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CD8 tolerance

JooYeon Jhun, Seung Hoon Lee, Soon Kyu Lee, Hee Yeon Kim, Eun Sun Jung, Dong Goo Kim, JeongWon Choi, Si Hyun Bae, Seung Kew Yoon, Byung Ha Chung, Chul Woo Yang, Mi-La Cho, Jong Young Choi
Recipients of liver transplantation (LT) require long-term immunosuppressive drug treatment, but lifelong immunosuppressive treatment has severe side effects. It is known that some LT recipients develop immune tolerance, and although the development of such operational tolerance should allow a decrease in the burden of immunosuppressive drug treatment, the factors that indicate operational tolerance are not clear. This study aimed to monitor immunological markers over time in LT recipients to identify those markers indicating the development of operational tolerance...
2018: Frontiers in Immunology
Jason T C Lee, Iryna Shanina, Yung Ning Chu, Marc S Horwitz, James D Johnson
Pancreatic beta-cells are selectively destroyed by the host immune system in type 1 diabetes. Thus, drugs that preserve beta-cell mass and/or function have the potential to prevent or slow the progression of this disease. We recently reported that the use-dependent sodium channel blocker, carbamazepine, protects beta-cells from inflammatory cytokines in vitro. Here, we tested the effects of carbamazepine treatment in female non-obese diabetic (NOD) mice by supplementing LabDiet 5053 with 0.5% w/w carbamazepine to achieve serum carbamazepine levels of 14...
March 15, 2018: Scientific Reports
Lambros Kordelas, Fabiola da Silva Nardi, Bettina Wagner, Markus Ditschkowski, Tobias Liebregts, Monika Lindemann, Falko M Heinemann, Peter A Horn, Dietrich W Beelen, Vera Rebmann
HLA-G is a non-classical class I molecule which induces tolerance in allogeneic situations by inhibition of cytotoxic NK and CD8 + T cells and by induction of regulatory T cells. Concordantly, in solid organ transplantation HLA-G is associated with a lower risk for acute and chronic rejection, whereas its role in allogeneic stem cell transplantation (allo-SCT) is less established. We here present detailed analyses of HLA-G-levels in patients after allo-SCT showing a correlation of elevated soluble HLA-G (sHLA-G) levels with less severe acute (p = 0...
March 14, 2018: Bone Marrow Transplantation
Ye Zheng, Anhui Shi, Weihu Wang, Huiming Yu, Rong Yu, Dongming Li, Bo Xu, Huimin Ma, Jing You, Dan Zhao, Leilei Jiang, Jianhao Geng, Guangying Zhu
PURPOSE: Stereotactic ablative body radiotherapy (SABR) represents an exciting, tolerable, and highly effective form of radiotherapy. Ongoing investigations into the interactions between radiotherapy and the immune system have uncovered new mechanisms that can be exploited to improve efficacy. We determined whether baseline or posttreatment immune parameters could predict disease control and toxicity in stage I non-small-cell lung cancer (NSCLC) patients treated with SABR. PATIENTS AND METHODS: Peripheral blood samples were collected from 62 patients 24 hours before treatment and within 4 weeks after treatment for lymphocyte subset count analysis...
January 4, 2018: Clinical Lung Cancer
Akira Utsunomiya, Noritaka Oyama, Shiro Iino, Natsuki Baba, Takenao Chino, Natsuko Utsunomiya, Minoru Hasegawa
Immune checkpoint inhibitors, such as ipilimumab and nivolumab, reverse the imbalance of antitumor self-tolerance and enhance T-cell responses. Currently, ipilimumab and nivolumab have a reported therapeutic impact on unresectable or metastatic melanomas; however, they also induce immune-related adverse events (irAEs). Ipilimumab-induced cutaneous irAEs are mostly low grade and manageable, although all-grade rash may occur in approximately 45% of all patients. We here report the case of a young woman with erythema multiforme major, which developed after sequential use of these 2 immune checkpoint inhibitors for advanced melanoma of the scalp...
