Auto-Immunity Highlights最新文献

{"title":"A comprehensive analysis of antigen-specific autoimmune liver disease related autoantibodies in patients with multiple sclerosis.","authors":"Zisis Tsouris,&nbsp;Christos Liaskos,&nbsp;Efthymios Dardiotis,&nbsp;Thomas Scheper,&nbsp;Vana Tsimourtou,&nbsp;Wolfgang Meyer,&nbsp;George Hadjigeorgiou,&nbsp;Dimitrios P Bogdanos","doi":"10.1186/s13317-020-00130-4","DOIUrl":"https://doi.org/10.1186/s13317-020-00130-4","url":null,"abstract":"<p><strong>Introduction: </strong>Abnormal liver function tests are frequently seen in patients with multiple sclerosis (MS) and their origin at times is attributed to the possible co-occurrence or the de novo induction of autoimmune liver diseases (AILD), namely autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC), but comprehensive analysis of AILD-related autoantibody has not been carried out.</p><p><strong>Aim: </strong>To assess the presence of AILD-related autoantibodies in a well-defined cohort of MS patients, and to assess their clinical significance.</p><p><strong>Materials and methods: </strong>133 MS (93 female) patients (102 RRMS, 27 SPMS, and 5 PPMS), mean age 42.7 ± 11.9 SD years, mean duration of disease 11.2 ± 7.2 years were studied. 150 age and sex-matched healthy individuals were tested as normal controls (NCs).Autoantibody testing was performed by indirect immunofluorescence (IF) using triple tissue and HEp-2, a multiparametric line immunoassay detecting anti-LKM1(anti-CYP2D6), anti-LC1(anti-FTCD), soluble liver antigen/liver-pancreas(anti-SLA/LP), AMA-M2, and AMA-MIT3 (BPO), PBC-specific ANA (anti-gp210, anti-sp100 and anti-PML), and ELISA for anti-F-actin SMA and anti-dsDNA antibodies.</p><p><strong>Results: </strong>Reactivity to at least one autoantibody was more frequent in MS patients compared to NCs (30/133, 22.6% vs 12/150, 8%) NCs (p = 0.00058). SMAs by IIF were more frequent in MS patients (18/133, 13.53%) compared to NCs (6/150, 4%, p = 0.002%). The AIH-1 related anti-F-actin SMA by ELISA were present in 21 (15.8%), at relatively low titres (all but three of the SMA-VG pattern by IF); anti-dsDNA in 3 (2.3%), and anti-SLA/LP in none; AIH-2 anti-LKM1 autoantibodies in 1 (0.8%, negative by IF), and anti-LC1 in none; PBC-specific AMA-M2 in 2 (1.5%, both negative for AMA-MIT3 and AMA by IF) and PBC-specific ANA anti-PML in 6 (4.5%), anti-sp100 in 1 (0.8%) and anti-gp210 in 1 (0.8%). Amongst the 30 MS patients with at least one autoantibody positivity, only 4 (3%) had overt AILD (2 AIH-1 and 2 PBC). Autoantibody positivity did not differ between naïve MS patients and patients under treatment.</p><p><strong>Conclusions: </strong>Despite the relatively frequent presence of liver autoantibodies, tested either by IF or molecular assays, overt AILD is rather infrequent discouraging autoantibody screening strategies of MS patients in the absence of clinical suspicion.</p>","PeriodicalId":8655,"journal":{"name":"Auto-Immunity Highlights","volume":" ","pages":"7"},"PeriodicalIF":0.0,"publicationDate":"2020-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s13317-020-00130-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37851361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The search for the Holy Grail: autoantigenic targets in primary sclerosing cholangitis associated with disease phenotype and neoplasia.","authors":"Steffi Lopens, Marcin Krawczyk, Maria Papp, Piotr Milkiewicz, Peter Schierack, Yudong Liu, Ewa Wunsch, Karsten Conrad, Dirk Roggenbuck","doi":"10.1186/s13317-020-00129-x","DOIUrl":"10.1186/s13317-020-00129-x","url":null,"abstract":"<p><p>Unlike in other autoimmune liver diseases such as autoimmune hepatitis and primary biliary cholangitis, the role and nature of autoantigenic targets in primary sclerosing cholangitis (PSC), a progressive, chronic, immune-mediated, life threatening, genetically predisposed, cholestatic liver illness, is poorly elucidated. Although anti-neutrophil cytoplasmic antibodies (ANCA) have been associated with the occurrence of PSC, their corresponding targets have not yet been identified entirely. Genome-wide association studies revealed a significant number of immune-related and even disease-modifying susceptibility loci for PSC. However, these loci did not allow discerning a clear autoimmune pattern nor do the therapy options and the male gender preponderance in PSC support a pathogenic role of autoimmune responses. Nevertheless, PSC is characterized by the co-occurrence of inflammatory bowel diseases (IBD) demonstrating autoimmune responses. The identification of novel autoantigenic targets in