M Eric Gershwin, Zhe-Xiong Lian
Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by the destruction of interlobular biliary ductules, which progressively leads to cholestasis, hepatic fibrosis, cirrhosis, and eventually liver failure. Several mouse models have been used to clarify the pathogenesis of PBC and are generally considered reflective of an autoimmune cholangitis. Most models focus on issues of molecular mimicry between the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), the major mitochondrial autoantigen of PBC and xenobiotic cross reactive chemicals...
November 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29123519/two-distinct-myeloid-subsets-at-the-term-human-fetal-maternal-interface
#2
Maria Laura Costa, Michelle L Robinette, Mattia Bugatti, Mark S Longtine, Bryanne N Colvin, Erica Lantelme, William Vermi, Marco Colonna, D Michael Nelson, Marina Cella
During pregnancy, immune cells infiltrate the placenta at different stages of fetal development. NK cells and macrophages are the most predominant cell types. These immune cells play pleiotropic roles, as they control spiral artery remodeling to ensure appropriate blood supply and maintain long-term tolerance to a true allograft; yet, they must be able to mount appropriate immune defenses to pathogens that may threaten the fetus. Whether the same cell type accomplishes all these tasks or if there are dedicated subsets remains controversial...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29119643/a-phase-i-study-of-lenalidomide-plus-chemotherapy-with-mitoxantrone-etoposide-and-cytarabine-for-the-reinduction-of-patients-with-acute-myeloid-leukemia
#3
Daniel J DeAngelo, Andrew M Brunner, Lillian Werner, David Avigan, Amir T Fathi, Adam S Sperling, Abigail Washington, Dina Stroopinsky, Jacalyn Rosenblatt, Malgorzata McMasters, Katarina Luptakova, Martha Wadleigh, David P Steensma, Gabriela S Hobbs, Eyal C Attar, Philip C Amrein, Benjamin L Ebert, Richard M Stone, Karen K Ballen
Patients with relapsed AML have a poor prognosis and limited responses to standard chemotherapy. Lenalidomide is an immunomodulatory drug that may modulate anti-tumor immunity. We performed a study to evaluate the safety and tolerability of lenalidomide with mitoxantrone, etoposide and cytarabine (MEC) in relapsed/refractory AML. Adult patients with relapsed/refractory AML were eligible for this phase I dose-escalation study. We enrolled 35 patients using a '3 + 3' design, with a 10 patient expansion cohort at the maximum tolerated dose (MTD)...
November 9, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/29116089/resistance-to-tgf%C3%AE-suppression-and-improved-anti-tumor-responses-in-cd8-t-cells-lacking-ptpn22
#4
Rebecca J Brownlie, Celine Garcia, Mate Ravasz, Dietmar Zehn, Robert J Salmond, Rose Zamoyska
Transforming growth factor β (TGFβ) is important in maintaining self-tolerance and inhibits T cell reactivity. We show that CD8(+) T cells that lack the tyrosine phosphatase Ptpn22, a major predisposing gene for autoimmune disease, are resistant to the suppressive effects of TGFβ. Resistance to TGFβ suppression, while disadvantageous in autoimmunity, helps Ptpn22 (-/-) T cells to be intrinsically superior at clearing established tumors that secrete TGFβ. Mechanistically, loss of Ptpn22 increases the capacity of T cells to produce IL-2, which overcomes TGFβ-mediated suppression...
November 7, 2017: Nature Communications
https://www.readbyqxmd.com/read/29100944/regulatory-dendritic-cells-for-promotion-of-liver-transplant-operational-tolerance-rationale-for-a-clinical-trial-and-accompanying-mechanistic-studies
#5
REVIEW
Angus W Thomson, Abhinav Humar, Fadi G Lakkis, Diana M Metes
Dendritic cells (DC) are rare, bone marrow (BM)-derived innate immune cells that critically maintain self-tolerance in the healthy steady-state. Regulatory DC (DCreg) with capacity to suppress allograft rejection and promote transplant tolerance in pre-clinical models can readily be generated from BM precursors or circulating blood monocytes. These DCreg enhance allograft survival via various mechanisms, including promotion of regulatory T cells. In non-human primates receiving minimal immunosuppressive drug therapy (IS), infusion of DCreg of donor origin, one week before transplant, safely prolongs renal allograft survival and selectively attenuates anti-donor CD8(+) memory T cell responses in the early post-transplant period...
