scholarly journals PROTEASOME INHIBITION EFFECTIVELY TREATS ACUTE CELLULAR REJECTION, ANTIBODY MEDIATED REJECTION, AND PROVIDES LONG-TERM REDUCTION OF DONOR SPECIFIC ANTIBODIES

2008 ◽  
Vol 86 (Supplement) ◽  
pp. 68-69 ◽  
Author(s):  
M Everly ◽  
J Everly ◽  
P Brailey ◽  
B Susskind ◽  
L Arend ◽  
...  
Keyword(s):  
Proteasome Inhibition ◽  
Acute Cellular Rejection ◽  
Specific Antibodies ◽  
Antibody Mediated Rejection ◽  
Donor Specific Antibodies ◽  
Cellular Rejection

scholarly journals Proteomics Reveals Extracellular Matrix Injury in the Glomeruli and Tubulointerstitium of Kidney Allografts with Early Antibody-Mediated Rejection

2020 ◽  
Author(s):  
Sergi Clotet-Freixas ◽  
Caitriona M. McEvoy ◽  
Ihor Batruch ◽  
Julie Van ◽  
Chiara Pastrello ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Hla Antigens ◽  
Acute Cellular Rejection ◽  
Ecm Remodeling ◽  
Specific Antibodies ◽  
Antibody Mediated Rejection ◽  
Tubular Necrosis ◽  
Ecm Proteins ◽  
Donor Specific Antibodies ◽  
Cellular Rejection

ABSTRACTAntibody-mediated rejection (AMR) accounts for >50% of kidney allograft losses. AMR is caused by donor-specific antibodies (DSA) against HLA and non-HLA antigens in the glomeruli and the tubulointerstitium, which together with inflammatory cytokines such as tumor necrosis factor alpha (TNFα) and interferon gamma (IFNɣ), trigger graft injury. Unfortunately, the mechanisms governing cell-specific injury in AMR remain unclear. We studied 30 for-cause kidney biopsies with early AMR, acute cellular rejection or acute tubular necrosis (‘non-AMR’). We laser-captured and microdissected glomeruli and tubulointerstitium, and subjected them to unbiased proteome analysis. 120/2026 glomerular and 180/2399 tubulointerstitial proteins were significantly differentially expressed in AMR vs. non-AMR biopsies (P<0.05). Basement membrane and extracellular matrix (ECM) proteins were significantly decreased in both AMR compartments. We verified decreased glomerular and tubulointerstitial LAMC1 expression, and decreased glomerular NPHS1 and PTPRO expression in AMR. Cathepsin-V (CTSV) was predicted to cleave ECM-proteins in the AMR glomeruli, and CTSL, CTSS and LGMN in the tubulointerstitium. We identified galectin-1, an immunomodulatory protein upregulated in the AMR glomeruli and linked to the ECM. Anti-HLA class-I antibodies significantly increased CTSV expression, and galectin-1 expression and secretion, in human glomerular endothelial cells. Glutathione S-transferase omega-1 (GSTO1), an ECM-modifying enzyme, was significantly increased in the AMR tubulointerstitium, and in TNFα-treated proximal tubular epithelial cells. IFNɣ and TNFα significantly increased CTSS and LGMN expression in these cells. Basement membranes are often remodeled in chronic AMR, and we demonstrated that this remodeling begins early in glomeruli and tubulointerstitium. Targeting ECM-remodeling in AMR may represent a new therapeutic opportunity.SIGNIFICANCE STATEMENTAntibody-mediated rejection (AMR) accounts for >50% of kidney allograft loss, and is caused by donor-specific antibodies against HLA antigens, which induce maladaptive responses in the kidney glomeruli and tubulointerstitium. This is the first unbiased proteomics analysis of laser-captured/microdissected glomeruli and tubulointerstitium from 30 indication kidney biopsies with early AMR, acute cellular rejection or acute tubular necrosis. >2,000 proteins were quantified in each compartment. We discovered that basement membrane and extracellular matrix (ECM) proteins were significantly decreased in both AMR compartments. Two ECM-modifying proteins, LGALS1 and GSTO1, were significantly increased in glomeruli and tubulointerstitium, respectively. LGALS1 and GSTO1 were upregulated by anti-HLA antibodies or AMR-related cytokines in primary kidney cells, and may represent therapeutic targets to ameliorate ECM-remodeling in AMR.

