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Preemptive CD20+ B cell Depletion Attenuates Cardiac Allograft Vasculopathy in CD154-Treated Monkeys.

ABSTRACT: Anti-CD154 monotherapy is associated with antidonor allo-antibody (Ab) elaboration, cardiac allograft vasculopathy (CAV), and allograft failure in preclinical primate cell and organ transplant models. In the context of calcineurin inhibitors (CNI), these pathogenic phenomena are delayed by preemptive "induction" B cell depletion.?CD154 (IDEC-131)-treated cynomolgus monkey heart allograft recipients were given peritransplant rituximab (?CD20) alone or with rabbit antihuman thymocyte globulin.Relative to previously reported reference groups, ?CD20 significantly prolonged survival, delayed Ab detection, and attenuated CAV within 3 months in ?CD154-treated recipients (?CD154 + ?CD20 graft median survival time > 90 days, n = 7, vs 28 days for ?CD154 alone (IDEC-131), n = 21; P = 0.05). Addition of rabbit antihuman thymocyte globulin to ?CD154 (n = 6) or ?CD154 + ?CD20 (n = 10) improved graft protection from graft rejection and failure during treatment but was associated with significant morbidity in 8 of 16 recipients (6 infections, 2 drug-related complications). In ?CD20-treated animals, detection of antidonor Ab and relatively severe CAV were anticipated by appearance of CD20 cells (>1% of lymphocytes) in peripheral blood and were associated with low ?CD154 trough levels (below 100 ?g/mL).These observations support the hypothesis that efficient preemptive "induction" CD20 B cell depletion consistently modulates pathogenic alloimmunity and attenuates CAV in this translational model, extending our prior findings with calcineurin inhibitors to the context of CD154 blockade.

SUBMITTER: Azimzadeh AM

PROVIDER: S-EPMC5179283 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Preemptive CD20+ B cell Depletion Attenuates Cardiac Allograft Vasculopathy in CD154-Treated Monkeys.

Azimzadeh Agnes M AM Zhang Tianshu T Wu Guosheng G Kelishadi Shahrooz S SS Stoddard Tiffany T OʼNeill Natalie N Nguyen Bao-Ngoc BN Welty Emily E Avon Christopher C Higuchi Mitch M Mitchell Stuart L SL Hershfeld Alena A Cheng Xiang-Fei XF Kronfli Anthony A Rybak Elana E Burdorf Lars L Pierson Richard N RN

Transplantation 20170101 1

<h4>Background</h4>Anti-CD154 monotherapy is associated with antidonor allo-antibody (Ab) elaboration, cardiac allograft vasculopathy (CAV), and allograft failure in preclinical primate cell and organ transplant models. In the context of calcineurin inhibitors (CNI), these pathogenic phenomena are delayed by preemptive "induction" B cell depletion.<h4>Methods</h4>αCD154 (IDEC-131)-treated cynomolgus monkey heart allograft recipients were given peritransplant rituximab (αCD20) alone or with rabbi ...[more]

PMID: 27362307

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Project description:BackgroundSelective CD28 inhibition is actively pursued as an alternative to B7 blockade using cytotoxic T lymphocyte antigen 4 Ig based on the hypothesis that the checkpoint immune regulators cytotoxic T lymphocyte antigen 4 and programmed death ligand 1 will induce tolerogenic immune signals. We previously showed that blocking CD28 using a monovalent nonactivating reagent (single-chain anti-CD28 Fv fragment linked to alpha-1 antitrypsin [sc28AT]) synergizes with calcineurin inhibitors in nonhuman primate (NHP) kidney and heart transplantation. Here, we explored the efficacy of combining a 3-week "induction" sc28AT treatment with prolonged CD154 blockade.MethodsCynomolgus monkey heterotopic cardiac allograft recipients received sc28AT (10 mg/kg, d0-20, n = 3), hu5C8 (10-30 mg/kg, d0-84, n = 4), or combination (n = 6). Graft survival was monitored by telemetry. Protocol biopsies and graft explants were analyzed for International Society of Heart and Lung Transplantation acute rejection grade and cardiac allograft vasculopathy score. Alloantibody, T-cell phenotype and regulatory T cells were analyzed by flow cytometry. Immunochemistry and gene expression (NanoString) characterized intra-graft cellular infiltration.ResultsRelative to modest prolongation of median graft survival time with sc28AT alone (34 days), hu5C8 (133 days), and sc28AT + hu5C8 (141 days) prolonged survival to a similar extent. CD28 blockade at induction, added to hu5C8, significantly attenuated the severity of acute rejection and cardiac allograft vasculopathy during the first 3 months after transplantation relative to hu5C8 alone. These findings were associated with decreased proportions of circulating CD8 and CD3CD28 T cells, and modulation of inflammatory gene expression within allografts.ConclusionsInduction with sc28AT promotes early cardiac allograft protection in hu5C8-treated NHPs. These results support further investigation of prolonged selective CD28 inhibition with CD40/CD154 blockade in NHP transplants.

Project description:BackgroundThe association between genetic polymorphisms and early cardiac allograft vasculopathy (CAV) development is relatively unexplored. Identification of genes involved in the CAV process may offer new insights into pathophysiology and lead to a wider range of therapeutic options.MethodsThis prospective study of 109 patients investigated 44 single nucleotide polymorphisms (SNPs) within the susceptibility loci potentially related to coronary artery disease, carotid artery intima-media thickness (cIMT), and in nitric oxide synthase gene. Genotyping was done by the Fluidigm SNP Type assays and Fluidigm 48.48 Dynamic Array IFC. The intima thickness progression (IT) was evaluated by coronary optical coherence tomography performed 1 month and 12 months after heart transplantation (HTx).ResultsDuring the first post-HTx year, the mean intima thickness (IT) increased by 24.0 ± 34.2 µm (p < 0.001) and lumen area decreased by ‒0.9 ± 1.8 mm2 (p < 0.001). The rs1570360 (A/G) SNP of the vascular endothelial growth factor A (VEGFA) gene showed the strongest association with intima thickness progression, even in the presence of the traditional CAV risk factors. SNPs previously related to carotid artery intima-media thickness rs11785239 (PRAG1), rs6584389 (PAX2), rs13225723 (LINC02577) and rs17477177 (CCDC71L), were among the five most significantly associated with IT progression but lost their significance once traditional CAV risk factors had been added.ConclusionResults of this study suggest that genetic variability may play an important role in CAV development. The vascular endothelial growth factor A gene SNP rs1570360 showed the strongest association with intima thickness (IT) progression measured by OCT, even in the presence of the traditional CAV risk factors (Tab. 3, Fig. 3, Ref. 36). Text in PDF www.elis.sk Keywords: cardiac allograft vasculopathy, optical coherence tomography, vascular endothelial growth factor A, intimal thickening, genetic polymorphism.

Dataset Information

Preemptive CD20+ B cell Depletion Attenuates Cardiac Allograft Vasculopathy in CD154-Treated Monkeys.

Publications

Preemptive CD20+ B cell Depletion Attenuates Cardiac Allograft Vasculopathy in CD154-Treated Monkeys.

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