October 31, 2017: Human Immunology
https://www.readbyqxmd.com/read/29097869/delayed-and-short-course-of-rapamycin-prevents-organ-rejection-after-allogeneic-liver-transplantation-in-rats
#6
Salim Hamdani, Allan Thiolat, Sina Naserian, Cynthia Grondin, Stéphane Moutereau, Anne Hulin, Julien Calderaro, Philippe Grimbert, José Laurent Cohen, Daniel Azoulay, Caroline Pilon
AIM: To test whether a delayed and short course of rapamycin would induce immunosuppressive effects following allogeneic orthotopic liver transplantation (OLT) in rats. METHODS: Allogeneic OLTs were performed using Dark Agouti livers transplanted into Lewis recipients, and syngeneic OLTs were performed using the Lewis rat strain. Rapamycin (1 mg/kg per day) was administered by gavage from day 4 to day 11 post-transplantation. Lymphocyte cellular compartments were analyzed by flow cytometry in draining lymph nodes, non-draining lymph nodes and the spleen at days 11 and 42 in rapamycin-treated rats, untreated control rats and syngeneic grafted rats...
October 14, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/29093272/t-cells-presenting-viral-antigens-or-autoantigens-induce-cytotoxic-t-cell-anergy
#7
Nathalie E Blachère, Dana E Orange, Emily C Gantman, Bianca D Santomasso, Graeme C Couture, Teresa Ramirez-Montagut, John Fak, Kevin J O'Donovan, Zhong Ru, Salina Parveen, Mayu O Frank, Michael J Moore, Robert B Darnell
In the course of modeling the naturally occurring tumor immunity seen in patients with paraneoplastic cerebellar degeneration (PCD), we discovered an unexpectedly high threshold for breaking CD8+ cytotoxic T cell (CTL) tolerance to the PCD autoantigen, CDR2. While CDR2 expression was previously found to be strictly restricted to immune-privileged cells (cerebellum, testes, and tumors), unexpectedly we have found that T cells also express CDR2. This expression underlies inhibition of CTL activation; CTLs that respond to epithelial cells expressing CDR2 fail to respond to T cells expressing CDR2...
November 2, 2017: JCI Insight
https://www.readbyqxmd.com/read/29093083/dynamics-of-sendai-virus-spread-clearance-and-immunotherapeutic-efficacy-after-hematopoietic-cell-transplant-imaged-non-invasively-in-mice
#8
Heba H Mostafa, Peter Vogel, Ashok Srinivasan, Charles J Russell
There are no approved vaccines or virus-specific treatments for human parainfluenza viruses (PIVs), which have recently been reclassified into species human respirovirus 1 and 3 and human rubulavirus 2 and 4 These viruses cause morbidity and mortality in immunocompromised patients including those undergoing hematopoietic cell transplant (HCT). No small-animal models exist for non-invasive imaging of respiratory viral infection in the HCT host despite the utility such a system would offer to monitor prolonged infection, its clearance, and treatment options...
November 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/29075263/intestinal-barrier-interactions-with-specialized-cd8-t-cells
#9
REVIEW
Špela Konjar, Cristina Ferreira, Birte Blankenhaus, Marc Veldhoen
The trillions of microorganisms that reside in the gastrointestinal tract, essential for nutrient absorption, are kept under control by a single cell barrier and large amounts of immune cells. Intestinal epithelial cells (IECs) are critical in establishing an environment supporting microbial colonization and immunological tolerance. A large population of CD8(+) T cells is in direct and constant contact with the IECs and the intraepithelial lymphocytes (IELs). Due to their location, at the interphase of the intestinal lumen and external environment and the host tissues, they seem ideally positioned to balance immune tolerance and protection to preserve the fragile intestinal barrier from invasion as well as immunopathology...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29074182/t-cell-ignorance-is-bliss-t-cells-are-not-tolerized-by-langerhans-cells-presenting-human-papillomavirus-antigens-in-the-absence-of-costimulation
#10
Andrew W Woodham, Lisa Yan, Joseph G Skeate, Daniel van der Veen, Heike E Brand, Michael K Wong, Diane M Da Silva, W Martin Kast
Human papillomavirus type 16 (HPV16) infections are intra-epithelial, and thus, HPV16 is known to interact with Langerhans cells (LCs), the resident epithelial antigen-presenting cells (APCs). The current paradigm for APC-mediated induction of T cell anergy is through delivery of T cell receptor signals via peptides on MHC molecules (signal 1), but without costimulation (signal 2). We previously demonstrated that LCs exposed to HPV16 in vitro present HPV antigens to T cells without costimulation, but it remained uncertain if such T cells would remain ignorant, become anergic, or in the case of CD4+ T cells, differentiate into Tregs...
