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Search results for: Angiotensin II receptor (AT-1r), Antibody

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#34380734   // To Up

Novel allosteric ligands of the angiotensin receptor AT1R as autoantibody blockers.

While orthosteric ligands of the angiotensin II (AngII) type 1 receptor (AT1R) are available for clinical and research applications, allosteric ligands are not known for this important G protein-coupled receptor (GPCR). Allosteric ligands are useful tools to modulate receptor pharmacology and subtype selectivity. Here, we report AT1R allosteric ligands for a potential application to block autoimmune antibodies. The epitope of autoantibodies for AT1R is outside the orthosteric pocket in the extracellular loop 2. A molecular dynamics simulation study of AT1R structure reveals the presence of a druggable allosteric pocket encompassing the autoantibody epitope. Small molecule binders were then identified for this pocket using structure-based high-throughput virtual screening. The top 18 hits obtained inhibited the binding of antibody to AT1R and modulated agonist-induced calcium response of AT1R. Two compounds out of 18 studied in detail exerted a negative allosteric modulator effect on the functions of the natural agonist AngII. They blocked antibody-enhanced calcium response and reactive oxygen species production in vascular smooth muscle cells as well as AngII-induced constriction of blood vessels, demonstrating their efficacy in vivo. Our study thus demonstrates the feasibility of discovering inhibitors of the disease-causing autoantibodies for GPCRs. Specifically, for AT1R, we anticipate development of more potent allosteric drug candidates for intervention in autoimmune maladies such as preeclampsia, bilateral adrenal hyperplasia, and the rejection of organ transplants.
Khuraijam Dhanachandra Singh, Zaira P Jara, Terri Harford, Prasenjit Prasad Saha, Triveni R Pardhi, Russell Desnoyer, Sadashiva S Karnik

2745 related Products with: Novel allosteric ligands of the angiotensin receptor AT1R as autoantibody blockers.

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#34305943   2021/07/06 To Up

Non-HLA Antibodies and Epitope Mismatches in Kidney Transplant Recipients With Histological Antibody-Mediated Rejection.

Correlation between antibody-mediated rejection (ABMR) and circulating HLA donor-specific antibodies (HLA-DSA) is strong but imperfect in kidney transplant (KT) recipients, raising the possibility of undetected HLA-DSA or non-HLA antibodies contributing to ABMR. Detailed evaluation of the degree of HLA matching together with the identification of non-HLA antibodies in KT may help to decipher the antibody involved.
Marta Crespo, Laura Llinàs-Mallol, Dolores Redondo-Pachón, Carrie Butler, Javier Gimeno, María José Pérez-Sáez, Carla Burballa, Anna Buxeda, Carlos Arias-Cabrales, Montserrat Folgueiras, Sara Sanz-Ureña, Nicole M Valenzuela, Elaine F Reed, Julio Pascual

2091 related Products with: Non-HLA Antibodies and Epitope Mismatches in Kidney Transplant Recipients With Histological Antibody-Mediated Rejection.

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#34186057   2021/06/26 To Up

The emerging field of non-human leukocyte antigen antibodies in transplant medicine and beyond.

The major medical advances in our knowledge of the human leukocyte antigen (HLA) system have allowed us to uncover several gaps in our understanding of alloimmunity. Although the non-HLA system has long sparked the interest of the transplant community, recognition of the role of immunity to non-HLA antigenic targets has only emerged recently. In this review, we will provide a comprehensive summary of the paradigm-changing concept of immunity to the non-HLA angiotensin II type 1 receptor (AT1R), discovered by Duška Dragun et al., that began from careful bedside clinical observations, to validated detection of anti-AT1R antibodies and lead to clinical intervention. This scientific approach has also allowed the recognition of broader pathogenicity of anti-AT1R antibodies across multiple organ transplants and in other human diseases, the integration of both non-HLA and HLA systems to understand their immunologic effects on organ allografts, and the identification of future directions for therapeutic intervention to modulate immunity to AT1R. Rationally designed successful interventions to target AT1R system provide an exemplar for other non-HLA antibodies to cross borders between medical specialties, will generate new avenues in translational research beyond transplantation, and will foster the development of new and reliable tools to improve our understanding of non-HLA immunity and ultimately allow us to improve patient care.
Carmen Lefaucheur, Kevin Louis, Aurélie Philippe, Alexandre Loupy, P Toby Coates

1131 related Products with: The emerging field of non-human leukocyte antigen antibodies in transplant medicine and beyond.

