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Belatacept

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https://www.readbyqxmd.com/read/29874474/belatacept-ctla4ig-an-update-and-critical-appraisal-of-pre-clinical-and-clinical-results
#1
Christoph Schwarz, Benedikt Mahr, Moritz Muckenhuber, Thomas Wekerle
The B7/CD28/CTLA4 signaling cascade is the most thoroughly studied costimulatory pathway and blockade with CTLA4Ig (abatacept) or its derivative belatacept has emerged as a valuable option for pharmacologic immune modulation. Several clinical studies have ultimately led to the approval of belatacept for immunosuppression in kidney transplant recipients. Areas covered: This review will discuss the immunological background of costimulation blockade and recent preclinical data and clinical results of CTLA4Ig/belatacept...
June 6, 2018: Expert Review of Clinical Immunology
https://www.readbyqxmd.com/read/29848279/toward-small-molecule-inhibition-of-protein-protein-interactions-general-aspects-and-recent-progress-in-targeting-costimulatory-and-coinhibitory-immune-checkpoint-interactions
#2
Damir Bojadzic, Peter Buchwald
Protein-protein interactions (PPIs) that are part of the costimulatory and coinhibitory (immune checkpoint) signaling are critical for adequate T cell response and are important therapeutic targets for immunomodulation. Biologics targeting them have already achieved considerable clinical success in the treatment of autoimmune diseases or transplant recipients (e.g., abatacept, belatacept, and belimumab) as well as cancer (e.g., ipilimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab). In view of such progress, there have been only relatively limited efforts toward developing small-molecule PPI inhibitors (SMPPIIs) targeting these cosignaling interactions, possibly because they, as all other PPIs, are difficult to target by small molecules and were not considered druggable...
May 30, 2018: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/29787522/belatacept-in-solid-organ-transplant-review-of-current-literature-across-transplant-types
#3
Caroline P Perez, Neha Patel, Caitlin R Mardis, Holly B Meadows, David J Taber, Nicole A Pilch
Calcineurin inhibitors (CNIs) have been the backbone immunosuppressant for solid organ transplant recipients for decades. Long-term use of CNIs unfortunately is associated with multiple toxicities, with the biggest concern being CNI-induced nephrotoxicity. Belatacept is a novel agent approved for maintenance immunosuppression in renal transplant recipients. In the kidney transplant literature, it has shown promise as being an alternative agent by preserving renal function and having a minimal adverse effect profile...
May 22, 2018: Transplantation
https://www.readbyqxmd.com/read/29778558/successful-kidney-transplant-with-eculizumab-thymoglobulin-and-belatacept-therapy-in-a-highly-sensitised-patient-with-atypical-haemolytic-uraemic-syndrome-due-to-factor-h-mutation
#4
John Fredy Nieto-Ríos, Mónica Zuluaga-Quintero, Diana Carolina Bello-Márquez, Arbey Aristizabal-Alzate, Catalina Ocampo-Kohn, Lina María Serna-Higuita, Lina Arias, Gustavo Zuluaga-Valencia
Atypical haemolytic uremic syndrome is a disease caused by complement regulation abnormalities that generally progresses to chronic end-stage renal disease with a high rate of recurrence in kidney transplantation and a high risk of graft loss. Anti-complement therapy has improved the prognosis of these patients, achieving disease remission in most cases, increasing the likelihood of a successful kidney transplant and increasing patient and graft survival. Drugs with low risk of induction of thrombotic microangiopathies such as belatacept and mycophenolate have also been used with satisfactory results...
May 16, 2018: Nefrología: Publicación Oficial de la Sociedad Española Nefrologia
https://www.readbyqxmd.com/read/29767445/comparison-of-de-novo-igm-and-igg-anti-hla-dsa-between-belatacept-and-calcineurin-treated-patients-an-analysis-of-the-benefit-and-benefit-ext-trial-cohorts
#5
Matthew J Everly, Mustimbo Roberts, Robert Townsend, Robert A Bray, Howard M Gebel
Preventing conversion of donor-specific anti-HLA antibodies (DSA) from an IgM-to-IgG could a way to prevent chronic rejection. We evaluated whether belatacept-treated patients [belatacept less-intensive (LI) more-intensive (MI) regimens] have a lower rate of conversion than cyclosporine A (CsA) treated patients. We included 330 HLA mismatched patients from two phase-3 trials with either (a) complete donor/recipient HLA-A,-B,-DR, and -DQ loci typing or (b) incomplete HLA typing with IgG DSA detected pre- or post-transplant...