December 2016: Papillomavirus Research
https://www.readbyqxmd.com/read/29070044/neoadjuvant-everolimus-plus-letrozole-versus-fluorouracil-epirubicin-and-cyclophosphamide-for-er-positive-her2-negative-breast-cancer-study-protocol-for-a-randomized-pilot-trial
#11
Wei Wu, Heran Deng, Nanyan Rao, Na You, Yaping Yang, Minghui Cao, Jieqiong Liu
BACKGROUND: The response to neoadjuvant chemotherapy (NAC) varies by estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) statuses, with responses being lower in ER-positive, HER2-negative tumors as compared with ER-negative, HER2-positive or triple-negative tumors. Neoadjuvant endocrine therapy (NET) is an attractive alternative to NAC for ER-positive, HER2-negative cancer. However, a prior trial comparing NET with standard NAC in ER-positive tumor showed that the difference of response was not significant...
October 25, 2017: Trials
https://www.readbyqxmd.com/read/29055791/the-role-of-decidual-immune-cells-on-human-pregnancy
#12
REVIEW
Su Liu, Lianghui Diao, Chunyu Huang, Yuye Li, Yong Zeng, Joanne Y H Kwak-Kim
The maternal-fetal interface undergoes dynamic changes to allow the fetus to grow and develop in the uterus, despite being recognized by the maternal immune cells. Within the innate immune system, decidual natural killer cells and antigen presenting cells (including macrophages and dendritic cells) that comprise a large proportion of the decidual leukocyte populations play an important role in modulating trophoblast invasion, angiogenesis and vascular remodeling. On the other hand, within the adaptive immune system, CD8(+) T cells, effector CD4(+) T cells, Foxp3(+) regulatory T cells and CD4(+)HLA-G(+) suppressor T cells are identified as potential players in maintaining immune tolerance toward the semi-allogeneic fetus...
October 18, 2017: Journal of Reproductive Immunology
https://www.readbyqxmd.com/read/29055004/stat4-regulates-the-cd8-regulatory-t-cell-t-follicular-helper-cell-axis-and-promotes-atherogenesis-in-insulin-resistant-ldlr-mice
#13
Parésa L Taghavie-Moghadam, Tayab C Waseem, Julian Hattler, Lindsey M Glenn, Anca D Dobrian, Mark H Kaplan, Yi Yang, Roza Nurieva, Jerry L Nadler, Elena V Galkina
The metabolic syndrome and diabetic conditions support atherosclerosis, but the exact mechanisms for accelerated atherogenesis remain unclear. Although the proinflammatory role of STAT4 in atherosclerosis and diet-induced insulin resistance (IR) was recently established, the impact of STAT4 on atherogenesis in conditions of IR is not known. In this study, we generated Stat4(-/-)Ldlr(-/-) mice that were fed a diabetogenic diet with added cholesterol (DDC). DDC-fed Stat4(-/-)Ldlr(-/-) mice demonstrated improved glucose tolerance, insulin sensitivity, and a 36% reduction in atherosclerosis compared with Ldlr(-/-) controls...
November 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29053967/friends-in-low-places-intestinal-commensals-limit-colitis-through-molecular-mimicry
#14
D Garrett Brown, June L Round
Inflammatory bowel disease is thought to arise from inappropriate inflammation to gut bacteria, yet mechanisms preventing these responses remain elusive. In this issue of Cell, Nanjundappa et al. report that Bacteroides share an epitope with a pancreas-specific peptide that induces protective CD8+ T cells, identifying molecular mimicry as a mechanism to enforce tolerance in the gut.
October 19, 2017: Cell
https://www.readbyqxmd.com/read/29052782/clinical-and-immunologic-evaluation-of-three-metastatic-melanoma-patients-treated-with-autologous-melanoma-reactive-tcr-transduced-t-cells
#15
Tamson Moore, Courtney Regan Wagner, Gina M Scurti, Kelli A Hutchens, Constantine Godellas, Ann Lau Clark, Elizabeth Motunrayo Kolawole, Lance M Hellman, Nishant K Singh, Fernando A Huyke, Siao-Yi Wang, Kelly M Calabrese, Heather D Embree, Rimas Orentas, Keisuke Shirai, Emilia Dellacecca, Elizabeth Garrett-Mayer, Mingli Li, Jonathan M Eby, Patrick J Stiff, Brian D Evavold, Brian M Baker, I Caroline Le Poole, Boro Dropulic, Joseph I Clark, Michael I Nishimura
Malignant melanoma incidence has been increasing for over 30 years, and despite promising new therapies, metastatic disease remains difficult to treat. We describe preliminary results from a Phase I clinical trial (NCT01586403) of adoptive cell therapy in which three patients received autologous CD4(+) and CD8(+) T cells transduced with a lentivirus carrying a tyrosinase-specific TCR and a marker protein, truncated CD34 (CD34t). This unusual MHC Class I-restricted TCR produces functional responses in both CD4(+) and CD8(+) T cells...