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#34032705   // To Up

Early critical cortical infarction by anti-angiotensin II type 1 receptor antibody: A case report and literature review.

Anti-angiotensin II type 1 receptor antibodies (AT1R-Abs) have been demonstrated to increase the risk of antibody-mediated rejection. We report a case of AT1R-Ab mediated rejection which caused early critical cortical infarction.
Jeong-Hoon Lim, Man-Hoon Han, Yong-Jin Kim, Seung Huh, Chan-Duck Kim

2879 related Products with: Early critical cortical infarction by anti-angiotensin II type 1 receptor antibody: A case report and literature review.

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#33988339   2021/02/22 To Up

Angiotensin II Type 1 Receptor Antibody Mediated Rejection Following Orthotopic Heart Transplant: A Single Center Experience.

Antibody mediated rejection (AMR) following orthotopic heart transplant (OHT) causes significant morbidity and mortality. There is limited data on antibodies to the angiotensin II type 1 receptor (AT1R-Ab) causing rejection following OHT.
Jonathan D Moreno, Amanda M Verma, Benjamin J Kopecky, Carina Dehner, Nicolas Kostelecky, Justin M Vader, Chieh-Yu Lin, Joel D Schilling

2919 related Products with: Angiotensin II Type 1 Receptor Antibody Mediated Rejection Following Orthotopic Heart Transplant: A Single Center Experience.

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#33980688   2021/05/12 To Up

Critical Determinants of Cytokine Storm and Type I Interferon Response in COVID-19 Pathogenesis.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), a rapidly evolving pandemic worldwide with at least 68 million COVID-19-positive cases and a mortality rate of about 2.2%, as of 10 December 2020. About 20% of COVID-19 patients exhibit moderate to severe symptoms. Severe COVID-19 manifests as acute respiratory distress syndrome (ARDS) with elevated plasma proinflammatory cytokines, including interleukin 1β (IL-1β), IL-6, tumor necrosis factor α (TNF-α), C-X-C motif chemokine ligand 10 (CXCL10/IP10), macrophage inflammatory protein 1 alpha (MIP-1α), and chemokine (C-C motif) ligand 2 (CCL2), with low levels of interferon type I (IFN-I) in the early stage and elevated levels of IFN-I during the advanced stage of COVID-19. Most of the severe and critically ill COVID-19 patients have had preexisting comorbidities, including hypertension, diabetes, cardiovascular diseases, and respiratory diseases. These conditions are known to perturb the levels of cytokines, chemokines, and angiotensin-converting enzyme 2 (ACE2), an essential receptor involved in SARS-CoV-2 entry into the host cells. ACE2 downregulation during SARS-CoV-2 infection activates the angiotensin II/angiotensin receptor (AT1R)-mediated hypercytokinemia and hyperinflammatory syndrome. However, several SARS-CoV-2 proteins, including open reading frame 3b (ORF3b), ORF6, ORF7, ORF8, and the nucleocapsid (N) protein, can inhibit IFN type I and II (IFN-I and -II) production. Thus, hyperinflammation, in combination with the lack of IFN responses against SARS-CoV-2 early on during infection, makes the patients succumb rapidly to COVID-19. Therefore, therapeutic approaches involving anti-cytokine/anti-cytokine-signaling and IFN therapy would favor the disease prognosis in COVID-19. This review describes critical host and viral factors underpinning the inflammatory "cytokine storm" induction and IFN antagonism during COVID-19 pathogenesis. Therapeutic approaches to reduce hyperinflammation and their limitations are also discussed.
Santhamani Ramasamy, Selvakumar Subbian

2465 related Products with: Critical Determinants of Cytokine Storm and Type I Interferon Response in COVID-19 Pathogenesis.

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#33928341   // To Up

Autoantibody against angiotensin II type I receptor induces pancreatic β-cell apoptosis via enhancing autophagy.

