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Diabetes and ctla-4

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https://www.readbyqxmd.com/read/29409002/ptpn22-and-ctla-4-polymorphisms-are-associated-with-polyglandular-autoimmunity
#1
Juliane Houcken, Christina Degenhart, Klaus Bender, Jochem König, Lara Frommer, George J Kahaly
Context: Single nucleotide polymorphisms (SNP) of various genes increase susceptibility to monoglandular autoimmunity. Scarce data are available in autoimmune polyglandular syndromes (APS). Objective: Evaluate potential associations of eight SNP with APS. Setting: Academic referral endocrine clinic. Patients: A total of 543 patients with APS, monoglandular autoimmunity and controls. Intervention: The SNP protein tyrosine phosphatase non-receptor type 22 (PTPN22) rs2476601 (+1858), cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) rs3087243 (CT60) and rs231775 (AG49), Vitamin D Receptor (VDR) rs1544410 (Bsm I), rs7975232 (Apa I), rs731236 (Taq I), tumor necrosis factor alpha rs1800630 (-863) and Interleukin-2 receptor alpha rs10795791 were tested by single base extension in all subjects...
February 1, 2018: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/29367462/high-self-reactivity-drives-t-bet-and-potentiates-treg-function-in-tissue-specific-autoimmunity
#2
Maran L Sprouse, Marissa A Scavuzzo, Samuel Blum, Ivan Shevchenko, Thomas Lee, George Makedonas, Malgorzata Borowiak, Matthew L Bettini, Maria Bettini
T cell receptor (TCR) affinity is a critical factor of Treg lineage commitment, but whether self-reactivity is a determining factor in peripheral Treg function remains unknown. Here, we report that a high degree of self-reactivity is crucial for tissue-specific Treg function in autoimmunity. Based on high expression of CD5, we identified a subset of self-reactive Tregs expressing elevated levels of T-bet, GITR, CTLA-4, and ICOS, which imparted significant protection from autoimmune diabetes. We observed that T-bet expression in Tregs, necessary for control of Th1 autoimmunity, could be induced in an IFNγ-independent fashion and, unlike in conventional T cells (Tconv), was strongly correlated with the strength of TCR signaling...
January 25, 2018: JCI Insight
https://www.readbyqxmd.com/read/29337446/-endocrinopathies-induced-by-immune-checkpoint-inhibitors
#3
Jaafar Jaafar, Maria Mavromati, Jacques Philippe
Immune checkpoint Inhibitors are new immunomodulatory treatments that have proven their anti-tumor efficacy in several advanced cancers. Nevertheless, their use has paved the way for multiple immunological adverse effects that affect many systems and organs including endocrine glands such as the pituitary, thyroid, adrenal and pancreas. Hypophysitis is the most common complication of anti-CTLA-4 monoclonal antibodies, while anti-PD-1 and anti-PD-L1 antibodies cause more thyroid complications. Adrenal insufficiency and type 1 diabetes are relatively less common...
January 10, 2018: Revue Médicale Suisse
https://www.readbyqxmd.com/read/29258717/tolerogenic-ag-plg-nanoparticles-induce-tregs-to-suppress-activated-diabetogenic-cd4-and-cd8-t-cells
#4
Suchitra Prasad, Tobias Neef, Dan Xu, Joseph R Podojil, Daniel R Getts, Lonnie D Shea, Stephen D Miller
Type 1 diabetes (T1D) is mediated by destruction of pancreatic β cells by autoantigen-specific CD4+ and CD8+ T cells, thus the ideal solution for T1D is the restoration of immune tolerance to β cell antigens. We demonstrate the ability of carboxylated 500 nm biodegradable poly(lactide-co-glycolide) (PLG) nanoparticles PLG nanoparticles (either surface coupled with or encapsulating the cognate diabetogenic peptides) to rapidly and efficiently restore tolerance in NOD.SCID recipients of both activated diabetogenic CD4+ BDC2...
December 16, 2017: Journal of Autoimmunity
https://www.readbyqxmd.com/read/29025857/endocrine-side-effects-of-cancer-immunotherapy
#5
REVIEW
Priscilla Cukier, Fernando C Santini, Mariana Scaranti, Ana O Hoff
Immune checkpoint inhibitors have recently become a cornerstone for the treatment of different advanced cancers. These drugs, represented mainly by monoclonal antibodies anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4), anti-programmed cell death protein-1 (PD-1) and anti-PD-1 ligand molecules (PD-L1 and L2), have the ability to reactivate the immune system against tumor cells, but can also trigger a myriad of autoimmune side effects, termed immune-related adverse events (irAEs). In particular, there are a number of endocrine-related irAEs...
