Tolerance of mouse kidney allografts arises in grafts that develop regulatory tertiary lymphoid organs (rTLOs). Single-cell RNA-seq (scRNA-seq) data and adoptive transfer of alloreactive T cells after transplantation showed that cytotoxic CD8+ T cells are reprogrammed within the accepted graft to an exhausted/regulatory-like phenotype mediated by IFN-γ. Establishment of rTLOs was required because adoptive transfer of alloreactive T cells prior to transplantation results in kidney allograft rejection.
View Article and Find Full Text PDFKidney transplant (KTx) biopsies showing transplant glomerulopathy (TG) (glomerular basement membrane double contours (cg) > 0) and microvascular inflammation (MVI) in the absence of C4d staining and donor-specific antibodies (DSAs) do not fulfill the criteria for chronic active antibody-mediated rejection (CA-AMR) diagnosis and do not fit into any other Banff category. To investigate this, we initiated a multicenter intercontinental study encompassing 36 cases, comparing the immunomic and transcriptomic profiles of 14 KTx biopsies classified as cg+MVI DSA/C4d with 22 classified as CA-AMR DSA/C4d through novel transcriptomic analysis using the NanoString Banff-Human Organ Transplant (B-HOT) panel and subsequent orthogonal subset analysis using two innovative 5-marker multiplex immunofluorescent panels. Nineteen genes were differentially expressed between the two study groups.
View Article and Find Full Text PDFThe XVIth Banff Meeting for Allograft Pathology was held in Banff, Alberta, Canada, from September 19 to 23, 2022, as a joint meeting with the Canadian Society of Transplantation. In addition to a key focus on the impact of microvascular inflammation and biopsy-based transcript analysis on the Banff Classification, further sessions were devoted to other aspects of kidney transplant pathology, in particular T cell-mediated rejection, activity and chronicity indices, digital pathology, xenotransplantation, clinical trials, and surrogate endpoints. Although the output of these sessions has not led to any changes in the classification, the key role of Banff Working Groups in phrasing unanswered questions, and coordinating and disseminating results of investigations addressing these unanswered questions was emphasized.
View Article and Find Full Text PDFRecent human decedent model studies and compassionate xenograft use have explored the promise of porcine organs for human transplantation. To proceed to human studies, a clinically ready porcine donor must be engineered and its xenograft successfully tested in nonhuman primates. Here we describe the design, creation and long-term life-supporting function of kidney grafts from a genetically engineered porcine donor transplanted into a cynomolgus monkey model.
View Article and Find Full Text PDFDe novo membranous nephropathy (dnMN) is an uncommon immune complex-mediated late complication of human kidney allografts that causes proteinuria. We report here the first case of dnMN in a pig-to-baboon kidney xenograft. The donor was a double knockout (GGTA1 and β4GalNT1) genetically engineered pig with a knockout of the growth hormone receptor and addition of 6 human transgenes (hCD46, hCD55, hTBM, hEPCR, hHO1, and hCD47).
View Article and Find Full Text PDFCurr Opin Organ Transplant
October 2023
Purpose Of Review: This review aims to summarize the highlights from recent research that involved pathological and molecular analysis of kidney allografts.
Recent Findings: As the research on antibody-mediated rejection (AMR) continues to evolve, studies are focused on identification through transcript studies of pathogenetic pathways involved in the development of AMR as well as refinement of diagnostic methods either by correlating Banff pathologic lesions with clinical and molecular data or by machine learning. Of note, the past year has generated high impact research that underscore the importance of pathologic and molecular correlations and detection of transcripts or gene sets that would aid prognostication.
BackgroundAcute tubulointerstitial nephritis (AIN) is one of the few causes of acute kidney injury with diagnosis-specific treatment options. However, due to the need to obtain a kidney biopsy for histological confirmation, AIN diagnosis can be delayed, missed, or incorrectly assumed. Here, we identify and validate urinary CXCL9, an IFN-γ-induced chemokine involved in lymphocyte chemotaxis, as a diagnostic biomarker for AIN.
View Article and Find Full Text PDFMouse kidney allografts are spontaneously accepted in select, fully mismatched donor-recipient strain combinations, like DBA/2J to C57BL/6 (B6), by natural tolerance. We previously showed accepted renal grafts form aggregates containing various immune cells within 2 weeks posttransplant, referred to as regulatory T cell-rich organized lymphoid structures, which are a novel regulatory tertiary lymphoid organ. To characterize the cells within T cell-rich organized lymphoid structures, we performed single-cell RNA sequencing on CD45 sorted cells from accepted and rejected renal grafts from 1-week to 6-months posttransplant.
