Journal of Clinical Investigation

Primary Epstein-Barr virus (EBV) infection can lead to post-transplantation lymphoproliferative disorder (PTLD) following renal transplantation (RTx). Despite EBV-driven PTLD (ePTLD) being rare, it is potentially lethal. CD8+ T-cells play a crucial role in controlling viral infections and malignant transformation of cells. We therefore hypothesized that aberrant EBV-specific CD8+ T cell maturation may contribute to ePTLD development. We performed multichannel flow cytometry on MHC class I tetram...

Immunosuppression in solid organ transplant recipients inhibits protective immune responsiveness to pathogens and vaccines. However, specific cell states that associate with failure to generate protective immunity are not known. Here, we perform scRNAseq and CyTOF analyses of PBMC from 12 pediatric solid organ transplant recipients and 8 healthy children revealing the full spectrum of immune cell states present in these individuals, and examine the association of these cell states with the gener...

Transplant-associated thrombotic microangiopathy (TA-TMA) is a severe endothelial complication following allogeneic hematopoietic stem-cell transplantation (allo-HSCT), associated with high mortality when not promptly diagnosed and treated. This study aimed to delineate the genetic landscape associated with TA-TMA and assess its impact on clinical outcomes. We retrospectively analyzed 1069 allo-HSCT recipients between January 2016 and May 2020, identifying 131 patients who met diagnostic criteri...

It is unknown how intestinal B cell populations and B cell receptor (BCR) repertoires are established and maintained over time in humans. Following intestinal transplantation (ITx), surveillance ileal mucosal biopsies provide a unique opportunity to map the dynamic establishment of gut lymphocyte populations. Using polychromatic flow cytometry that includes HLA allele group-specific mAbs distinguishing donor from recipient cells along with high throughput BCR sequencing, we tracked the establish...

In solid organ transplantation, monocytes and macrophages play a cross-cutting role in the rejection process, irrespective of the transplanted tissue and the type of rejection. Here, we integrated multiple single-cell assays (>150,000 cells) with a broad spectrum of blood-derived and renal allograft-derived cells. We observed 6 myeloid cell trajectories enriched in the allograft during rejection, ranging from circulating CD14+ monocytes to differentiated macrophages in the kidney, with one traje...

Killer immunoglobulin-like receptor (KIR) and KIR-ligand (KIRL) interactions play an important role in natural killer cell mediated graft versus leukemia effect (GVL) after hematopoietic stem cell transplant (HCT) for AML. Mathematically accounting for KIR-KIRL interactions may identify donors with optimal NK cell mediated alloreactivity and GVL. In this retrospective study of 2359 donor recipient pairs (DRP) who underwent unrelated donor (URD) HCT for AML, KIR-KIRL interaction scores were deter...

Novel mRNA-based vaccines have been proven powerful tools to combat the global pandemic caused by SARS-CoV2 with BNT162b2 efficiently protecting individuals from COVID-19 across a broad age range. Still, it remains largely unknown how renal insufficiency and immunosuppressive medication affect development of vaccine induced immunity. We therefore comprehensively analyzed humoral and cellular responses in kidney transplant recipients after prime-boost vaccination with BNT162b2. As opposed to all ...

BackgroundMultiple factors affecting COVID19 vaccine induced antibody responses in SARS-CoV2 uninfected immunosuppressed solid organ transplant recipients have been reported; however, there is still a lack of information on non-ACE2 competing cross-CoV2 neutralizing functional antibodies induced in these cohorts, and similarly the vaccine efficacy in prior CoV2-infected immunosuppressed individuals is not well understood. MethodsCOVID19 vaccine efficacy was compared in a panel of kidney and hea...

ImportancePassive antibody transfer is a longstanding treatment strategy for infectious diseases that involve the respiratory system. In this context, human convalescent plasma has been used to treat coronavirus disease 2019 (COVID-19), but the efficacy remains uncertain. ObjectiveTo explore potential signals of efficacy of COVID-19 convalescent plasma. DesignOpen-label, Expanded Access Program (EAP) for the treatment of COVID-19 patients with human convalescent plasma. SettingMulticenter, in...

Killer immunoglobulin-like receptor (KIR) and KIR-ligand (KIRL) interactions play an important role in natural killer cell-mediated effects after hematopoietic stem cell transplantation (HCT). Previous work has shown that accounting for known KIR-KIRL interactions may identify donors with optimal NK cell-mediated alloreactivity in the adult transplant setting. Pediatric acute leukemia patients were retrospectively analyzed and KIR-KIRL combinations and maximal inhibitory KIR ligand (IM-KIR) sco...

