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Belatacept

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https://www.readbyqxmd.com/read/28544101/belatacept-combined-with-transient-calcineurin-inhibitor-therapy-prevents-rejection-and-promotes-improved-long-term-renal-allograft-function
#1
A B Adams, J Goldstein, C Garrett, R Zhang, R E Patzer, K A Newell, N A Turgeon, A S Chami, A Guasch, A D Kirk, S O Pastan, T C Pearson, C P Larsen
Belatacept, a T cell costimulation-blocker demonstrated superior renal function, lower cardiovascular risk, and improved graft/patient survival in renal transplant recipients. Despite the potential benefits, adoption of belatacept has been limited in part due to concerns regarding higher rates and grades of acute rejection in clinical trials. Since July 2011 we have utilized belatacept-based immunosuppression regimens in clinical practice. In this retrospective analysis of 745 patients undergoing renal transplantation at our center, we compared patients treated with belatacept (n=535) to a historical cohort receiving a tacrolimus-based protocol (n=205)...
May 23, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/28540602/late-conversion-from-tacrolimus-to-a-belatacept-based-immuno-suppression-regime-in-kidney-transplant-recipients-improves-renal-function-acid-base-derangement-and-mineral-bone-metabolism
#2
Kevin Schulte, Clara Vollmer, Vera Klasen, Jan Hinrich Bräsen, Jodok Püchel, Christoph Borzikowsky, Ulrich Kunzendorf, Thorsten Feldkamp
BACKGROUND: Calcineurin inhibitor (CNI)-induced nephrotoxicity and chronic graft dysfunction with deteriorating glomerular filtration rate (GFR) are common problems of kidney transplant recipients. The aim of this study was to analyze the role of belatacept as a rescue therapy in these patients. METHODS: In this retrospective, observational study we investigated 20 patients (10 females, 10 males) who were switched from a CNI (tacrolimus) to a belatacept-based immunosuppression because of CNI intolerance or marginal transplant function...
May 24, 2017: Journal of Nephrology
https://www.readbyqxmd.com/read/28540252/belatacept-the-challenges-with-transformational-drugs
#3
COMMENT
Flavio Vincenti
No abstract text is available yet for this article.
April 2017: Translational Andrology and Urology
https://www.readbyqxmd.com/read/28525959/challenges-and-opportunities-in-targeting-the-cd28-ctla-4-pathway-in-transplantation-and-autoimmunity
#4
Rebecca L Crepeau, Mandy L Ford
Introduction T cell activation is a complex process that requires multiple cell signaling pathways, including a primary recognition signal and additional costimulatory signals. One of the best-characterized costimulatory pathways includes the Ig superfamily members CD28 and CTLA-4 and their ligands CD80 and CD86. Areas Covered This review discusses past, current and future biological therapies that have been utilized to block the CD28/CTLA-4 cosignaling pathway in the settings of autoimmunity and transplantation, as well the challenges facing successful implementation of these therapies...
May 19, 2017: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/28502128/belatacept-resistant-rejection-is-associated-with-cd28-memory-cd8-t-cells
#5
D V Mathews, W C Wakwe, S C Kim, M C Lowe, C Breeden, M E Roberts, A B Farris, E A Strobert, J B Jenkins, C P Larsen, M L Ford, R Townsend, A B Adams
Recently newer therapies have been designed to more specifically target rejection in an effort to improve efficacy and limit unwanted toxicity. Belatacept, a CD28-CD80/86 specific reagent is associated with superior patient survival and graft function than traditional therapy but its adoption as a mainstay immunosuppressive therapy has been tempered by increased rejection rates. It is essential that the underlying mechanisms associated with this rejection be elucidated before belatacept is more widely employed...