December 2017: Endocrine-related Cancer
https://www.readbyqxmd.com/read/28973656/incidence-of-endocrine-dysfunction-following-the-use-of-different-immune-checkpoint-inhibitor-regimens-a-systematic-review-and-meta-analysis
#6
Romualdo Barroso-Sousa, William T Barry, Ana C Garrido-Castro, F Stephen Hodi, Le Min, Ian E Krop, Sara M Tolaney
Importance: If not promptly recognized, endocrine dysfunction can be life threatening. The incidence and risk of developing such adverse events (AEs) following the use of immune checkpoint inhibitor (ICI) regimens are unknown. Objective: To compare the incidence and risk of endocrine AEs following treatment with US Food and Drug Administration-approved ICI regimens. Data Sources: A PubMed search through July 18, 2016, using the following keywords was performed: "ipilimumab," "MDX-010," "nivolumab," "BMS-963558," "pembrolizumab," "MK-3475," "atezolizumab," "MPDL3280A," and "phase...
September 28, 2017: JAMA Oncology
https://www.readbyqxmd.com/read/28941965/gestational-respiratory-infections-interacting-with-offspring-hla-and-ctla-4-modifies-incident-%C3%AE-cell-autoantibodies
#7
Kristian F Lynch, Hye-Seung Lee, Carina Törn, Kendra Vehik, Jeffrey P Krischer, Helena Elding Larsson, Michael J Haller, William A Hagopian, Marian J Rewers, Jin-Xiong She, Olli G Simell, Jorma Toppari, Anette-G Ziegler, Beena Akolkar, Heikki Hyöty, Ezio Bonifacio, Åke Lernmark
β-cell autoantibodies against insulin (IAA), GAD65 (GADA) and IA-2 (IA-2A) precede onset of childhood type 1 diabetes (T1D). Incidence of the first appearing β-cell autoantibodies peaks at a young age and is patterned by T1D-associated genes, suggesting an early environmental influence. Here, we tested if gestational infections and interactions with child's human leukocyte antigen (HLA) and non-HLA genes affected the appearance of the first β-cell autoantibody. Singletons of mothers without diabetes (n = 7472) with T1D-associated HLA-DR-DQ genotypes were prospectively followed quarterly through the first 4 years of life, then semiannually until age 6 years, using standardized autoantibody analyses...
September 20, 2017: Journal of Autoimmunity
https://www.readbyqxmd.com/read/28878738/overlooked-mechanisms-in-type-1-diabetes-etiology-how-unique-costimulatory-molecules-contribute-to-diabetogenesis
#8
REVIEW
David H Wagner
Type 1 Diabetes (T1D) develops when immune cells invade the pancreatic islets resulting in loss of insulin production in beta cells. T cells have been proven to be central players in that process. What is surprising, however, is that classic mechanisms of tolerance cannot explain diabetogenesis; alternate mechanisms must now be considered. T cell receptor (TCR) revision is the process whereby T cells in the periphery alter TCR expression, outside the safety-net of thymic selection pressures. This process results in an expanded T cell repertoire, capable of responding to a universe of pathogens, but limitations are that increased risk for autoimmune disease development occurs...
2017: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/28815218/capturing-the-systemic-immune-signature-of-a-norovirus-infection-an-n-of-1-case-study-within-a-clinical-trial
#9
Antony J Cutler, Joao Oliveira, Ricardo C Ferreira, Ben Challis, Neil M Walker, Sarah Caddy, Jia Lu, Helen E Stevens, Deborah J Smyth, Marcin L Pekalski, Jane Kennet, Kara M D Hunter, Ian Goodfellow, Linda S Wicker, John A Todd, Frank Waldron-Lynch
BACKGROUND:  The infection of a participant with norovirus during the adaptive study of interleukin-2 dose on regulatory T cells in type 1 diabetes (DILT1D) allowed a detailed insight into the cellular and cytokine immune responses to this prevalent gastrointestinal pathogen. METHODS:  Serial blood, serum and peripheral blood mononuclear cell (PBMC) samples were collected pre-, and post-development of the infection. To differentiate between the immune response to norovirus and to control for the administration of a single dose of aldesleukin (recombinant interleukin-2, rIL-2) alone, samples from five non-infected participants administered similar doses were analysed in parallel...
2017: Wellcome Open Research
https://www.readbyqxmd.com/read/28747257/cells-with-treg-specific-foxp3-demethylation-but-low-cd25-are-prevalent-in-autoimmunity
#10
Ricardo C Ferreira, Henry Z Simons, Whitney S Thompson, Daniel B Rainbow, Xin Yang, Antony J Cutler, Joao Oliveira, Xaquin Castro Dopico, Deborah J Smyth, Natalia Savinykh, Meghavi Mashar, Tim J Vyse, David B Dunger, Helen Baxendale, Anita Chandra, Chris Wallace, John A Todd, Linda S Wicker, Marcin L Pekalski
Identification of alterations in the cellular composition of the human immune system is key to understanding the autoimmune process. Recently, a subset of FOXP3(+) cells with low CD25 expression was found to be increased in peripheral blood from systemic lupus erythematosus (SLE) patients, although its functional significance remains controversial. Here we find in comparisons with healthy donors that the frequency of FOXP3(+) cells within CD127(low)CD25(low) CD4(+) T cells (here defined as CD25(low)FOXP3(+) T cells) is increased in patients affected by autoimmune disease of varying severity, from combined immunodeficiency with active autoimmunity, SLE to type 1 diabetes...