Autoantibody against the angiotensin II type I receptor (AT1-AA) has been found in the serum of patients with diabetes mellitus (DM). However, it remains unclear whether AT1-AA induces β-cell apoptosis and participates in the development of DM. In this study, an AT1-AA-positive rat model was set up by active immunization, and AT1-AA IgG was purified. INS-1 cells were treated with AT1-AA, and cell viability, apoptosis, and autophagy-related proteins were detected by Cell Counting Kit-8 assay, flow cytometry, and western blot analysis, respectively. Results showed that existence of AT1-AA impaired the islet function and increased the apoptosis of pancreatic islet cells in rats, and the autophagy level in rat pancreatic islet tissues tended to increase gradually with the prolongation of immunization time. AT1-AA markedly reduced INS-1 cell viability, promoted cell apoptosis, and decreased insulin secretion in vitro. In addition, the autophagy level was gradually increased along with the prolongation of AT1-AA treatment time. Meanwhile, it was determined that treatment with autophagy inhibitor 3-methyladenine and angiotensin II type 1 receptor (AT1R) blocker telmisartan could improve insulin secretion and apoptosis in vitro and in vivo. In conclusion, it is deduced that upregulation of autophagy contributed to the AT1-AA-induced β-cell apoptosis and islet dysfunction, and AT1R mediated the signal transduction.
Jin Wang, Dan Li, Zhinan Zhang, Yan Zhang, Zhandong Lei, Wenwen Jin, Jimin Cao, Xiangying Jiao

2130 related Products with: Autoantibody against angiotensin II type I receptor induces pancreatic β-cell apoptosis via enhancing autophagy.

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#33871888   2021/04/25 To Up

Autoantibodies to LG3 are associated with poor long-term survival after liver retransplantation.

Autoantibodies are detrimental to the survival of organ transplantation. We demonstrated that Angiotensin II Type I Receptor agonistic autoantibodies (AT1R-AA) were associated with poor outcomes after liver retransplantation. To examine the effect of other autoantibodies, we studied a retrospective cohort of 93 patients who received a second liver transplant. Pre-retransplant sera were tested with Luminex-based solid-phase assays. Among 33 tested autoantibodies, 15 were significantly higher in 48 patients who lost their regrafts than 45 patients whose regrafts were still functioning. Specifically, patients with autoantibodies to the C-terminal laminin-like globular domain of Perlecan (LG3) experienced significantly worse regraft survival (p = .002) than those with negative LG3 autoantibodies (LG3-A). In multivariate analysis, LG3-A (HR = 2.35 [1.11-4.98], p = .027) and AT1R-AA (HR = 2.09 [1.07-4.10], p = .032) remained significant predictors of regraft loss after adjusting for recipient age and sex. There were synergistic deleterious effects on regraft survival in patients who were double-positive for LG3-A and donor-specific antibody (DSA) (HR = 5.26 [2.15-12.88], p = .001), or LG3-A and AT1R-AA (HR = 3.23 [1.37-7.66], p = .008). All six double-positive patients lost their liver regrafts. In conclusion, LG3-A is associated with inferior long-term outcomes of a second liver transplant. Screening anti-HLA antibodies and autoantibodies such as LG3-A/AT1R-AA identifies patients with a higher risk for liver transplantation.
Qingyong Xu, Vivian C McAlister, Andrew A House, Michele Molinari, Steve Leckie, Adriana Zeevi

2576 related Products with: Autoantibodies to LG3 are associated with poor long-term survival after liver retransplantation.

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#33838295   2021/04/07 To Up

The early impact of preformed angiotensin II type 1 receptor antibodies on graft function in a low immunological risk cohort of kidney transplant recipients.

Intruduction and aim: Angiotensin II type 1 receptor antibodies (AT1R-Ab) are associated with graft rejection and poor graft outcomes in kidney transplantation (KT). We aimed to assess the frequency of preformed AT1R-Ab and their impact on graft function and survival at 1 year after KT in a low immunological risk cohort.
Bogdan Marian Sorohan, Gener Ismail, Andreea Berechet, Bogdan Obrișcă, Ileana Constantinescu, Ion Mărunțelu, Dorina Tacu, Cătălin Baston, Ioanel Sinescu

1423 related Products with: The early impact of preformed angiotensin II type 1 receptor antibodies on graft function in a low immunological risk cohort of kidney transplant recipients.

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