May 14, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/28502091/increased-pre-transplant-frequency-of-cd28-cd4-tem-predicts-belatacept-resistant-rejection-in-human-renal-transplant-recipients
#6
Miriam Cortes-Cerisuelo, Sonia J Laurie, David V Mathews, Pamela D Winterberg, Christian P Larsen, Andrew B Adams, Mandy L Ford
While most human T cells express the CD28 costimulatory molecule constitutively, it is well-known that age, inflammation, and viral infection can drive the generation of CD28(null) T cells. In vitro studies have demonstrated that CD28(null) cell effector function is not impacted by the presence of the CD28 costimulation blocker belatacept. As such, a prevailing hypothesis suggests that CD28(null) cells may precipitate costimulation blockade-resistant rejection. However, CD28(+) cells possess more proliferative and multi-functional capacity, factors that may increase their ability to successfully mediate rejection...
May 14, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/28489305/prolonged-survival-following-pig-to-primate-liver-xenotransplantation-utilizing-exogenous-coagulation-factors-and-co-stimulation-blockade
#7
J A Shah, M S Patel, N Elias, N Navarro-Alvarez, I Rosales, R A Wilkinson, N J Louras, M Hertl, J A Fishman, R B Colvin, A B Cosimi, J F Markmann, D H Sachs, P A Vagefi
Since the first attempt in 1968, survival following pig-to-primate liver xenotransplantation (LXT) has been limited. We evaluated a model utilizing α-1,3-galactosyltransferase knockout donors, continuous post-transplant infusion of human prothrombin concentrate complex and immunosuppression including anti-thymocyte globulin, FK-506, methylprednisone and co-stimulation blockade (belatacept, n=3 or anti-CD40mAb, n=1) to extend survival. Baboon #1 remained well until POD25 when euthanasia was required due to cholestasis and plantar ulcers...
May 10, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/28469082/ctla4-ig-in-combination-with-fty720-promotes-allograft-survival-in-sensitized-recipients
#8
Stella H Khiew, Jinghui Yang, James S Young, Jianjun Chen, Qiang Wang, Dengping Yin, Vinh Vu, Michelle L Miller, Roger Sciammas, Maria-Luisa Alegre, Anita S Chong
Despite recent evidence of improved graft outcomes and safety, the high incidence of early acute cellular rejection with belatacept, a high-affinity CTLA4-Ig, has limited its use in clinical transplantation. Here we define how the incomplete control of endogenous donor-reactive memory T cells results in belatacept-resistant rejection in an experimental model of BALB/c.2W-OVA donor heart transplantation into C57BL/6 recipients presensitized to donor splenocytes. These sensitized mice harbored modestly elevated numbers of endogenous donor-specific memory T cells and alloantibodies compared with naive recipients...
May 4, 2017: JCI Insight
https://www.readbyqxmd.com/read/28460546/an-update-on-chemical-pharmacotherapy-options-for-the-prevention-of-kidney-transplant-rejection-with-a-focus-on-costimulation-blockade
#9
Florian Kälble, Matthias Schaier, Sebastian Schäfer, Caner Süsal, Martin Zeier, Claudia Sommerer, Christian Morath
The introduction of calcineurin inhibitors (CNI) has greatly improved graft survival in the past three decades. However, long-term graft survival is still limited due to chronic allograft injury and side-effects of immunosuppressive medication. Areas covered: The present overview gives an update on pharmacotherapeutic strategies after kidney transplantation. The main focus is on CNI-sparing regimens using co-stimulatory blockade and on new substances on the horizone. Expert opinion: CNI sparing regimens are well-established...
June 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/28452165/cutaneous-toxicities-from-transplant-related-medications
#10
M Ilyas, O R Colegio, B Kaplan, A Sharma
Despite the abundance of information on cutaneous malignancies associated with solid organ transplantation in the transplant literature, there is limited information regarding non-malignant skin changes after transplantation. There are numerous skin toxicities secondary to immunosuppressive and other transplant-related medications that can vary in presentation, severity, and prognosis. In order to limit associated morbidity and mortality, SOTR care providers should effectively identify and manage cutaneous manifestations secondary to drug toxicity...