November 2017: Journal of Autoimmunity
https://www.readbyqxmd.com/read/28640512/a-major-responder-to-ipilimumab-and-nivolumab-in-metastatic-uveal-melanoma-with-concomitant-autoimmunity
#11
Pui Ying Chan, Peter Hall, Gordon Hay, Victoria M L Cohen, Peter W Szlosarek
The use of immune checkpoint inhibition has led to major improvements in outcome for patients with metastatic cutaneous melanoma. The combination of ipilimumab and nivolumab has demonstrated greater activity over single-agent immunotherapy in phase III trials. Clinical trials of combination CTLA-4 and PD-1 inhibition are underway in uveal melanoma, for which there are currently no data. Here, we present the case of a 74-year-old male patient with metastatic uveal melanoma, who was treated with a combination of ipilimumab and nivolumab...
June 22, 2017: Pigment Cell & Melanoma Research
https://www.readbyqxmd.com/read/28603205/immune-related-adverse-events-by-immune-checkpoint-inhibitors
#12
REVIEW
Takafumi Kadono
Recent introduction of immune checkpoint inhibitors represented by anti-PD-1 antibodies such as nivolumab and pembrolizumab, and anti-CTLA-4 antibody such as ipilimumab had a great impact on cancer immunotherapy especially for melanoma, non-small cell lung cancer, renal cell carcinoma, and Hodgkin's lymphoma. On the other hand, immune checkpoint inhibitors have their own distinctive adverse events, which are collectively named as "immune-related adverse events". Although immune-related adverse events may occur at any part of the body, interstitial pneumonia, colitis, hypothyroidism, liver dysfunction, skin rash, vitiligo, hypophysitis, type 1 diabetes, renal dysfunction, myasthenia gravis, neuropathy, myositis, and uveitis are representative...
2017: Nihon Rinshō Men'eki Gakkai Kaishi, Japanese Journal of Clinical Immunology
https://www.readbyqxmd.com/read/28499411/paraneoplastic-acral-vascular-syndrome-in-a-patient-with-metastatic-melanoma-under-immune-checkpoint-blockade
#13
Thilo Gambichler, Stefanie Strutzmann, Andrea Tannapfel, Laura Susok
BACKGROUND: Paraneoplastic acral vascular syndrome (PAVS) is a rare phenomenon which is observed in patients with adenocarcinomas and other malignancies. Various potential pathogenic mechanisms such as tumour invasion of sympathetic nerves, hyperviscosity, hypercoagulability, vasoactive tumour-secreted substances, and immunological mechanisms have been suggested. CASE PRESENTATION: We report a 60-year-old Caucasian male attended our hospital with a bulky lymph node mass in the right axilla...
May 12, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28384040/ctla-4-49-g-a-polymorphism-confers-autoimmune-disease-risk-an-updated-meta-analysis
#14
Ke Wang, Qin Zhu, Yunjie Lu, Hao Lu, Feng Zhang, Xuehao Wang, Ye Fan
BACKGROUND: Cytotoxic T lymphocyte antigen-4 (CTLA-4) plays a pivotal role in immune homeostasis. Dysregulated expression of CTLA-4 leads to many autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes (T1D). There has been a controversial association between the CTLA-4 +49 G/A SNP (rs231775) and autoimmune diseases. Therefore, this meta-analysis was performed to assess the link between rs231775 and autoimmune disease risk. MATERIALS AND METHODS: We retrieved the available studies from PUBMED and EMBASE through February, 2016 and then performed meta-analyses that included all populations, as well as by ethnicity...
April 2017: Genetic Testing and Molecular Biomarkers
https://www.readbyqxmd.com/read/28060767/cytotoxic-t-lymphocyte-associated-protein-4-49a-g-polymorphisms-contribute-to-the-risk-of-type-1-diabetes-in-children-an-updated-systematic-review-and-meta-analysis-with-trial-sequential-analysis
#15
Bo Wang, Wei Du, Yutao Jia, Xiaobai Zhang, Guorui Ma
Type 1 diabetes (T1D) is a heritable disease associated with multiple genetic variants. This systematic review and meta-analysis assessed the correlation between cytotoxic T-lymphocyte-associated protein 4(CTLA-4) +49A/G polymorphisms and the risk of T1D in children. The random effects model was used to estimate the related odds ratios (ORs) and 95% confidence intervals (CIs). Trial sequential analysis (TSA) was used to determine whether the currently available evidence was sufficient and conclusive. Our results indicated that CTLA-4 gene polymorphisms significantly increased the risk of childhood T1D in an allelic model (G vs...