scholarly journals Diagnosis of Acute Cellular Rejection and Antibody-Mediated Rejection on Lung Transplant Biopsies: A Perspective From Members of the Pulmonary Pathology Society

2016 ◽  
Vol 141 (3) ◽  
pp. 437-444 ◽  
Author(s):  
Anja C. Roden ◽  
Dara L. Aisner ◽  
Timothy Craig Allen ◽  
Marie Christine Aubry ◽  
Roberto J. Barrios ◽  
...  
Keyword(s):  
Lung Transplant ◽  
Transbronchial Biopsy ◽  
Acute Cellular Rejection ◽  
Graft Dysfunction ◽  
Antibody Mediated Rejection ◽  
Triple Test ◽  
Pathologic Findings ◽  
Pulmonary Pathology ◽  
Donor Specific Antibodies ◽  
Cellular Rejection

Context.— The diagnosis and grading of acute cellular and antibody-mediated rejection (AMR) in lung allograft biopsies is important because rejection can lead to acute graft dysfunction and/or failure and may contribute to chronic graft failure. While acute cellular rejection is well defined histologically, no reproducible specific features of AMR are currently identified. Therefore, a combination of clinical features, serology, histopathology, and immunologic findings is suggested for the diagnosis of AMR. Objective.— To describe the perspective of members of the Pulmonary Pathology Society (PPS) on the workup of lung allograft transbronchial biopsy and the diagnosis of acute cellular rejection and AMR in lung transplant. Data Sources.— Reports by the International Society for Heart and Lung Transplantation (ISHLT), experience of members of PPS who routinely review lung allograft biopsies, and search of literature database (PubMed). Conclusions.— Acute cellular rejection should be assessed and graded according to the 2007 working formulation of the ISHLT. As currently no specific features are known for AMR in lung allografts, the triple test (clinical allograft dysfunction, donor-specific antibodies, pathologic findings) should be used for its diagnosis. C4d staining might be performed when morphologic, clinical, and/or serologic features suggestive of AMR are identified.

Abstract 13046: Treatment of Highly Sensitized Patients Before Heart Transplant Associated With Long-term Post-transplant Benefit

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Timothy Ho ◽  
Jignesh K Patel ◽  
Keith Nishihara ◽  
Michelle M Kittleson ◽  
David H Chang ◽  
...  
Keyword(s):  
Acute Cellular Rejection ◽  
Cardiac Events ◽  
Donor Pool ◽  
Antibody Mediated Rejection ◽  
Adverse Cardiac Events ◽  
Significant Difference ◽  
Desensitization Therapy ◽  
Cellular Rejection ◽  
Reactive Antibody

Introduction: Highly sensitized patients awaiting heart transplantation (HTx) are disadvantaged by a narrow donor pool due to incompatible potential donors. Desensitization therapy has been demonstrated to be effective in lowering antibodies and thereby enlarging the donor pool. By desensitization, the calculated panel reactive antibody (cPRA) has been reported to decrease and result in a shorter waitlist time. It has not been established whether desensitization before transplant can have impact after HTx outcomes. Methods: Between 2010 and 2015, we assessed 34 patients awaiting HTx who had a PRA >50% and underwent desensitization therapy. Desensitization therapy included combinations of IVIG, rituximab, plasmapheresis, and bortezomib. These patients who underwent HTx were then assessed for outcomes, which included 5-year survival, freedom from cardiac allograft vasculopathy (CAV), freedom from non-fatal major adverse cardiac events (NF-MACE), and freedom from donor specific antibody (DSA) development and 1-year freedom from rejection (any treated rejection (ATR), acute cellular rejection (ACR), antibody mediated rejection (AMR)). Patients who underwent desensitization were compared to a similar group of patients with PRA >50% who did not undergo desensitization and underwent HTx. Results: Patients who underwent desensitization compared to those who did not had significantly greater freedom from 5-year development of CAV (94.1 vs 78.8%, p=0.039). There was no significant difference in 5-year survival, 5-year freedom from NF-MACE or DSA development, and 1-year freedom from ATR, ACR, AMR. Conclusions: Desensitization in highly sensitized patients awaiting HTx appears to have long ranging effects to modulate the immune system after HTx, resulting in less development of CAV. Further investigation should be pursued to understand the mechanism of this intervention.