BackgroundThe effects of Covid-19 in pregnancy remain relatively unknown. We present a case of second trimester pregnancy with symptomatic Covid-19 complicated by severe preeclampsia and placental abruption. MethodsWe analyzed placenta for the presence of SARS-CoV-2 through molecular and immunohistochemical assays and by and electron microscopy, and we measured the maternal antibody response in blood to this infection. ResultsSARS-CoV-2 localized predominantly to syncytiotrophoblast cells at t...

Antibody-mediated rejection (AbMR), driven by donor-specific alloantibodies (DSAs), is a major cause of late-stage kidney allograft failure, leading to premature graft loss in over half of affected patients. Despite efforts to link DSA features (e.g., HLA-specific IgG titers) to rejection risk, the immune mechanisms distinguishing DSA+ patients who develop AbMR remain unclear. In this first-in-class study, we develop a sample-sparing and cost-effective technique to generate the most comprehensiv...

Despite advances in surgical techniques and immunosuppression, long-term survival after lung transplantation (LuTx) remains suboptimal due to high rates of rejection, infection and graft dysfunction. To address this, we investigated post-LuTx T cell dynamics--tracking repopulation, clonal distribution, alloreactivity, and microbial reactivity--through flow cytometry and TCR{beta} sequencing of serial bronchoalveolar lavage (BAL) and peripheral blood samples. Pre- transplant mixed lymphocyte reac...

Identifying biomarkers in kidney transplant patients is essential for early detection of rejection, personalized treatment and improved overall outcomes. It improves our ability to monitor the health of the transplanted organ and tailor interventions to the specific needs of each patient. Here we compiled a multicenter, multiomic dataset of the kidney transplant landscape. Using multi-omics factor analysis (MOFA), we sought to uncover sources of biological variability in patients blood, urine an...

BACKGROUNDChronic antibody-mediated rejection (CAMR) is the main cause of late kidney allograft loss, and no specific effective treatment has been identified so far. Here, we proposed to explore the non-invasive peripheral blood transcriptome signature of CAMR. METHODSFirst, we compared PBMC gene expression from bulk RNA-seq between 35 patients experiencing late CAMR (mean=7.1 years) vs. 43 patients without graft dysfunction at late stages (Stable, mean=4.4 years) to identify the molecular driv...

BackgroundHLA molecular mismatch (MM) has been shown to be a risk factor for de novo donor-specific antibody (dnDSA) development in solid organ transplantation (SOT). HLA expression differences have also been associated with adverse outcomes in hematopoietic cell transplantation. We sought to study both MM and expression in assessing dnDSA risk. MethodsOne-hundred-and-three HLA-DP-mismatched SOT pairs were retrospectively analysed. MM was computed using amino acids (aa), eplets and, supplementa...

IntroductionGraft-versus host disease (GVHD) is a major limitation to the success of allogeneic hematopoietic cell transplant (HCT). We hypothesized that the GVHD prophylaxis regimen of post-transplant cyclophosphamide (PTCy), tacrolimus (Tac) and mycophenolate mofetil (MMF) would reduce the incidence of GVHD in patients receiving a matched or single antigen mismatched HCT without an increase in risk of malignant relapse. MethodsThis is a phase II study conducted at the University of Minnesota ...

ObjectivesTo evaluate the clinical implications of adjunctive molecular gene expression analysis (MMDx) of biopsy specimens in heart transplant (HT) recipients with suspected rejection. IntroductionHistopathological evaluation remains the standard method for rejection diagnosis in HT. However, the wide interobserver variability combined with a relatively common incidence of "biopsy-negative" rejection has raised concerns about the likelihood of false-negative results. MMDx, which uses gene expr...

1.The BK polyomavirus (BKPyV) persists asymptomatically in the kidney and active replication is only seen in immunosuppressed individuals, such as kidney transplant (KTx) recipients, in whom BKPyV reactivation can cause significant morbidity. KTx recipients with BKPyV reactivation mount a robust humoral response, but this often fails to clear the virus. In order to characterize the BKPyV-specific B-cell receptor (BCR) repertoire in KTx recipients, we used fluorescence-labeled BKPyV virus-like pa...

The emergence of the Coronavirus disease 2019 (COVID-19) pandemic in 2020 has profoundly impacted global health systems, particularly affecting vulnerable populations like kidney transplant recipients (KTRs).We prospectively collected blood samples from 17 PCR-confirmed COVID-19 KTR patients and 10 non-COVID-19 KTRs between May and September 2020. Using tandem mass tag-based quantitative proteomics, we characterized peripheral blood mononuclear cells (PBMCs) from KTRs alongside plasma protein bi...