January 2018: Case Reports in Dermatology
Bruno Francois, Robin Jeannet, Thomas Daix, Andrew H Walton, Matthew S Shotwell, Jacqueline Unsinger, Guillaume Monneret, Thomas Rimmelé, Teresa Blood, Michel Morre, Anne Gregoire, Gail A Mayo, Jane Blood, Scott K Durum, Edward R Sherwood, Richard S Hotchkiss
BACKGROUND: A defining pathophysiologic feature of sepsis is profound apoptosis-induced death and depletion of CD4+ and CD8+ T cells. Interleukin-7 (IL-7) is an antiapoptotic common γ-chain cytokine that is essential for lymphocyte proliferation and survival. Clinical trials of IL-7 in over 390 oncologic and lymphopenic patients showed that IL-7 was safe, invariably increased CD4+ and CD8+ lymphocyte counts, and improved immunity. METHODS: We conducted a prospective, randomized, double-blind, placebo-controlled trial of recombinant human IL-7 (CYT107) in patients with septic shock and severe lymphopenia...
March 8, 2018: JCI Insight
Jennifer M Reinhart, Warren Rose, Daniel J Panyard, Michael A Newton, Tyler K Liebenstein, Jeremiah Yee, Lauren A Trepanier
The lymphocyte toxicity assay (LTA) is a proposed surrogate marker of sulfonamide antibiotic hypersensitivity. In the LTA, peripheral blood mononuclear cells (PBMCs) undergo apoptosis more readily in hypersensitive versus tolerant patients when exposed to drug-hydroxylamine metabolites in vitro. The purpose of this study was to identify key gene transcripts associated with increased cytotoxicity from sulfamethoxazole-hydroxylamine in human PBMCs in the LTA. The LTA was performed on PBMCs of 10 patients hypersensitive to trimethoprim-sulfamethoxazole (HS) and 10 drug-tolerant controls (TOL), using two cytotoxicity assays: YO-PRO (n = 20) and MTT (n = 12)...
April 2018: Pharmacology Research & Perspectives
Khawar Ali Shahzad, Xin Wan, Lei Zhang, Weiya Pei, Aifeng Zhang, Muhammad Younis, Wei Wang, Chuanlai Shen
Biomimetic nanoparticles have been reported as immune modulators in autoimmune diseases and allograft rejections by numerous researchers. However, most of the therapeutics carrying antigens, toxins or cytokines underlay the mechanism of antigen presentation by cellular uptake of NPs through pinocytosis and phagocytosis. Few researches focus on the direct and antigen-specific modulation on T cells by NPs and combined use of multiple regulatory molecules. Here, polylactic-co-glycolic acid nanoparticles (PLGA-NPs) were fabricated as scaffold to cocoupling H-2Kb -Ig dimer, anti-Fas mAb, PD-L1-Fc, TGF-β and CD47-Fc for the generation of alloantigen-presenting and tolerance-inducing NPs, termed killer NPs and followed by i...
November 2018: Drug Delivery
Diane G Carnathan, Joseph J Mackel, Shelby L Sweat, Chiamaka A Enemuo, Etse H Gebru, Pallavi Dhadvai, Sailaja Gangadhara, Sakeenah Hicks, Thomas H Vanderford, Rama R Amara, José Esparza, Wei Lu, Jean-Marie Andrieu, Guido Silvestri
A major obstacle to development of an effective AIDS vaccine is that along with intended beneficial responses, immunization regimen may activate CD4+ T cells that can facilitate acquisition of HIV by serving as target cells for the virus. Lu et al. reported that intra-gastric administration of chemically inactivated SIVmac239 (iSIV) and Lactobacillus plantarum (LP) (iSIV+LP) protected 15/16 Chinese-origin rhesus macaques (RMs) from high-dose intra-rectal SIVmac239 challenge at three months post-immunization...
February 28, 2018: Journal of Virology
Fei Hua, Yueqiu Chen, Ziying Yang, Xiaomei Teng, Haoyue Huang, Zhenya Shen
BACKGROUND: Bone marrow-derived mesenchymal stem cells (BMSCs) could exert a potent immunosuppressive effect, and therefore may have a therapeutic potential in T-cell-dependent pathologies. We aimed to examine the effects of BMSCs on immune tolerance of allogeneic heart transplantation and the involvement of CD45RB+ dendritic cells (DCs). METHODS: Bone marrow-derived DCs and BMSCs were co-cultured, with CD45RB expression on the surface of DCs measured by flow cytometry...