April 27, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/28444889/invasive-fungal-infections-in-paediatric-patients-treated-with-macromolecular-immunomodulators-other-than-tumour-necrosis-alpha-inhibitors
#11
REVIEW
Ioannis Kyriakidis, Athanasios Tragiannidis, Ilse Zündorf, Andreas H Groll
An expanding list of immunomodulatory or immunosuppressive monoclonal antibodies (mAbs) and biologic therapeutics is currently entering clinical practice, particularly in the areas of oncology, transplantation and autoimmune disorders. These agents are directed against molecules or cells involved in inflammation and immunity and may therefore be associated with serious and opportunistic infections. The purpose of this review was to critically analyse the literature on invasive fungal infections (IFIs) occurring in association with mAbs and fusion proteins other than tumour necrosis alpha (TNF-α) inhibitors, including therapeutics modulating T-cell-mediated pathologies (muromonab, abatacept, belatacept, ipilimumab, basiliximab, daclizumab), inducing lymphopenia (alemtuzumab), depleting CD20+ B cells (rituximab) and interfering with various targets (anakinra, natalizumab, blodalumab, ixekizumab and others) with a focus on children, and to provide a framework of evaluating the risk for IFIs in this population...
April 26, 2017: Mycoses
https://www.readbyqxmd.com/read/28434523/belatacept-where-the-benefits-outweigh-the-risk
#12
EDITORIAL
Hallvard Holdaas, Geir Mjøen, Alan G Jardine
No abstract text is available yet for this article.
May 2017: American Journal of Kidney Diseases: the Official Journal of the National Kidney Foundation
https://www.readbyqxmd.com/read/28403127/a-randomized-controlled-clinical-trial-comparing-belatacept-with-tacrolimus-after-de-novo-kidney-transplantation
#13
Gretchen de Graav, Carla C Baan, Marian C Clahsen-van Groningen, Rens Kraaijeveld, Marjolein Dieterich, Wenda Verschoor, Jan H von der Thusen, Dave L Roelen, Monique Cadogan, Jacqueline van de Wetering, Joost van Rosmalen, Wilem Weimar, Dennis A Hesselink
BACKGROUND: Belatacept, an inhibitor of the CD28-CD80/86 co-stimulatory pathway, allows for calcineurin-inhibitor free immunosuppressive therapy in kidney transplantation but is associated with a higher acute rejection risk than ciclosporin. Thus, no biomarker for belatacept-resistant rejection has been validated. In this randomized controlled trial, acute rejection-rate was compared between belatacept- and tacrolimus-treated patients and immunological biomarkers for acute rejection were investigated...
April 11, 2017: Transplantation
https://www.readbyqxmd.com/read/28401625/fatal-case-of-cutaneous-sparing-oro-laryngeal-zoster-in-a-renal-transplant-recipient
#14
Elie Helou, Matthew Grant, Marie Landry, Xinyu Wu, Jon S Morrow, Maricar F Malinis
Herpesvirus infections in solid organ transplant (SOT) recipients are a significant cause of morbidity and mortality. We report a case of herpes zoster (HZ) in a kidney transplant recipient while receiving belatacept, a CTLA-4 inhibitor that prevents acute rejection. The patient presented with oropharyngolaryngeal mucosal lesions that subsequently disseminated resulting in pneumonitis and meningo-encephalitis. Very late-onset HZ can occur and can present atypically in SOT recipients. Delayed recognition and treatment may result in poor outcomes, as illustrated by this case...
April 12, 2017: Transplant Infectious Disease: An Official Journal of the Transplantation Society
https://www.readbyqxmd.com/read/28376033/causes-and-consequences-of-the-worldwide-belatacept-shortage
#15
Steven Gabardi, Teun van Gelder
No abstract text is available yet for this article.
April 4, 2017: Transplantation
https://www.readbyqxmd.com/read/28363404/acute-antibody-mediated-rejection-following-sleeve-gastrectomy-in-a-kidney-transplant-recipient-treated-with-a-belatacept-mycophenolate-mofetil-based-therapy
#16
Jamale Rizkallah, Nassim Kamar, Arnaud Del Bello
No abstract text is available yet for this article.