May 16, 2018: American Journal of Transplantation
https://www.readbyqxmd.com/read/29723921/de-novo-belatacept-in-clinical-vascularized-composite-allotransplantation
#6
Linda C Cendales, David S Ruch, Adela R Cardones, Guy Potter, Joshua Dooley J, Daniel Dore, Jonah Orr, Gregory Ruskin, Minqing Song, Dong-Feng Chen, Maria A Selim, Allan D Kirk
Most immunosuppressive regimens used in clinical vascularized composite allotransplantation (VCA) have been calcineurin inhibitor (CNI)-based. As such, most recipients have experienced CNI-related side effects. Costimulation blockade, specifically CD28/B7 inhibition with belatacept, has emerged as a clinical replacement for CNI-based immunosuppression in kidney transplantation. We have previously shown that belatacept can be used as a centerpiece immunosuppressant for VCA in non-human primates, and subsequently reported successful conversion from a CNI-based regimen to a belatacept-based regimen after clinical hand transplantation...
May 3, 2018: American Journal of Transplantation
https://www.readbyqxmd.com/read/29719109/belatacept-during-pregnancy-in-renal-transplant-recipients-two-case-reports
#7
Jenna Combs, Anna Kagan, Mark Boelkins, Lisa Coscia, Michael Moritz, R Michael Hofmann
Impaired fertility is common among patients with chronic organ failure, including end stage renal disease (ESRD). Women of child-bearing age undergoing transplantation may experience rapid return of fertility. Pregnancy post-transplant presents numerous risks for the patient, fetus, and allograft. Maternal risks include hypertension and preeclampsia. Allograft risks include acute rejection and failure of the organ, and fetal risks include miscarriage, birth defects from immunosuppressants, premature delivery, and low birth weight...
May 2, 2018: American Journal of Transplantation
https://www.readbyqxmd.com/read/29707621/improved-glucose-tolerance-in-a-kidney-transplant-recipient-with-type-2-diabetes-mellitus-after-switching-from-tacrolimus-to-belatacept-a-case-report-and-review-of-potential-mechanisms
#8
Gretchen N de Graav, Marieke van der Zwan, Carla C Baan, Joop A M J L Janssen, Dennis A Hesselink
The introduction of immunosuppressant belatacept, an inhibitor of the CD28-80/86 pathway, has improved 1-year outcomes in kidney transplant recipients with preexistent diabetes mellitus and has also reduced the risk of posttransplant diabetes mellitus. So far, no studies have compared a tacrolimus-based with a belatacept-based immunosuppressive regimen with regard to improving glucose tolerance after kidney transplantation. Here, we present the case of a 54-year-old man with type 2 diabetes mellitus who was converted from belatacept to tacrolimus 1 year after a successful kidney transplantation...
March 2018: Transplantation Direct
https://www.readbyqxmd.com/read/29672443/belatacept-and-auto-immune-adverse-events
#9
Simon Ville, Diego Cantarovich
No abstract text is available yet for this article.
April 18, 2018: Transplantation
https://www.readbyqxmd.com/read/29594146/early-conversion-from-tacrolimus-to-belatacept-in-a-highly-sensitized-renal-allograft-recipient-with-calcineurin-inhibitor-induced-de-novo-post-transplant-hemolytic-uremic-syndrome
#10
Vasishta S Tatapudi, Bonnie E Lonze, Ming Wu, Robert A Montgomery
Background: Kidney transplantation is the first-line therapy for patients with end-stage renal disease since it offers greater long-term survival and improved quality of life when compared to dialysis. The advent of calcineurin inhibitor (CNI)-based maintenance immunosuppression has led to a clinically significant decline in the rate of acute rejection and better short-term graft survival rates. However, these gains have not translated into improvement in long-term graft survival. CNI-related nephrotoxicity and metabolic side effects are thought to be partly responsible for this...