View Article and Find Full Text PDFBackground: In most CKDs, lysyl oxidase oxidation of collagen forms allysine side chains, which then form stable crosslinks. We hypothesized that MRI with the allysine-targeted probe Gd-oxyamine (OA) could be used to measure this process and noninvasively detect renal fibrosis.
Methods: Two mouse models were used: hereditary nephritis in Col4a3-deficient mice (Alport model) and a glomerulonephritis model, nephrotoxic nephritis (NTN).
The blockade of the CD154-CD40 pathway with anti-CD154 monoclonal antibody has been a promising immunomodulatory approach to prevent allograft rejection. However, clinical trials of immunoglobulin G1 antibodies targeting this pathway revealed thrombogenic properties, which were subsequently shown to be mediated by crystallizable fragment (Fc)-gamma receptor IIa-dependent platelet activation. To prevent thromboembolic complications, an immunoglobulin G4 anti-CD154 monoclonal antibody, TNX-1500, which retains the fragment antigen binding region of ruplizumab (humanized 5c8, BG9588), was modified by protein engineering to decrease Fc binding to Fc-gamma receptor IIa while retaining certain other effector functions and pharmacokinetics comparable with natural antibodies.
View Article and Find Full Text PDFHematopoietic stem cell transplantation (HSCT) has many potential applications beyond current standard indications, including treatment of autoimmune disease, gene therapy, and transplant tolerance induction. However, severe myelosuppression and other toxicities after myeloablative conditioning regimens have hampered wider clinical use. To achieve donor hematopoietic stem cell (HSC) engraftment, it appears essential to establish niches for the donor HSCs by depleting the host HSCs.
View Article and Find Full Text PDFBackground: To seek insights into the pathogenesis of chronic active antibody-mediated rejection (CAMR), we performed mRNA analysis and correlated transcripts with pathologic component scores and graft outcomes.
Methods: We utilized the NanoString nCounter platform and the Banff Human Organ Transplant gene panel to quantify transcripts on 326 archived renal allograft biopsy samples. This system allowed correlation of transcripts with Banff pathology scores from the same tissue block and correlation with long-term outcomes.
Antibody-mediated rejection (ABMR) is a major cause of kidney allograft failure. Biopsy-based surrogate endpoints reflecting ABMR progression on sequential biopsies that predict long-term outcome offer the potential to make treatment trials for ABMR feasible. However, the Banff transplant glomerulopathy (TG) scoring system (chronic glomerular injury score [cg]) relies on relatively crude and arbitrary ordinal grades and has low inter-observer concordance that currently limits its usefulness as a surrogate endpoint for ABMR progression in clinical drug trials.
View Article and Find Full Text PDFElectronic cigarettes (e-cigarettes) have been used widely as an alternative to conventional cigarettes and have become particularly popular among young adults. A growing body of evidence has shown that e-cigarettes are associated with acute lung injury and adverse effects in multiple other organs. Previous studies showed that high emissions of aldehydes (formaldehyde and acetaldehyde) in aerosols were associated with increased usage of the same e-cigarette coils.
View Article and Find Full Text PDFThe leading cause of death in coronavirus disease 2019 (COVID-19) is severe pneumonia, with many patients developing acute respiratory distress syndrome (ARDS) and diffuse alveolar damage (DAD). Whether DAD in fatal COVID-19 is distinct from other causes of DAD remains unknown. To compare lung parenchymal and vascular alterations between patients with fatal COVID-19 pneumonia and other DAD-causing etiologies using a multidimensional approach.
View Article and Find Full Text PDFBackground: Vascularized composite allografts (VCAs) allow reconstruction of devastating injuries and amputations, yet require lifelong immunosuppression that is associated with significant morbidity. Induction of immune tolerance of VCAs would permit widespread use of these procedures. VCAs are acquired from deceased donors most likely to be -MHC-mismatched (in contrast to living-related renal transplant donor-recipient pairs matched at one MHC haplotype).
View Article and Find Full Text PDFInterstitial fibrosis, tubular atrophy, and inflammation are major contributors to kidney allograft failure. Here we sought an objective, quantitative pathological assessment of these lesions to improve predictive utility and constructed a deep-learning-based pipeline recognizing normal vs. abnormal kidney tissue compartments and mononuclear leukocyte infiltrates.
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