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Paul J Martin, Wenhong Fan, Barry E Storer, David M Levine, Lue Ping Zhao, Edus H Warren, Mary E D Flowers, Stephanie J Lee, Paul A Carpenter, Michael Boeckh, Sangeeta Hingorani, Li Yan, Qiang Hu, Leah Preus, Song Liu, Stephen Spellman, Xiaochun Zhu, Marcelo Pasquini, Philip McCarthy, Daniel Stram, Xin Sheng, Loreall Pooler, Christopher A Haiman, Lara Sucheston-Campbell, Theresa Hahn, John A Hansen
Previous studies have identified single-nucleotide polymorphisms (SNPs) associated with the risk of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). The current study determined whether these associations could be replicated in large cohorts of donors and recipients. Each SNP was tested with cohorts of patients having the same donor type (HLA-matched related, unrelated or both) reported in the original publication, and testing was limited to the same genome (recipient or donor) and genetic model (dominant, recessive or allelic) reported in the original study...
October 6, 2016: Blood
Ryoyo Ikebuchi, Shunsuke Teraguchi, Alexis Vandenbon, Tetsuya Honda, Francis H W Shand, Yasutaka Nakanishi, Takeshi Watanabe, Michio Tomura
Foxp3(+) regulatory T cells (Tregs) migrating from the skin to the draining lymph node (dLN) have a strong immunosuppressive effect on the cutaneous immune response. However, the subpopulations responsible for their inhibitory function remain unclear. We investigated single-cell gene expression heterogeneity in Tregs from the dLN of inflamed skin in a contact hypersensitivity model. The immunosuppressive genes Ctla4 and Tgfb1 were expressed in the majority of Tregs. Although Il10-expressing Tregs were rare, unexpectedly, the majority of Il10-expressing Tregs co-expressed Gzmb and displayed Th1-skewing...
October 19, 2016: Scientific Reports
Florian Rouaud, Jean-Luc Boucher, Anny Slama-Schwok, Stéphane Rocchi
Melanoma is one of the most lethal cancers when it reaches a metastatic stage. Despite the spectacular achievements of targeted therapies (BRAF inhibitors) or immuno-therapies (anti-CTLA4 or anti-PD1), most patients with melanoma will need additional treatments. Here we used a photoactive NADPH analogue called NS1 to induce cell death by inhibition of NADPH oxidases NOX in melanoma cells, including melanoma cells isolated from patients. In contrast, healthy melanocytes growth was unaffected by NS1 treatment...
October 14, 2016: Oncotarget
David Wojciechowski, Flavio Vincenti
Kidney transplantation immunosuppression relies on a calcineurin inhibitor backbone. Calcineurin inhibitors have reduced early-acute rejection rates but failed to improve long-term allograft survival. Their nephrotoxicity has shifted the focus of investigation to calcineurin inhibitor-free regimens. Costimulation blockade with belatacept, a second generation, higher avidity variant of CTLA4-Ig, has emerged as part of a calcineurin inhibitor-free regimen. Belatacept has demonstrated superior glomerular filtration rate compared with calcineurin inhibitors albeit with an increased risk of early and histologically severe rejection...
September 2016: Advances in Chronic Kidney Disease
Jan Čáp
Treatment with tyrosine kinase inhibitors leads to thyroid dysfunction in up to one half of treated patients, hypothyroidism being the most common. It is caused by destructive thyroiditis, impaired transport of T4 into the cell and deiodinase induction. Bexarotene is a nuclear retinoid X receptor agonist. Its application is accompanied with central hypothyroidism and hypertriglyceriaemia in virtually all patients and it also increases thyroxin metabolism. Autoimmune endocrine side effects are common in cancer immunotherapy...
2016: Vnitr̆ní Lékar̆ství
Dan Holmberg, Karin Ruikka, Petter Lindgren, Mats Eliasson, Sofia Mayans
BACKGROUND: T1D and AITD are autoimmune disorders commonly occurring in the same family and even in the same individual. The genetic contribution to these disorders is complex making uncovering of susceptibility genes very challenging. The general aim of this study was to identify loci and genes contributing to T1D/AITD susceptibility. Our strategy was to perform linkage and association studies in the relatively genetically homogenous population of northern Sweden. We performed a GWLS to find genomic regions linked to T1D/AITD in families from northern Sweden and we performed an association study in the families to test for association between T1D/AITD and variants in previously published candidate genes as well as a novel candidate gene, CD247...
October 4, 2016: BMC Medical Genetics
L Cavicchioli, S Ferraresso, S Westmoreland, S Kaliyaperumal, H Knight, C Crossan, L Scobie, A Danesi, M Vadori, D Trez, R Aron Badin, P Hantraye, E Cozzi
Posttransplant lymphoproliferative disorders (PTLDs) are a heterogeneous group of lymphoid proliferations that occur in the setting of depressed T-cell function due to immunosuppressive therapy used following solid organ transplantation, hematopoietic stem cell transplantation, and also xenotransplantation. In the present study, 28 immunosuppressed parkinsonian Macaca fascicularis were intracerebrally injected with wild-type or CTLA4-Ig transgenic porcine xenografts to identify a suitable strategy to enable long-term cell survival, maturation, and differentiation...