IS THE PRESENCE OF HLA DONOR SPECIFIC ANTIBODIES AT THE END OF THE FIRST YEAR POST-TRASPLANTATION INFLUENCED BY THE OCURRENCE OF ACUTE CELLULAR REJECTION DURING THE FIRST YEAR?

2010 ◽  
Vol 90 ◽  
pp. 885
Author(s):  
Vázquez R.A. Hernández ◽  
J. Perez-Garrido ◽  
L. E. Morales-Buenrostro ◽  
C. De-Leo ◽  
L. García-Covarrubias ◽  
...  
Keyword(s):  
Acute Cellular Rejection ◽  
First Year ◽  
Specific Antibodies ◽  
Donor Specific Antibodies ◽  
Cellular Rejection

scholarly journals Long-term survival of the transplanted kidney and the clinical relevance of donor-specific antibodies

2020 ◽  
Vol 3 (1) ◽  
pp. 17-22
Author(s):  
Eva Svobodova ◽  
Sarka Valhova ◽  
Ondrej Viklicky ◽  
Ilja Striz ◽  
Jelena Skibova ◽  
...  
Keyword(s):  
Graft Survival ◽  
Solid Phase ◽  
Kidney Graft ◽  
Term Survival ◽  
Specific Antibodies ◽  
Antibody Mediated Rejection ◽  
Number Of Patients ◽  
Single Antigen ◽  
Donor Specific Antibodies

The aim of our study was to evaluate the relevance of donor-specific antibodies (DSA) as defined by solid-phase single-antigen (SA) assays for predicting long-term graft survival after kidney transplantation. Sera from 132 kidney transplant recipients were retrospectively tested before, 3, 6 and 12 months after transplantation. The incidence of rejection and graft survival was followed up for 7 years. We found 29 episodes of acute cellular rejection (CR), 21 cases of antibody-mediated rejection (AMR) and 18 graft failures due to immunological reasons. Pre-transplant DSA and DSA three months after transplantation correlated with an increased rate of AMR and impaired graft function. After the fourth year, recipients with persistent DSA were at a higher risk of graft failure (p = 0.0317). Antibody specificity was prevailingly to HLA class I antigens (66.6% DSA, 75% non-DSA). During the first year after transplantation, the number of patients with non-DSA decreased (30.3% to 10.7%), while, due to de novo production of antibodies, the number of DSA positive patients remained constant. Conclusion: Detection of antibodies to HLA antigens using solid-phase assays, especially single-antigen bead technology before and three months after transplantation is predictive for increased incidence of antibody-mediated rejection and impaired long-term kidney graft survival.

scholarly journals Late and Chronic Antibody-Mediated Rejection: Main Barrier to Long Term Graft Survival

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Qiquan Sun ◽  
Yang Yang
Keyword(s):  
Graft Survival ◽  
Graft Loss ◽  
Limited Effect ◽  
Hla Antibodies ◽  
Specific Antibodies ◽  
Antibody Mediated Rejection ◽  
Donor Specific Antibodies ◽  
Main Barrier ◽  
Lines Of Evidence

Antibody-mediated rejection (AMR) is an important cause of graft loss after organ transplantation. It is caused by anti-donor-specific antibodies especially anti-HLA antibodies. C4d had been regarded as a diagnosis marker for AMR. Although most early AMR episodes can be successfully controlled or reversed, late and chronic AMR remains the leading cause of late graft loss. The strategies which work in early AMR have limited effect on late/chronic episodes. Here, we reviewed the lines of evidence that late/chronic AMR is the leading cause of late graft loss, characteristics of late AMR, and current strategies in managing late/chronic AMR. More effort should be put on the management of late/chronic AMR to make a better long term graft survival.

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