October 20, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/29051322/a-multicenter-phase-i-study-evaluating-dual-pi3k-and-braf-inhibition-with-px-866-and-vemurafenib-in-patients-with-advanced-braf-v600-mutant-solid-tumors
#16
Clinton Yam, Xiaowei Xu, Michael A Davies, Phyllis A Gimotty, Jennifer Jd Morrissette, Michael T Tetzlaff, Khalida Wani, Shujing Liu, Wanleng Deng, Meghan Buckley, Jianhua Zhao, Ravi K Amaravadi, Naomi Haas, Ragini R Kudchadkar, Anna Pavlick, Jeffrey A Sosman, Hussein Tawbi, Luke Walker, Lynn M Schuchter, Giorgos C Karakousis, Tara C Gangadhar
PURPOSE: The objectives of the study were to evaluate the safety of daily oral PX-866 in combination with twice daily vemurafenib and to identify potential predictive biomarkers for this novel combination. EXPERIMENTAL DESIGN: We conducted a phase I, open-label, dose escalation study in patients with advanced BRAF V600 mutant solid tumors. PX-866 was administered on a continuous schedule in combination with vemurafenib. Patients underwent a baseline and on-treatment biopsy after 1-week of PX-866 monotherapy for biomarker assessment...
October 19, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29050282/effective-antitumor-peptide-vaccines-can-induce-severe-autoimmune-pathology
#17
Hussein Sultan, Jimena Trillo-Tinoco, Paulo Rodriguez, Esteban Celis
Immunotherapy has shown a tremendous success in treating cancer. Unfortunately, this success is frequently associated with severe autoimmune pathology. In this study, we used the transgenic RIP-gp mouse model to assess the antitumor therapeutic benefit of peptide vaccination while evaluating the possible associated autoimmune pathology. We report that palmitoylated gp33-41 peptide and poly-IC adjuvant vaccine (BiVax) generated ∼ 5-10 % of antigen specific T cell responses in wild type and supposedly immune tolerant RIP-gp mice...
September 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29038654/cpg-odn-facilitates-effective-intratracheal-immunization-and-recall-of-memory-against-neoantigen-expressing-alveolar-cells
#18
Mathias Riehn, Marcin Cebula, Hansjörg Hauser, Dagmar Wirth
Intrapulmonary immune reactions are impaired by the tolerogenic environment of the lung. This is manifested by the absence of effective endogenous T cell responses upon neoantigen expression. This tolerance is considered to contribute to lung cancer and inefficient immune therapeutic interventions. To investigate the mechanisms contributing to lung tolerance and to overcome these restrictions, we developed a transgenic mouse model with induction of a neoantigen (OVA) exclusively in alveolar type II epithelial cells...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29037255/objective-measurement-and-clinical-significance-of-ido1-protein-in-hormone-receptor-positive-breast-cancer
#19
Daniel E Carvajal-Hausdorf, Nikita Mani, Vamsidhar Velcheti, Kurt A Schalper, David L Rimm
BACKGROUND: Immunostimulatory therapies targeting immune-suppressive pathways produce durable responses in advanced solid tumors. Indoleamine 2,3-dioxygenase (IDO) is the rate-limiting oxidoreductase that catalyzes the degradation of tryptophan to kynurenine. IDO induces immune tolerance by downregulating CD8+ and effector CD4+ T cell responses. IDO1, the most active isoform, is expressed in diverse tumor types and can be targeted using small molecule inhibitors. We used an objective, in situ assay to measure IDO1 in a collection of hormone receptor-positive breast cancers (HR+ BC)...
October 17, 2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/29033940/pi3k%C3%AE-inhibition-enhances-the-antitumor-fitness-of-adoptively-transferred-cd8-t-cells
#20
Jacob S Bowers, Kinga Majchrzak, Michelle H Nelson, Bulent Arman Aksoy, Megan M Wyatt, Aubrey S Smith, Stefanie R Bailey, Lillian R Neal, Jeffrey E Hammerbacher, Chrystal M Paulos
Phosphatidylinositol-3-kinase p110δ (PI3Kδ) inhibition by Idelalisib (CAL-101) in hematological malignancies directly induces apoptosis in cancer cells and disrupts immunological tolerance by depleting regulatory T cells. Yet, little is known about the direct impact of PI3Kδ blockade on effector T cells from CAL-101 therapy. Herein, we demonstrate a direct effect of p110δ inactivation via CAL-101 on murine and human CD8(+) T cells that promotes a strong undifferentiated phenotype (elevated CD62L/CCR7, CD127, and Tcf7)...
2017: Frontiers in Immunology
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