IBD such as the major zymogen granule membrane glycoprotein 2 (GP2) or the appearance of proteinase 3 (PR3) autoantibodies (autoAbs) have refocused the interest on a putative association of loss of tolerance with the IBD phenotype and consequently with the PSC phenotype. Not surprisingly, the report of an association between GP2 IgA autoAbs and disease severity in patients with PSC gave a new impetus to autoAb research for autoimmune liver diseases. It might usher in a new era of serological research in this field. The mucosal loss of tolerance against the microbiota-sensing GP2 modulating innate and adaptive intestinal immunity and its putative role in the pathogenesis of PSC will be elaborated in this review. Furthermore, other potential PSC-related autoantigenic targets such as the neutrophil PR3 will be discussed. GP2 IgA may represent a group of new pathogenic antibodies, which share characteristics of both type 2 and 3 of antibody-mediated hypersensitive reactions according to Coombs and Gell.</p>","PeriodicalId":8655,"journal":{"name":"Auto-Immunity Highlights","volume":" ","pages":"6"},"PeriodicalIF":0.0,"publicationDate":"2020-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077156/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37743086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-domain 1 β2 glycoprotein antibodies increase expression of tissue factor on monocytes and activate NK Cells and CD8+ cells in vitro.","authors":"Gayane Manukyan,&nbsp;Anush Martirosyan,&nbsp;Ludek Slavik,&nbsp;Sona Margaryan,&nbsp;Jana Ulehlova,&nbsp;Zuzana Mikulkova,&nbsp;Antonin Hlusi,&nbsp;Tomas Papajik,&nbsp;Eva Kriegova","doi":"10.1186/s13317-020-00128-y","DOIUrl":"https://doi.org/10.1186/s13317-020-00128-y","url":null,"abstract":"<p><strong>Background: </strong>β2-Glycoprotein I (β2GPI) represents the major antigenic target for antiphospholipid antibodies (aPL), with domain 1 (D1) being identified as a risk factor for thrombosis and pregnancy complications in APS. We aimed to analyse the ability of aPL, and particularly anti-D1 β2GPI, to stimulate prothrombotic and proinflammatory activity of immune cells in vitro.</p><p><strong>Methods: </strong>Peripheral blood mononuclear cells (PBMCs) from 11 healthy individuals were incubated with: (1) \"anti-D1(+)\"-pooled plasma derived from patients suspected of having APS contained anticardiolipin antibodies (aCL), lupus anticoagulant (LA), anti-β2GPI and anti-D1 β2GPI; (2) \"anti-D1(-)\"-pooled plasma from patients suspected of having APS contained aCL, LA, anti-β2GPI, and negative for anti-D1 β2GPI; (3) \"seronegative\"-negative for aPL.</p><p><strong>Results: </strong>The presence of anti-D1(+) and anti-D1(-) plasma resulted in increased HLA-DR and CD11b on monocytes. While only anti-D1(+) plasma markedly increased the percentage and median fluorescence intensity (MFI) of CD142 (tissue factor, TF) on monocytes in comparison with those cultured with anti-D1(-) and seronegative plasma. Anti-D1(+) plasma resulted in increased percentage and MFI of activation marker CD69 on NK and T cytotoxic cells. Expression of IgG receptor FcγRIII(CD16) on monocytes and NK cells was down-regulated by the anti-D1(+) plasma.</p><p><strong>Conclusions: </strong>Taking together, our study shows the ability of patient-derived aPL to induce immune cell activation and TF expression on monocytes. For the first time, we demonstrated the influence of anti-D1 β2GPI on the activation status of monocytes, NK and cytotoxic T cells. Our findings further support a crucial role of D1 epitope in the promotion of thrombosis and obstetrical complications in APS.</p>","PeriodicalId":8655,"journal":{"name":"Auto-Immunity Highlights","volume":" ","pages":"5"},"PeriodicalIF":0.0,"publicationDate":"2020-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s13317-020-00128-y","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37701745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The perspective on standardisation and harmonisation: the viewpoint of the EASI president.","authors":"Jan Damoiseaux","doi":"10.1186/s13317-020-0127-3","DOIUrl":"10.1186/s13317-020-0127-3","url":null,"abstract":"<p><p>Standardisation of immuno-assays for autoantibodies is a major challenge. Although multiple organisations participate in the generation of internationally accepted standards, adequate standardisation of assays has not yet been achieved. Harmonisation may offer an alternative approach to better align requesting, testing, reporting and interpretation of autoimmune diagnostics. The European Autoimmunity Standardisation Initiative (EASI) was founded to facilitate both standardisation as well as harmonisation of autoantibody tests, but over the years the focus has drifted away from standardisation in favour of harmonisation. In the current paper the options for harmonisation are highlighted.