September 30, 2016: Veterinary Pathology
Damian T Rieke, Sebastian Ochsenreither, Konrad Klinghammer, Tanguy Y Seiwert, Frederick Klauschen, Inge Tinhofer, Ulrich Keilholz
Immune checkpoints are emerging treatment targets, but mechanisms underlying checkpoint expression are poorly understood. Since alterations in DNA repair genes have been connected to the efficacy of checkpoint inhibitors, we investigated associations between methylation of DNA repair genes and CTLA4 and CD274 (PD-L1) expression.A list of DNA repair genes (179 genes) was selected from the literature, methylation status and expression of inflammation-associated genes (The Cancer Genome Atlas data) was correlated in head and neck squamous cell carcinoma (HNSCC), cervical and lung squamous cell carcinoma...
September 23, 2016: Oncotarget
M-O Grimm
Immune checkpoint inhibitors are establishing itselves as a new systemic treatment option (in addition to chemotherapy and targeted therapy) for metastatic tumours. (Re)activating the immune system, these antibodies may lead to impressive remissions lasting for a long time in some patients. Regarding urological tumours, the anti-PD-1 antibody Nivolumab (Opdivo(®)) has been approved this year for advanced, previously treated renal cell carcinoma. In the United States, Atezolizumab (Tecentriq(®)) has been approved for metastatic urothelial carcinoma after platinum-based chemotherapy...
September 2016: Aktuelle Urologie
Emily F Goode, Elizabeth C Smyth
Survival for patients with advanced oesophageal and stomach cancer is poor; together these cancers are responsible for more than a million deaths per year globally. As chemotherapy and targeted therapies such as trastuzumab and ramucirumab result in modest improvements in survival but not long-term cure for such patients, development of alternative treatment approaches is warranted. Novel immunotherapy drugs such as checkpoint inhibitors have been paradigm changing in melanoma, non-small cell lung cancer and urothelial cancers...
September 22, 2016: Journal of Clinical Medicine
Nadeem Riaz, Jonathan J Havel, Sviatoslav M Kendall, Vladimir Makarov, Logan A Walsh, Alexis Desrichard, Nils Weinhold, Timothy A Chan
Immune checkpoint blockade has shown significant promise as an anticancer treatment, yet the determinants of response are not completely understood. Here we show that somatic mutations in SERPINB3 and SERPINB4 are associated with survival after anti-CTLA4 immunotherapy in two independent cohorts of patients with melanoma (n = 174). Interestingly, serpins are homologs of the well-known ovalbumin antigen and are associated with autoimmunity. Our findings have implications for the personalization of immunotherapy...
September 26, 2016: Nature Genetics
B V Titov, N A Matveeva, M Yu Martynov, O O Favorova
Carriage frequencies of alleles and genotypes of polymorphic loci of inflammation genes (49A>G CTLA4, 41G>A and 87C>T PDE4D, -590C>T IL4, -308A>G TNF, 252G>A LTA, 874A>T IFNG, -509С>Т, 869T>C and 915G>C TGFB1) were determined in a sample of 200 patients diagnosed with ischemic stroke and in the control group similar in gender and age (146 individuals), all ethnic Russians. The positive association of the allele PDE4D*87C (р = 0.028) and genotype TGFB1*-509Т/Т (р = 0.02) carriage with ischemic stroke was shown...
July 2016: Molekuliarnaia Biologiia
Shinsuke Oshima, Yasutomo Fujii, Erik E Karrer, Fujiko Takamura, Steven J Chapin, Margaret Neighbors, Sridhar Viswanathan, Bruce H Devens, Yasuyuki Higashi, Hidekazu Mizuhara
The CTLA4-Ig fusion proteins abatacept and belatacept inhibit CD28-mediated T cell activation by binding CD80 (B7-1) and CD86 (B7-2) costimulatory ligands and are clinically proven immunosuppressants used for rheumatoid arthritis and renal transplantation, respectively. Abatacept and belatacept preferentially bind CD80, yet CD86 has been implicated as the dominant ligand for CD28-mediated costimulation of T cells. We investigated the immunosuppressive effects of ASP2408, a novel CTLA4-Ig with CD86 selectivity and high potency created by directed evolution methods...
September 19, 2016: International Immunopharmacology
Stefan Diem, Fabienne Keller, Reinhard Rüesch, Samia A Maillard, Daniel E Speiser, Reinhard Dummer, Marco Siano, Ursula Urner-Bloch, Simone M Goldinger, Lukas Flatz
Immunotherapy leads to significantly prolonged survival of patients with metastatic melanoma. Autoimmune side effects including colitis, dermatitis, and endocrine abnormalities are common in patients treated with ipilimumab [anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4)]. Antibodies such as pembrolizumab that interfere with the PD-1 (programmed cell death 1)/PD-L1 pathway show greater efficacy and less toxicity than ipilimumab. Here we report 2 cases of pembrolizumab-induced uveitis associated with complete or partial tumor response...