February 28, 2018: Clinical Transplantation
Silvia C Formenti, Percy Lee, Sylvia Adams, Judith D Goldberg, Xiaochun Li, Michael Xie, Josephine Ratikan, Carol Felix, Lin Hwang, Kym Faull, James W Sayre, Sara Hurvitz, John Glaspy, Begoña Comin-Anduix, Sandra Demaria, Dorthe Schaue, William H McBride
PURPOSE: This study examined the feasibility, efficacy (abscopal effect) and immune effects of TGFβ blockade during radiotherapy in metastatic breast cancer patients. EXPERIMENTAL DESIGN: Prospective randomized trial comparing two doses of TGFβ blocking antibody fresolimumab. Metastatic breast cancer patients with at least three distinct metastatic sites whose tumor had progressed after at least one line of therapy were randomized to receive 1 or 10 mg/kg of fresolimumab, every 3 weeks for 5 cycles, with focal radiotherapy to a metastatic site at week 1, (3 doses of 7...
February 23, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Rajani Ravi, Kimberly A Noonan, Vui Pham, Rishi Bedi, Alex Zhavoronkov, Ivan V Ozerov, Eugene Makarev, Artem V Artemov, Piotr T Wysocki, Ranee Mehra, Sridhar Nimmagadda, Luigi Marchionni, David Sidransky, Ivan M Borrello, Evgeny Izumchenko, Atul Bedi
A majority of cancers fail to respond to immunotherapy with antibodies targeting immune checkpoints, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) or programmed death-1 (PD-1)/PD-1 ligand (PD-L1). Cancers frequently express transforming growth factor-β (TGFβ), which drives immune dysfunction in the tumor microenvironment by inducing regulatory T cells (Tregs) and inhibiting CD8+ and TH 1 cells. To address this therapeutic challenge, we invent bifunctional antibody-ligand traps (Y-traps) comprising an antibody targeting CTLA-4 or PD-L1 fused to a TGFβ receptor II ectodomain sequence that simultaneously disables autocrine/paracrine TGFβ in the target cell microenvironment (a-CTLA4-TGFβRIIecd and a-PDL1-TGFβRIIecd)...
February 21, 2018: Nature Communications
Hidetoshi Tsuda, Charles A Su, Toshiaki Tanaka, Katayoun Ayasoufi, Booki Min, Anna Valujskikh, Robert L Fairchild
Recipient endogenous memory T cells with donor reactivity pose an important barrier to successful transplantation and costimulatory blockade-induced graft tolerance. Longer ischemic storage times prior to organ transplantation increase early posttransplant inflammation and negatively impact early graft function and long-term graft outcome. Little is known about the mechanisms enhancing endogenous memory T cell activation to mediate tissue injury within the increased inflammatory environment of allografts subjected to prolonged cold ischemic storage (CIS)...
February 22, 2018: JCI Insight
Rizwan Romee, Sarah Cooley, Melissa M Berrien-Elliott, Peter Westervelt, Michael R Verneris, John E Wagner, Daniel J Weisdorf, Bruce R Blazar, Celalettin Ustun, Todd E DeFor, Sithara Vivek, Lindsey Peck, John F DiPersio, Amanda F Cashen, Rachel Kyllo, Amy Musiek, András Schaffer, Milan J Anadkat, Ilana Rosman, Daniel Miller, Jack O Egan, Emily K Jeng, Amy Rock, Hing C Wong, Todd A Fehniger, Jeffrey S Miller
New therapies for patients with hematologic malignancies who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) are needed. Interleukin (IL)-15 is a cytokine that stimulates CD8+ T cell and NK cell anti-tumor responses, and we hypothesized this cytokine may augment anti-leukemia/lymphoma immunity in vivo. To test this, we performed a first-in-human multi-center phase 1 trial ( NCT01885897) of the IL-15 superagonist complex ALT-803 in patients who relapsed >60 days after allo-HCT...
February 20, 2018: Blood
Jia Liu, Qing Yu, Weimin Wu, Xuan Huang, Ruth Broering, Melanie Werner, Michael Roggendorf, Dongliang Yang, Mengji Lu
Hepatic APCs play a critical role in promoting immune tolerance in the liver. Recently, we have demonstrated that TLR2 stimulation on liver sinusoidal endothelial cells reverted their suppressive properties to induce T cell immunity. However, there is a paucity of information about how TLR2 stimulation modulates the immunological function of other hepatic APCs. In the current study, we investigated whether TLR2 stimulation influences the function of intrahepatic myeloid-derived cells (iMDCs) and elucidated the mechanisms involved in iMDC-induced T cell immunity...