</p>","PeriodicalId":8655,"journal":{"name":"Auto-Immunity Highlights","volume":" ","pages":"4"},"PeriodicalIF":0.0,"publicationDate":"2020-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065346/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37701809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Twenty years of research on the DFS70/LEDGF autoantibody-autoantigen system: many lessons learned but still many questions.","authors":"Greisha L Ortiz-Hernandez,&nbsp;Evelyn S Sanchez-Hernandez,&nbsp;Carlos A Casiano","doi":"10.1186/s13317-020-0126-4","DOIUrl":"https://doi.org/10.1186/s13317-020-0126-4","url":null,"abstract":"<p><p>The discovery and initial characterization 20 years ago of antinuclear autoantibodies (ANAs) presenting a dense fine speckled (DFS) nuclear pattern with strong staining of mitotic chromosomes, detected by indirect immunofluorescence assay in HEp-2 cells (HEp-2 IIFA test), has transformed our view on ANAs. Traditionally, ANAs have been considered as reporters of abnormal immunological events associated with the onset and progression of systemic autoimmune rheumatic diseases (SARD), also called ANA-associated rheumatic diseases (AARD), as well as clinical biomarkers for the differential diagnosis of these diseases. However, based on our current knowledge, it is not apparent that autoantibodies presenting the DFS IIF pattern fall into these categories. These antibodies invariably target a chromatin-associated protein designated as dense fine speckled protein of 70 kD (DFS70), also known as lens epithelium-derived growth factor protein of 75 kD (LEDGF/p75) and PC4 and SFRS1 Interacting protein 1 (PSIP1). This multi-functional protein, hereafter referred to as DFS70/LEDGF, plays important roles in the formation of transcription complexes in active chromatin, transcriptional activation of specific genes, regulation of mRNA splicing, DNA repair, and cellular survival against stress. Due to its multiple functions, it has emerged as a key protein contributing to several human pathologies, including acquired immunodeficiency syndrome (AIDS), leukemia, cancer, ocular diseases, and Rett syndrome. Unlike other ANAs, \"monospecific\" anti-DFS70/LEDGF autoantibodies (only detectable ANA in serum) are not associated with SARD and have been detected in healthy individuals and some patients with non-SARD inflammatory conditions. These observations have led to the hypotheses that these antibodies could be considered as negative biomarkers of SARD and might even play a protective or beneficial role. In spite of 20 years of research on this autoantibody-autoantigen system, its biological and clinical significance still remains enigmatic. Here we review the current state of knowledge of this system, focusing on the lessons learned and posing emerging questions that await further scrutiny as we continue our quest to unravel its significance and potential clinical and therapeutic utility.</p>","PeriodicalId":8655,"journal":{"name":"Auto-Immunity Highlights","volume":" ","pages":"3"},"PeriodicalIF":0.0,"publicationDate":"2020-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s13317-020-0126-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37701742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Associations between HLA and autoimmune neurological diseases with autoantibodies.","authors":"Sergio Muñiz-Castrillo,&nbsp;Alberto Vogrig,&nbsp;Jérôme Honnorat","doi":"10.1186/s13317-019-0124-6","DOIUrl":"https://doi.org/10.1186/s13317-019-0124-6","url":null,"abstract":"<p><p>Recently, several autoimmune neurological diseases have been defined by the presence of autoantibodies against different antigens of the nervous system. These autoantibodies have been demonstrated to be specific and useful biomarkers, and most of them are also pathogenic. These aspects have increased the value of autoantibodies in neurological practice, as they enable to establish more accurate diagnosis and to better understand the underlying mechanisms of the autoimmune neurological diseases when they are compared to those lacking them. Nevertheless, the exact mechanisms leading to the autoimmune response are still obscure. Genetic predisposition is likely to play a role in autoimmunity, HLA being the most reported genetic factor. Herein, we review the current knowledge about associations between HLA and autoimmune neurological diseases with autoantibodies. We report the main alleles and haplotypes, and discuss the clinical and pathogenic implications of these findings.