Pancreas transplantation, antibodies and rejection

Donor-specific antibodies (DSAs) have a deleterious effect on allografts and remain a major immunologic barrier in transplantation. Current therapies to eliminate DSAs are ineffective in highly HLA-sensitized patients. Proteasome inhibitors have been employed as a strategy to target bone marrow plasma cells (BMPCs), the source of long-term antibody production; however, their efficacy has been limited by poorly defined drug-resistance mechanisms. Here, we performed transcriptomic profiling of CD138 + BMPCs that survived in vivo desensitization therapy with the proteasome inhibitor carfilzomib to identify mechanisms of drug resistance. The results revealed a genomic signature that included increased expression of the immunoproteasome, a highly specialized proteasomal variant. Western blotting and functional studies demonstrated that catalytically active immunoproteasomes and the immunoproteasome activator PA28 were upregulated in carfilzomib-resistant BMPCs.Carfilzomib-resistant BMPCs displayed reduced sensitivity to the proteasome inhibitors carfilzomib, bortezomib, and ixazomib, but enhanced sensitivity to an immunoproteasome-specific inhibitor ONX-0914. Finally, in vitro carfilzomib treatment of BMPCs from HLA-sensitized patients increased levels of the immunoproteasome β5i (PSMB8) catalytic subunit suggesting that carfilzomib therapy directly induces an adaptive immunoproteasome response. Taken together, our results indicate that carfilzomib induces structural changes in proteasomes and immunoproteasome formation. K E Y W O R D Sbasic (laboratory)

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Proteasomal adaptations underlying carfilzomib-resistance in human bone marrow plasma cells

Woodle

Tremblay

Brailey³

et al. 2020

“…The reasons for this are not clear but may be important with respect to the known inferior long‐term outcomes of IP compared to SPK transplants . The hypotheses proposed to explain these include: (i) the greater immunocompetence of IP recipients in the absence of uremia ; (ii) an immunological effect of transplanting both organs simultaneously and (iii) the advantages of using the kidney in an SPK recipient as an early surrogate indicator of rejection . Although kidney rejection is not a robust indicator of pancreas rejection , the lack of a kidney graft in the IP group may result in the under‐treatment of some subclinical rejection episodes, contributing to poorer longer‐term outcomes.…”

Section: Discussionmentioning

confidence: 99%

De Novo Donor-Specific HLA Antibodies: Biomarkers of Pancreas Transplant Failure

Mittal

Page

Friend

et al. 2014

This study assesses the role of posttransplant HLA antibody monitoring in the surveillance of pancreas transplant recipients. Four hundred thirty‐three pancreas transplants were performed at the Oxford Transplant Centre 2006–2011 (317 simultaneous pancreas kidney [SPK] and 116 isolated pancreas [IP]). HLA antibody monitoring was performed at 0, 6 and 12 months and annually and during clinical events. There was no association between pancreas graft failure and recipient or donor characteristics. Posttransplant antibody status, available for 354 (81.8%) of recipients, demonstrated that 141 (39.8%) developed de novo HLA antibodies, of which 52 (36.9%) were de novo donor‐specific HLA antibodies (DSA) (34 SPK, 18 IP). The development of antibodies to donor HLA, but not to nondonor HLA, was significantly associated with poorer graft outcomes, with 1‐ and 3‐year graft survival inferior in SPK recipients (85.2% vs. 93.5%; 71.8% vs. 90.3%, respectively; log‐rank p = 0.002), and particularly in IP recipients (50.0% vs. 82.9%; 16.7 vs. 79.4%, respectively; log‐rank p = 0.001). In a multivariate analysis, development of de novo DSA emerged as a strong independent predictor of pancreas graft failure (hazard ratio 4.66, p < 0.001). This is the largest study to examine de novo HLA antibodies following pancreas transplantation and clearly defines a high‐risk group in need of specific intervention.

“…Acute AMR manifests consistently across kidney, heart, and pancreas allografts as organ dysfunction and microvascular pathology , recognized as intraluminal pooling and/or margination of various leukocyte subsets (monocytes, macrophages, lymphocytes, neutrophils, and eosinophils) in dilated/irregularly shaped capillaries . Liver allografts exhibit a well‐documented AMR resistance (reviewed in ), accounting for the low incidence of acute AMR.…”

Section: Introductionmentioning

confidence: 99%

2016 Comprehensive Update of the Banff Working Group on Liver Allograft Pathology: Introduction of Antibody-Mediated Rejection

Demetris

Bellamy

Hübscher

et al. 2016

490

626

The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5-10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5-10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.