February 24, 2017: Surgery for Obesity and related Diseases: Official Journal of the American Society for Bariatric Surgery
https://www.readbyqxmd.com/read/28316600/methylation-of-foxp3-tsdr-underlies-the-impaired-suppressive-function-of-tregs-from-long-term-belatacept-treated-kidney-transplant-patients
#17
Evelyn Katy Alvarez Salazar, Arimelek Cortés-Hernández, Germán Rodrigo Alemán-Muench, Josefina Alberú, Jesús R Rodríguez-Aguilera, Félix Recillas-Targa, Victoria Chagoya de Sánchez, Eric Cuevas, Eduardo Mancilla-Urrea, María Pérez García, Guillermo Mondragón-Ramírez, Mario Vilatobá, Ian Bostock, Erick Hernández-Méndez, David De Rungs, Eduardo A García-Zepeda, Gloria Soldevila
Regulatory T cells (Tregs) are considered key players in the prevention of allograft rejection in transplanted patients. Belatacept (BLT) is an effective alternative to calcineurin inhibitors that appears to preserve graft survival and function; however, the impact of this drug in the homeostasis of Tregs in transplanted patients remains controversial. Here, we analyzed the phenotype, function, and the epigenetic status of the Treg-specific demethylated region (TSDR) in FOXP3 of circulating Tregs from long-term kidney transplant patients under BLT or Cyclosporine A treatment...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28289708/interruption-of-ox40l-signaling-prevents-costimulation-blockade-resistant-allograft-rejection
#18
William H Kitchens, Ying Dong, David V Mathews, Cynthia P Breeden, Elizabeth Strobert, Maria E Fuentes, Christian P Larsen, Mandy L Ford, Andrew B Adams
The potential of costimulation blockade to serve as a novel transplant immunosuppression strategy has been explored for over 20 years, culminating in the recent clinical approval of belatacept for renal transplant patients. Despite improving long-term graft function and survival compared with calcineurin inhibitors, clinical acceptance of belatacept has been hindered by elevated rates of acute rejection. We examined the signaling pathways required to activate costimulation blockade-resistant alloreactive T cells and identified the OX40/OX40L secondary costimulatory pathway as a promising target...
March 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28267882/early-conversion-to-belatacept-after-renal-transplantation
#19
Vinay Nair, Luz Liriano-Ward, Rebecca Kent, Shirish Huprikar, Mena Rana, Sander S Florman, Veronica B Delaney, Madhav C Menon, Vinita Sehgal, Leandra Miko, Rafael Khaim, Alan Benvenisty, Susan Lerner, Antonios Arvelakis, Vikram Wadhera, Scott Ames, Ron Shapiro
Belatacept is a non-nephrotoxic immunosuppressive agent, which may make it the ideal agent for patients with delayed or slow graft function on calcineurin inhibitors. There are limited data on conversion of patients to belatacept within 6 months of transplantation. Between January 2012 and December 2015, 16 patients were converted to belatacept for delayed or poor graft function (eGFR<30 mL/min/1.73 m(2) , MDRD); three were HIV positive. Conversion protocols were analyzed in patients ≤4 months and 4-6 months post-transplantation...
March 7, 2017: Clinical Transplantation
https://www.readbyqxmd.com/read/28166398/belatacept-after-kidney-transplantation-in-adolescents-a-retrospective-study
#20
Christian Lerch, Nele K Kanzelmeyer, Thurid Ahlenstiel-Grunow, Kerstin Froede, Martin Kreuzer, Jens Drube, Murielle Verboom, Lars Pape
Regardless of recipient age at kidney transplantation (KTx), patients are at greatest risk for graft loss in adolescence, partly due to nonadherence to an oral immunosuppressive regimen. Belatacept, a non-nephrotoxic, first-in-class immunosuppressant that inhibits costimulation of T cells requires intravenous application only every 4 weeks, potentially leading to better adherence. However, it is only approved for use in adults. We report here the findings of the first study of belatacept in adolescents, comprising all patients in our department switched to belatacept post-KTx...
May 2017: Transplant International: Official Journal of the European Society for Organ Transplantation
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