</p>","PeriodicalId":8655,"journal":{"name":"Auto-Immunity Highlights","volume":" ","pages":"2"},"PeriodicalIF":0.0,"publicationDate":"2020-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s13317-019-0124-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37701744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Receptor autoimmunity: diagnostic and therapeutic implications.","authors":"Renato Tozzoli","doi":"10.1186/s13317-019-0125-5","DOIUrl":"10.1186/s13317-019-0125-5","url":null,"abstract":"<p><p>Receptor autoimmunity is one of the ways in which autoimmune diseases appear in humans. Graves' disease, myasthenia gravis, idiopathic membranous nephropathy, and autoimmune acute encephalitis are the major autoimmune diseases belonging to this particular group. Receptor autoimmune disease are dependent on the presence of autoantibodies directed against cell-surface antigens, namely TSH receptor in thyrocytes, acetylcholine receptor in neuromuscular junction, phospholipase 2 receptor in podocytes, and NMDA receptor in cortical neurons. In this article we outline the distinctive features of receptor autoimmunity and the specific relationship between the autoimmunology laboratory and the presence/concentration of autoantibodies. Some immunological features distinguish receptor autoimmunity. Anti-receptor autoantibody pathologies are considered T cell-dependent, B-cell-mediated autoimmune disorders: the knowledge about the presence of circulating and/or localized autoantibodies to target organs and identification of autoantigens involved in the autoimmune reaction is of paramount importance. Due to the close correlation between the concentration of anti-receptor autoantibodies, the autoimmune target of some cell-surface receptors and the intensity of symptoms, the measurement of these immunoglobulins has become central to diagnose autoimmune diseases in all affected patients, not just in clinically dubious cases. The measurement of autoantibodies is also relevant for differential diagnosis of autoimmune and non-autoimmune forms with similar symptoms. From the methodological point of view, quantitative immunoassay methods of measurement should be preferred over semi-quantitative ones, for the capacity of the first class of methods to define precisely the reference ranges and decision levels overcoming the measurement uncertainty of semi-quantitative methods.</p>","PeriodicalId":8655,"journal":{"name":"Auto-Immunity Highlights","volume":" ","pages":"1"},"PeriodicalIF":0.0,"publicationDate":"2020-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065331/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37701653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of <i>CD58</i> polymorphism and multiple sclerosis in Malaysia: a pilot study.","authors":"Yee Ming Ching,&nbsp;Shanthi Viswanathan,&nbsp;Nurhanani Mohamed Nor,&nbsp;Shuwahida Shuib,&nbsp;Balqis Kamarudin,&nbsp;Salawati Mansor,&nbsp;Ainur Yusniza Yusof,&nbsp;Masita Arip","doi":"10.1186/s13317-019-0123-7","DOIUrl":"https://doi.org/10.1186/s13317-019-0123-7","url":null,"abstract":"<p><strong>Background: </strong>Multiple sclerosis is an immune mediated disease targeting the central nervous system. Association of non-human leukocyte antigen gene, <i>CD58</i>, with multiple sclerosis has been reported in several populations but is unclear among Southeast Asians. This pilot study was conducted to explore the association between <i>CD58</i> polymorphism and multiple sclerosis among the Malay population in Malaysia.</p><p><strong>Methods: </strong>Blood samples were collected from 27 multiple sclerosis patients, and compared with 58 age- and gender matched healthy individuals. All patients were tested negative for anti-aquaporin 4. DNA was extracted from the blood and genotyped for 3 single nucleotide polymorphisms rs12044852, rs2300747 and rs1335532 of gene <i>CD58</i> by real-time PCR.</p><p><strong>Results: </strong>The majority of multiple sclerosis patients were female (85.2%). The general mean age of onset was 30.5 years. Genotyping results showed that frequencies of the alleles were between 40 and 50% for MS patients and healthy individuals. Association (allelic model) between multiple sclerosis and <i>CD58</i> gene polymorphism alleles rs12044852 (p = 0.410), rs2300747 (p = 0.881) and rs1335532 (p = 0.407) were indistinct.