January 2018: Case Reports in Nephrology and Dialysis
https://www.readbyqxmd.com/read/29573335/posttransplant-reduction-in-preexisting-donor-specific-antibody-levels-after-belatacept-versus-cyclosporine-based-immunosuppression-post-hoc-analyses-of-benefit-and-benefit-ext
#11
R A Bray, H M Gebel, R Townsend, M E Roberts, M Polinsky, L Yang, H-U Meier-Kriesche, C P Larsen
BENEFIT and BENEFIT-EXT were phase III studies of cytotoxic T-cell crossmatch-negative kidney transplant recipients randomized to belatacept more intense (MI)-based, belatacept less intense (LI)-based, or cyclosporine-based immunosuppression. Following study completion, presence/absence of HLA-specific antibodies was determined centrally via solid-phase flow cytometry screening. Stored sera from anti-HLA-positive patients were further tested with a single-antigen bead assay to determine antibody specificities, presence/absence of donor-specific antibodies (DSAs), and mean fluorescent intensity (MFI) of any DSAs present...
March 24, 2018: American Journal of Transplantation
https://www.readbyqxmd.com/read/29570163/conversion-to-belatacept-in-maintenance-kidney-transplant-patients-a-retrospective-multicenter-european-study
#12
Amandine Darres, Camillo Ulloa, Susanne Brakemeier, Cyril Garrouste, Oriol Bestard, Arnaud Del Bello, Rebecca Sberro Soussan, Michael Dürr, Klemens Budde, Christophe Legendre, Nassim Kamar
BACKGROUND: The use of belatacept is not yet approved for maintenance kidney-transplant patients. This retrospective multicenter European study aimed to assess the efficacy and safety of conversion to belatacept in a large cohort of patients in a real-life setting, and to identify the predictive factors for improved kidney function after the switch. METHODS: Two-hundred and nineteen maintenance kidney-transplant patients from 5 European kidney-transplant centers were converted to belatacept at 21...
March 22, 2018: Transplantation
https://www.readbyqxmd.com/read/29569634/response-commentary-belatacept-does-not-inhibit-follicular-t-cell-dependent-b-cell-differentiation-in-kidney-transplantation
#13
COMMENT
Carla C Baan, Gretchen N de Graav, Willem Weimar, Dennis A Hesselink
No abstract text is available yet for this article.
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29509571/fulminant-acute-respiratory-distress-syndrome-after-calcineurin-inhibitor-belatacept-conversion-in-a-lung-transplant-recipient
#14
Olivier Brugière, Aurelie Cazes, Laure Champion, MArie-Pierre Debray, Gisèle Mourin, Bruno Crestani, Deborah Sroussi, Vincent Bunel, Gilles Jebrak, Gaëlle Dauriat, Yves Castier, Pierre Mordant, Brice Lortat-Jacob, Sylvain Jean-Baptiste, Lila Bouadma, Hervé Mal, Gabriel Thabut
No abstract text is available yet for this article.
March 5, 2018: Transplantation
https://www.readbyqxmd.com/read/29509295/de-novo-donor-specific-antibodies-in-belatacept-treated-vs-cyclosporine-treated-kidney-transplant-recipients-post-hoc-analyses-of-the-randomized-phase-iii-benefit-and-benefit-ext-studies
#15
R A Bray, H M Gebel, R Townsend, M E Roberts, M Polinsky, L Yang, H-U Meier-Kriesche, C P Larsen
Donor-specific antibodies (DSAs) are associated with an increased risk of antibody-mediated rejection and graft failure. In BENEFIT and BENEFIT-EXT, kidney-transplant recipients were randomized to receive belatacept more intense (MI)-based, belatacept less intense (LI)-based, or cyclosporine-based immunosuppression for up to 7 years (84 months). The presence/absence of HLA-specific antibodies was determined at baseline, at months 6, 12, 24, 36, 48, 60, and 84, and at the time of clinically suspected episodes of acute rejection, using solid-phase flow-cytometry screening...