February 19, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Andreas T Björklund, Mattias Carlsten, Ebba Sohlberg, Lisa L Liu, Trevor Clancy, Mohsen Karimi, Sarah Cooley, Jeffrey S Miller, Monika Klimkowska, Marie Schaffer, Emma Watz, Kristina I Wikstrom, Pontus Blomberg, Bjorn E Wahlin, Marzia Palma, Lotta Hansson, Per Ljungman, Eva Hellström-Lindberg, Hans-Gustaf Ljunggren, Karl-Johan Malmberg
PURPOSE: To evaluate the safety, efficacy and immunobiological correlates of allogeneic NK cell-based therapy in primary chemotherapy-refractory or relapsed high-risk myelodysplastic syndrome (MDS), secondary AML (MDS/AML), and de novo AML patients. EXPERIMENTAL DESIGN: Sixteen patients received fludarabine/cyclophosphamide conditioning combined with total lymphoid irradiation followed by adoptive immunotherapy with IL-2-activated haploidentical NK cells. RESULTS: NK cell infusions were well tolerated with only transient adverse events observed in the 16 patients...
February 14, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Yufeng Xie, Jie Wu, Aizhang Xu, Shahid Ahmeqd, Amer Sami, Rajni Chibbar, Andrew Freywald, Changyu Zheng, Jim Xiang
DNA vaccines composed of heterologous human HER2 and rat neu sequences induce stronger antibody response and protective antitumor immunity than either HER2 or neu DNA vaccines in transgenic mice. We previously developed HER2-specific exosome-targeted T-cell vaccine HER2-TEXO capable of stimulating HER2-specific CD8+ T-cell responses, but only leading to partial protective immunity in double-transgenic HLA-A2/HER2 mice with self-immune tolerance to HER2. Here, we constructed an adenoviral vector AdVHuRt expressing HuRt fusion protein composed of NH2-HER21-407 (Hu) and COOH-neu408-690 (Rt) fragments, and developed a heterologous human/rat HER2-specific exosome-targeted T-cell vaccine HuRt-TEXO using polyclonal CD4+ T-cells uptaking exosomes released by AdVHuRt-transfected dendritic cells...
February 5, 2018: Vaccine
George C Prendergast, William J Malachowski, Arpita Mondal, Peggy Scherle, Alexander J Muller
The tryptophan catabolic enzyme indoleamine 2,3-dioxygenase-1 (IDO1) has attracted enormous attention in driving cancer immunosuppression, neovascularization, and metastasis. IDO1 suppresses local CD8+ T effector cells and natural killer cells and induces CD4+ T regulatory cells (iTreg) and myeloid-derived suppressor cells (MDSC). The structurally distinct enzyme tryptophan dioxygenase (TDO) also has been implicated recently in immune escape and metastatic progression. Lastly, emerging evidence suggests that the IDO1-related enzyme IDO2 may support IDO1-mediated iTreg and contribute to B-cell inflammed states in certain cancers...
2018: International Review of Cell and Molecular Biology
Joseph R Leventhal, Suzanne T Ildstad
Successful solid organ transplantation currently requires the life-long use of medications to suppress the immune system in order to prevent transplant rejection. Drug-based immunosuppression significantly increases the risk of infection and cancer, as well as being very costly. Development of new therapies to minimize or eliminate entirely the need for anti-rejection drugs is of great interest to the transplant community. Therapeutic cell transfer for the control of the human immune system represents a compelling approach to reduce or eliminate the need for anti-rejection drugs...
February 2, 2018: Human Immunology
Yoh Zen, Matthew M Yeh
The adverse effects of immune checkpoint inhibitors in various organs may be attributed to immune-mediated processes triggered by disrupted self-tolerance; however, it remains unclear whether they are similar or dissimilar to classic organ-specific autoimmune diseases. The present study aimed to compare clinicopathologic features between checkpoint inhibitor-induced liver injury and acutely presenting autoimmune hepatitis or idiosyncratic drug-induced liver injury. Seven patients treated with nivolumab (n = 5) or ipilimumab (n = 2) presented with liver dysfunction a median of 41 days (range 21-120) after the initiation of immunotherapy...
February 5, 2018: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
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