A common rejection module (CRM) for acute rejection across multiple organs identifies novel therapeutics for organ transplantation

Khatri, Purvesh; Roedder, Silke; Kimura, Naoyuki; Vusser, Katrien De; Morgan, Alexander A.; Gong, Yongquan; Fischbein, Michael P.; Robbins, Robert C.; Naesens, Maarten; Butte, Atul J.; Sarwal, Minnie M.

doi:10.1084/jem.20122709

Cited by 213 publications

(273 citation statements)

References 75 publications

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“…In contrast, there is considerable heterogeneity among published studies with regard to how the molecular phenotype has been assessed and applied as a potential diagnostic and/or predictive tool 46. Over the last decade, transplant biopsies, blood, and urine have been studied comprehensively, primarily using transcriptomics, and have led to novel insights into the molecular phenotypes of organ transplants 47, 48, 49, 50, 51, 52, 53. Current ongoing studies—for example, the INTERCOM studies 47, 48—are assessing a molecular microscope approach in real time for examining kidney allograft biopsies and comparing the gene expression classifiers and diagnosis to the current gold standard histopathology.…”

Section: Prospects For Adopting Molecular Pathology In Renal Allografmentioning

confidence: 99%

The Banff 2015 Kidney Meeting Report: Current Challenges in Rejection Classification and Prospects for Adopting Molecular Pathology

Loupy

Haas

Solez

et al. 2017

American Journal of Transplantation

567

581

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The XIII Banff meeting, held in conjunction the Canadian Society of Transplantation in Vancouver, Canada, reviewed the clinical impact of updates of C4d‐negative antibody‐mediated rejection (ABMR) from the 2013 meeting, reports from active Banff Working Groups, the relationships of donor‐specific antibody tests (anti‐HLA and non‐HLA) with transplant histopathology, and questions of molecular transplant diagnostics. The use of transcriptome gene sets, their resultant diagnostic classifiers, or common key genes to supplement the diagnosis and classification of rejection requires further consensus agreement and validation in biopsies. Newly introduced concepts include the i‐IFTA score, comprising inflammation within areas of fibrosis and atrophy and acceptance of transplant arteriolopathy within the descriptions of chronic active T cell–mediated rejection (TCMR) or chronic ABMR. The pattern of mixed TCMR and ABMR was increasingly recognized. This report also includes improved definitions of TCMR and ABMR in pancreas transplants with specification of vascular lesions and prospects for defining a vascularized composite allograft rejection classification. The goal of the Banff process is ongoing integration of advances in histologic, serologic, and molecular diagnostic techniques to produce a consensus‐based reporting system that offers precise composite scores, accurate routine diagnostics, and applicability to next‐generation clinical trials.

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Section: Prospects For Adopting Molecular Pathology In Renal Allografmentioning

confidence: 99%

The Banff 2015 Kidney Meeting Report: Current Challenges in Rejection Classification and Prospects for Adopting Molecular Pathology

Loupy

Haas

Solez

et al. 2017

American Journal of Transplantation

567

581

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“…Experimental and clinical evidence support the idea that statins could be a useful adjunct conventional immunosuppressant (85)(86)(87)(88). Using a bioinformatic approach, Khatri et al (89) lately identified statins as potential drug candidates for the prevention of transplant rejection. They furthermore demonstrated that atorvastatin significantly extended allograft survival in mice and humans.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Protein Geranylgeranylation Specifically Interferes with CD40-Dependent B Cell Activation, Resulting in a Reduced Capacity To Induce T Cell Immunity

Shimabukuro‐Vornhagen

Zoghi

Liebig

et al. 2014

The Journal of Immunology

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Ab-independent effector functions of B cells, such as Ag presentation and cytokine production, have been shown to play an important role in a variety of immune-mediated conditions such as autoimmune diseases, transplant rejection, and graft-versus-host disease. Most current immunosuppressive treatments target T cells, are relatively unspecific, and result in profound immunosuppression that places patients at an increased risk of developing severe infections and cancer. Therapeutic strategies, which interfere with B cell activation, could therefore be a useful addition to the current immunosuppressive armamentarium. Using a transcriptomic approach, we identified upregulation of genes that belong to the mevalonate pathway as a key molecular event following CD40-mediated activation of B cells. Inhibition of 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme of the mevalonate pathway, by lipophilic statins such as simvastatin and atorvastatin resulted in a specific inhibition of B cell activation via CD40 and impaired their ability to act as stimulatory APCs for allospecific T cells. Mechanistically, the inhibitory effect resulted from the inhibition of protein geranylgeranylation subsequent to the depletion of mevalonate, the metabolic precursor for geranylgeranyl. Thus, inhibition of geranylgeranylation either directly through geranylgeranyl transferase inhibitors or indirectly through statins represents a promising therapeutic approach for the treatment of diseases in which Ag presentation by B cells plays a role.

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“…Consistent with the idea that hyperlipidemia negatively affects transplant outcome, reducing lipids can reduce the incidence of rejection. Statins decreased the incidence of acute rejection, improved 1-year survival, and reduced the development of CAV (26). However, in some studies, other cholesterol-lowering drugs did not improve transplant outcome (27).…”

Section: Hsd and Transplant Fatementioning

confidence: 99%

“…While improved transplant survival may be related to the ability of statins to lower lipid levels, statins also have immuno modulatory properties that are independent of lipid-lowering effects (28)(29)(30) in monocytes (31)(32)(33)(34)(35)(36)(37)(38)(39) and T cells (33,34,40,41). Indeed, when treated with lipid-lowering agents, mice with normal lipid levels exhibited prolonged transplant survival (26). cell differentiation despite HSD (9).…”

Section: Hsd and Transplant Fatementioning

confidence: 99%

Impact of environmental factors on alloimmunity and transplant fate

Riella

Bagley

Iacomini

et al. 2017

Journal of Clinical Investigation

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A common rejection module (CRM) for acute rejection across multiple organs identifies novel therapeutics for organ transplantation

Abstract: A set of 11 genes, termed the common rejection module, predicts acute graft rejection in solid organ transplant patients and may help to identify novel drug targets in transplantation.

Cited by 213 publications

References 75 publications

The Banff 2015 Kidney Meeting Report: Current Challenges in Rejection Classification and Prospects for Adopting Molecular Pathology

The Banff 2015 Kidney Meeting Report: Current Challenges in Rejection Classification and Prospects for Adopting Molecular Pathology

Inhibition of Protein Geranylgeranylation Specifically Interferes with CD40-Dependent B Cell Activation, Resulting in a Reduced Capacity To Induce T Cell Immunity

Impact of environmental factors on alloimmunity and transplant fate

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