March 6, 2018: American Journal of Transplantation
https://www.readbyqxmd.com/read/29461660/outcomes-at-7-years-post-transplant-in-black-vs-nonblack-kidney-transplant-recipients-administered-belatacept-or-cyclosporine-in-benefit-and-benefit-ext
#16
Sander Florman, Flavio Vincenti, Antoine Durrbach, Marwan Abouljoud, Barbara Bresnahan, Valter Duro Garcia, Laura Mulloy, Kim Rice, Lionel Rostaing, Carlos Zayas, Kellie Calderon, Ulf Meier-Kriesche, Martin Polinsky, Lingfeng Yang, Jose Medina Pestana, Christian P Larsen
Clinical outcomes are generally worse for black vs nonblack renal allograft recipients. In BENEFIT and BENEFIT-EXT, recipients were randomized to belatacept more intense-based, belatacept less intense-based, or cyclosporine-based immunosuppression. At year 7, belatacept was associated with superior graft survival vs cyclosporine in BENEFIT (recipients of living or standard criteria deceased donor kidneys); belatacept was associated with similar graft survival vs cyclosporine in BENEFIT-EXT (recipients of extended criteria donor kidneys)...
April 2018: Clinical Transplantation
https://www.readbyqxmd.com/read/29358873/stricturing-crohn-s-disease-like-colitis-in-a-patient-treated-with-belatacept
#17
Anne Bozon, Guillaume Jeantet, Benjamin Rivière, Natalie Funakoshi, Gaspard Dufour, Roman Combes, Jean-Christophe Valats, Sylvie Delmas, Jean Emmanuel Serre, Michael Bismuth, Jeanne Ramos, Moglie Le Quintrec, Pierre Blanc, Guillaume Pineton de Chambrun
Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) modifying agents have been involved in the development of intestinal inflammation, especially therapeutic monoclonal antibodies directed against CTLA-4. Here we report the appearance of a severe stricturing Crohn's disease-like colitis in a patient with a kidney allograft who was treated with belatacept, a recombinant CTLA-4-Ig fusion protein.
December 28, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/29321374/selective-cd28-blockade-attenuates-ctla-4-dependent-cd8-memory-t-cell-effector-function-and-prolongs-graft-survival
#18
Danya Liu, I Raul Badell, Mandy L Ford
Memory T cells pose a significant problem to successful therapeutic control of unwanted immune responses during autoimmunity and transplantation, as they are differentially controlled by cosignaling receptors such as CD28 and CTLA-4. Treatment with abatacept and belatacept impede CD28 signaling by binding to CD80 and CD86, but they also have the unintended consequence of blocking the ligands for CTLA-4, a process that may inadvertently boost effector responses. Here, we show that a potentially novel anti-CD28 domain antibody (dAb) that selectively blocks CD28 but preserves CTLA-4 coinhibition confers improved allograft survival in sensitized recipients as compared with CTLA-4 Ig...
January 11, 2018: JCI Insight
https://www.readbyqxmd.com/read/29321143/control-of-humoral-response-in-renal-transplantation-by-belatacept-depends-on-a-direct-effect-on-b-cells-and-impaired-t-follicular-helper-b-cell-crosstalk
#19
Claire Leibler, Allan Thiolat, Carole Hénique, Chloé Samson, Caroline Pilon, Marie Tamagne, France Pirenne, Benoit Vingert, José L Cohen, Philippe Grimbert
Generation of de novo donor-specific antibodies ( dn DSAs) after renal transplant is recognized as the leading cause of late transplant failure. Hence, the optimal immunosuppressive strategies to limit dn DSA development need to be defined. Recent clinical trials using the novel costimulatory blockade agent CTLA4-Ig (Belatacept) have shown that kidney transplant recipients (KTRs) treated with Belatacept have better graft survival and function and a lower proportion of dn DSAs than control-treated KTRs. Mechanisms involved in the control of humoral responses by Belatacept remain to be investigated...
March 2018: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/29309803/effect-of-cyclosporine-tacrolimus-and-sirolimus-on-cellular-senescence-in-renal-epithelial-cells
#20
Christian Koppelstaetter, Georg Kern, Gisela Leierer, Sabine Maria Mair, Gert Mayer, Johannes Leierer
INTRODUCTION: In transplantation medicine calcineurin inhibitors (CNI) still represent the backbone of immunosuppressive therapy. The nephrotoxic potential of the CNI Cyclosporine A (CsA) and Tacrolimus (FK506) is well recognized and CNI not only have been linked with toxicity, but also with cellular senescence which hinders parenchymal tissue regeneration and thus may prime kidneys for subsequent insults. To minimize pathological effects on kidney grafts, alternative immunosuppressive agents like mTOR inhibitors or the T-cell co-stimulation blocker Belatacept have been introduced...
April 2018: Toxicology in Vitro: An International Journal Published in Association with BIBRA
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