February 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/27934619/a-case-of-fulminant-type-1-diabetes-mellitus-with-a-precipitous-decrease-in-pancreatic-volume-induced-by-nivolumab-for-malignant-melanoma-analysis-of-hla-and-ctla-4-polymorphisms
#16
Kazushi Ishikawa, Tomoko Shono-Saito, Tomoko Yamate, Yoshitaka Kai, Takashi Sakai, Fumiaki Shimizu, Yasunari Yamada, Hiromu Mori, Shinsuke Noso, Hiroshi Ikegami, Hiroto Kojima, Hidenori Tanaka, Sakuhei Fujiwara, Yutaka Hatano
No abstract text is available yet for this article.
December 8, 2016: European Journal of Dermatology: EJD
https://www.readbyqxmd.com/read/27424137/cytotoxic-t-lymphocyte-antigen-4-gene-variants-in-type-2-diabetic-patients-with-or-without-neuropathy
#17
Javad Kiani, Saedeh Khadempar, Mehrdad Hajilooi, Hamzeh Rezaei, Fatemeh Keshavarzi, Ghasem Solgi
Many studies have shown that cytotoxic T lymphocyte antigen-4 (CTLA-4) gene variants are associated with several autoimmune diseases particularly type 1 diabetes. Due to the lack of consistent data for this association with type 2 diabetes (T2D), this study explored the possible influence of CTLA-4 gene polymorphisms at -1722 (T/C), -318 (C/T), and +49 (G/A) positions for susceptibility to T2D in relation with neuropathy. One hundred and eleven unrelated patients with T2D [49 patients with diabetic peripheral neuropathy (DPN) and 62 patients without PDN] and 100 healthy ethnic- and gender-matched controls were included in this study...
June 2016: Iranian Journal of Allergy, Asthma, and Immunology
https://www.readbyqxmd.com/read/27357431/altered-regulatory-t-cell-phenotype-in-latent-autoimmune-diabetes-of-the-adults-lada
#18
M Radenkovic, C Silver, J Arvastsson, K Lynch, Å Lernmark, R A Harris, C-D Agardh, C M Cilio
Latent autoimmune diabetes of the adults (LADA) accounts for up to 12% of all patients with diabetes. Initially the disease resembles type 2 diabetes (T2D); however, the typical presence of β cell autoantibodies indicates an autoimmune basis of LADA. While dysfunctional regulatory T cells (Tregs ) have been implicated in autoimmune diabetes, these cells have been scarcely studied in LADA. The aim of this study was to investigate the frequency and phenotype of circulating Tregs in LADA patients early during disease progression...
October 2016: Clinical and Experimental Immunology
https://www.readbyqxmd.com/read/27328412/reparixin-a-cxcr1-2-inhibitor-in-islet-allotransplantation
#19
Rena L Pawlick, John Wink, Andrew R Pepper, Antonio Bruni, Nasser Abualhassen, Yasmin Rafiei, Boris Gala-Lopez, Mariusz Bral, A M James Shapiro
Quality of life in Type 1 diabetic patients may be improved with islet transplantation, but lifelong immunosuppression is required to prevent rejection. Allo-immune response is a key player in graft dysfunction and although the adaptive immune response is well characterized, the effect of the innate immune reaction after transplantation is only recently becoming appreciated. In this study, we address how the innate response affects long-term outcomes in a murine islet allotransplant model. CTLA-4 Ig treatment is known to significantly prolong kidney subcapsular islet allograft survival and enhance glucose tolerance...
September 2, 2016: Islets
https://www.readbyqxmd.com/read/27210268/progress-and-challenges-for-treating-type-1-diabetes
#20
REVIEW
Justin W Garyu, Eric Meffre, Chris Cotsapas, Kevan C Herold
It has been more than 30 years since the initial trials of Cyclosporin A to treat patients with new onset Type 1 diabetes (T1D). Since that time, there have been insights into genetic predisposition to the disease, the failures of immune tolerance, and mechanisms that cause the immune mediated β cell destruction. The genetic loci associated affect lymphocyte development and tolerance mechanisms. Discoveries related to the roles of specific immune responses gene such as the major histocompatibility complex, PTPN22, CTLA-4, IL-2RA, as well as the mechanisms of antigen presentation in the thymus have suggested ways in which autoreactivity may follow changes in the functions of these genes that are associated with risk...
July 2016: Journal of Autoimmunity
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