November 2016: Journal of Immunotherapy
Lauren M Kropp, Jennifer F De Los Santos, Svetlana B McKee, Robert M Conry
Durable local control of irradiated cancer and distant abscopal effects are presumably immune mediated. To evaluate the role of radiotherapy (RT) for limited progression after anti-CTLA4 checkpoint inhibition, medical records of all patients with surgically incurable stage III or IV melanoma from a single institution who received ipilimumab as first-line immunotherapy and subsequent RT were reviewed. Sixteen patients who received RT to all sites of limited melanoma progression were analyzed. Eight patients with an incomplete initial response to ipilimumab received RT to new or progressive disease, whereas the remaining 8 patients with a complete initial response to ipilimumab received RT to sites of subsequent recurrence...
November 2016: Journal of Immunotherapy
Elizabeth I Buchbinder, Anasuya Gunturi, Jessica Perritt, Janice Dutcher, Sandra Aung, Howard L Kaufman, Marc S Ernstoff, Girald P Miletello, Brendan D Curti, Gregory A Daniels, Sapna P Patel, John M Kirkwood, Sigrun Hallmeyer, Joseph I Clark, Rene Gonzalez, John M Richart, Joe Lutzky, Michael A Morse, Ryan J Sullivan, David F McDermott
BACKGROUND: High dose interleukin-2 (HD IL-2) can induce durable responses in a subset of patients leading to long-term survival. Immune checkpoint blockade (ICB) has demonstrated similarly durable responses in a larger proportion of patients. However, not all patients respond to immune checkpoint blockade and subsequent therapeutic options need to be explored. METHODS: The PROCLAIM database was queried for patients with metastatic melanoma who had received HD IL-2 after treatment with ipilimumab or without prior ICB...
2016: Journal for Immunotherapy of Cancer
Wensheng Zhang, Vijay S Gorantla, Phil G Campbell, Yang Li, Yang Yang, Chiaki Komatsu, Lee E Weiss, Xin Xiao Zheng, Mario G Solari
Pancreatic islet transplantation (PIT) represents a potential therapy to circumvent the need for exogenous insulin in type 1 diabetes. However, PIT remains limited by lack of donor islets and need for long-term multi-drug immunosuppression to prevent alloimmune islet rejection. Our goal was to evaluate a local immunoregulatory strategy that sustains islet allograft survival and restores glucose homeostasis in the absence of systemic immunosuppression. Nanogram quantities of murine CTLA4/Fc fusion protein were controllably delivered within human acellular dermal matrix scaffolds using an inkjet-based biopatterning technology and co-transplanted with allogeneic islets under the renal capsule to create an immunoregulatory microenvironment around the islet allograft...
September 20, 2016: Diabetes
S J E Hwang, R Anforth, G Carlos, P Fernandez-Peñas
Over the past decade, targeted therapies such as BRAF inhibitors, MEK inhibitors and immunotherapies such as anti-CTLA4 and anti-PD1 antibodies have emerged as novel treatments of advanced melanoma. Along with increased use of these therapies, a range of cutaneous adverse events have also emerged, varying from more serious and frequent cutaneous squamous cell carcinoma to mere cosmetic changes such as curly hair or rare severe toxic epidermal necrolysis. Early detection and management of these cutaneous adverse events will aid patients to receive accurate treatment, avoid unnecessary discontinuation of anti-tumour treatment and improve the patient's overall quality of life...
September 15, 2016: Actas Dermo-sifiliográficas
Matthew J Butcher, Adam R Filipowicz, Tayab C Waseem, Christopher McGary, Kevin J Crow, Nathaniel Magilnick, Mark Boldin, Patric S Lundberg, Elena Galkina
RATIONALE: Foxp3(+)T regulatory cells (Tregs) are key players in maintaining immune homeostasis. Evidence suggests that Tregs respond to environmental cues to permit or suppress inflammation. In atherosclerosis, Th1-driven inflammation affects Treg homeostasis, but the mechanisms governing this phenomenon are unclear. OBJECTIVE: Here, we address whether atherosclerosis impacts Treg plasticity and functionality in Apoe(-/-) mice, and what effect Treg plasticity might have on the pathology of atherosclerosis...
September 15, 2016: Circulation Research
Shin Foong Ngiow, Arabella Young, Stephen J Blake, Geoffrey R Hill, Hideo Yagita, Michele Wl Teng, Alan J Korman, Mark J Smyth
The durability and efficacy of anti-human PD1 monoclonal antibodies (PD1 mAb) vary across different malignancies. Although an absence of tumor-infiltrating cytotoxic T lymphocytes has been identified as a cause for resistance to PD1 mAb, the presence of intratumor exhausted PD1hi T cells also contributes to insensitivity to this immune checkpoint therapy. In this study, we used mouse tumor models of PD1 mAb resistance that harbored PD1hi T cells and flow cytometry analysis of tumor-infiltrating leukocytes immediately post-therapy as a screening platform to identify agents that could resensitize T cells to PD1 blockade...
September 9, 2016: Cancer Research
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