Sensitive HLA antibody testing and the risk of antibody-mediated rejection and graft failure.

Solid phase detection and identification of HLA antibodies in kidney transplantation currently relies on single antigen bead (Luminex®) assays, which is more sensitive than the previously used enzyme-linked immunosorbent assays (ELISA). To evaluate the impact of more sensitive HLA testing on antibody-mediated rejection (AMR) occurrence and allograft survival, we analysed 1818 renal allograft recipients transplanted between March 2004 and May 2021. In 2008, solid phase testing switched from ELISA to Luminex.

A spatial architecture-embedding HLA signature to predict clinical response to immunotherapy in renal cell carcinoma.

An important challenge in the real-world management of patients with advanced clear-cell renal cell carcinoma (aRCC) is determining who might benefit from immune checkpoint blockade (ICB). Here we performed a comprehensive multiomics mapping of aRCC in the context of ICB treatment, involving discovery analyses in a real-world data cohort followed by validation in independent cohorts. We cross-connected bulk-tumor transcriptomes across >1,000 patients with validations at single-cell and spatial resolutions, revealing a patient-specific crosstalk between proinflammatory tumor-associated macrophages and (pre-)exhausted CD8 T cells that was distinguished by a human leukocyte antigen repertoire with higher preference for tumoral neoantigens.

Association of Predicted HLA T-Cell Epitope Targets and T-Cell-Mediated Rejection After Kidney Transplantation.

Rationale & Objective: The relationship between human leukocyte antigen (HLA) molecular mismatches and T-cell-mediated rejection (TCMR) is unknown. We investigated the associations between the different donor HLA-derived T-cell targets and the occurrence of TCMR and borderline histologic changes suggestive of TCMR after kidney transplantation.

Study Design: Retrospective cohort study.

An ECHO of Cartilage: Prediction of Combinatorial Treatments to Switch Between Transient and Permanent Cartilage Phenotypes With Validation.

A fundamental question in cartilage biology is: what determines the switch between permanent cartilage found in the articular joints and transient hypertrophic cartilage that functions as a template for bone? This switch is observed both in a subset of OA patients that develop osteophytes, as well as in cell-based tissue engineering strategies for joint repair. A thorough understanding of the mechanisms regulating cell fate provides opportunities for treatment of cartilage disease and tissue engineering strategies. The objective of this study was to understand the mechanisms that regulate the switch between permanent and transient cartilage using a computational model of chondrocytes, ECHO.

Eplet Mismatch Load and Occurrence of Donor-Specific Anti-HLA Antibodies, Rejection, and Graft Failure after Kidney Transplantation: An Observational Cohort Study.

Background: In kidney transplantation, evaluating mismatches of HLA eplets-small patches of surface-exposed amino acids of the HLA molecule-instead of antigen mismatches might offer a better approach to assessing donor-recipient HLA incompatibility and improve risk assessment and prediction of transplant outcomes.

Methods: To evaluate the effect of number of eplet mismatches (mismatch load) on formation of donor-specific HLA antibodies (DSAs) and transplant outcomes, we conducted a cohort study that included consecutive adult kidney recipients transplanted at a single center from March 2004 to February 2013. We performed retrospective high-resolution genotyping of HLA loci of 926 transplant pairs and used the HLAMatchmaker computer algorithm to count HLA eplet mismatches.

ECHO, the executable CHOndrocyte: A computational model to study articular chondrocytes in health and disease.

Computational modeling can be used to investigate complex signaling networks in biology. However, most modeling tools are not suitable for molecular cell biologists with little background in mathematics. We have built a visual-based modeling tool for the investigation of dynamic networks.

Computational Modeling and Reverse Engineering to Reveal Dominant Regulatory Interactions Controlling Osteochondral Differentiation: Potential for Regenerative Medicine.

The specialization of cartilage cells, or chondrogenic differentiation, is an intricate and meticulously regulated process that plays a vital role in both bone formation and cartilage regeneration. Understanding the molecular regulation of this process might help to identify key regulatory factors that can serve as potential therapeutic targets, or that might improve the development of qualitative and robust skeletal tissue engineering approaches. However, each gene involved in this process is influenced by a myriad of feedback mechanisms that keep its expression in a desirable range, making the prediction of what will happen if one of these genes defaults or is targeted with drugs, challenging.

A Qualitative Model of the Differentiation Network in Chondrocyte Maturation: A Holistic View of Chondrocyte Hypertrophy.

Differentiation of chondrocytes towards hypertrophy is a natural process whose control is essential in endochondral bone formation. It is additionally thought to play a role in several pathophysiological processes, with osteoarthritis being a prominent example. We perform a dynamic analysis of a qualitative mathematical model of the regulatory network that directs this phenotypic switch to investigate the influence of the individual factors holistically.

A Semiquantitative Framework for Gene Regulatory Networks: Increasing the Time and Quantitative Resolution of Boolean Networks.

Boolean models have been instrumental in predicting general features of gene networks and more recently also as explorative tools in specific biological applications. In this study we introduce a basic quantitative and a limited time resolution to a discrete (Boolean) framework. Quantitative resolution is improved through the employ of normalized variables in unison with an additive approach.

Relating the chondrocyte gene network to growth plate morphology: from genes to phenotype.

During endochondral ossification, chondrocyte growth and differentiation is controlled by many local signalling pathways. Due to crosstalks and feedback mechanisms, these interwoven pathways display a network like structure. In this study, a large-scale literature based logical model of the growth plate network was developed.