</p><p><strong>Conclusions: </strong>The impact of the <i>CD58</i> gene polymorphism was not prominent in this pilot study, implying that genetic composition contributing to multiple sclerosis may be different between different populations, thus results in a heterogeneity of disease manifestation and distribution.</p>","PeriodicalId":8655,"journal":{"name":"Auto-Immunity Highlights","volume":"10 1","pages":"13"},"PeriodicalIF":0.0,"publicationDate":"2019-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s13317-019-0123-7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37808577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HERV-K and HERV-W transcriptional activity in myalgic encephalomyelitis/chronic fatigue syndrome.","authors":"Lucas S Rodrigues,&nbsp;Luiz H da Silva Nali,&nbsp;Cibele O D Leal,&nbsp;Ester C Sabino,&nbsp;Eliana M Lacerda,&nbsp;Caroline C Kingdon,&nbsp;Luis Nacul,&nbsp;Camila M Romano","doi":"10.1186/s13317-019-0122-8","DOIUrl":"https://doi.org/10.1186/s13317-019-0122-8","url":null,"abstract":"<p><strong>Background: </strong>Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/MS) is an incapacitating chronic disease that dramatically compromise the life quality. The CFS/ME pathogenesis is multifactorial, and it is believed that immunological, metabolic and environmental factors play a role. It is well documented an increased activity of Human endogenous retroviruses (HERVs) from different families in autoimmune and neurological diseases, making these elements good candidates for biomarkers or even triggers for such diseases.</p><p><strong>Methods: </strong>Here the expression of Endogenous retroviruses K and W (HERV-K and HERV-W) was determined in blood from moderately and severely affected ME/CFS patients through real time PCR.</p><p><strong>Results: </strong>HERV-K was overexpressed only in moderately affected individuals but HERV-W showed no difference.</p><p><strong>Conclusions: </strong>This is the first report about HERV-K differential expression in moderate ME/CFS. Although the relationship between HERVs and ME/CFS has yet to be proven, the observation of this phenomenon deserves further attention.</p>","PeriodicalId":8655,"journal":{"name":"Auto-Immunity Highlights","volume":"10 1","pages":"12"},"PeriodicalIF":0.0,"publicationDate":"2019-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s13317-019-0122-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37808576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical studies on the toxicology, pharmacokinetics and safety of K1-70^TM a human monoclonal autoantibody to the TSH receptor with TSH antagonist activity.","authors":"Jadwiga Furmaniak,&nbsp;Jane Sanders,&nbsp;Jill Clark,&nbsp;Jane Wilmot,&nbsp;Paul Sanders,&nbsp;Yang Li,&nbsp;Bernard Rees Smith","doi":"10.1186/s13317-019-0121-9","DOIUrl":"https://doi.org/10.1186/s13317-019-0121-9","url":null,"abstract":"<p><strong>Background: </strong>The human monoclonal autoantibody K1-70™ binds to the TSH receptor (TSHR) with high affinity and blocks TSHR cyclic AMP stimulation by TSH and thyroid stimulating autoantibodies.</p><p><strong>Methods: </strong>The preclinical toxicology assessment following weekly intravenous (IV) or intramuscular (IM) administration of K1-70™ in rats and cynomolgus monkeys for 29 days was carried out. An assessment of delayed onset toxicity and/or reversibility of toxicity was made during a further 4 week treatment free period. The pharmacokinetic parameters of K1-70™ and the effects of different doses of K1-70™ on serum thyroid hormone levels in the study animals were determined in rats and primates after IV and IM administration.</p><p><strong>Results: </strong>Low serum levels of T3 and T4 associated with markedly elevated levels of TSH were observed in the study animals following IV and IM administration of K1-70™. The toxicological findings were attributed to the pharmacology of K1-70™ and were consistent with the hypothyroid state. The no observable adverse effect level (NOAEL) could not be established in the rat study while in the primate study it was 100 mg/kg/dose for both males and females.</p><p><strong>Conclusions: </strong>The toxicology, pharmacodynamic and pharmacokinetic data in this preclinical study were helpful in designing the first in human study with K1-70™ administered to subjects with Graves' disease.</p>","PeriodicalId":8655,"journal":{"name":"Auto-Immunity Highlights","volume":"10 1","pages":"11"},"PeriodicalIF":0.0,"publicationDate":"2019-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s13317-019-0121-9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37808575","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}