Objective: Heart transplantation remains the definitive treatment for patients with advanced heart failure, but post-transplant complications such as acute cellular rejection (ACR) continue to limit long-term outcomes. The current standard for ACR surveillance is endomyocardial biopsy, which is invasive and associated with procedural risks, variability in interpretation, high healthcare utilization costs, and poor patient tolerability. For these reasons, there is increasing interest in identifying non-invasive biomarkers that can reliably detect ACR. This review details the range of non-invasive methods for detecting ACR and to provide practical guidance for clinicians considering a transition to less invasive monitoring protocols following heart transplantation. Methods: We conducted a narrative review of published literature focusing on non-invasive biomarkers for ACR in heart transplantation. We specifically focused on evaluating donor-derived cell-free DNA, gene expression profiling, plasma microRNA, metabolomics, cytokines and chemokines, and extracellular vesicle approaches, with emphasis on clinical applicability, diagnostic performance, and limitations. Results: Our review identified several promising non-invasive biomarkers for ACR detection, with donor-derived cell-free DNA and gene expression profiling showing the most advanced clinical integration. Emerging approaches such as microRNA profiling, metabolomics, cytokine or chemokine panels, and extracellular vesicle analysis demonstrate potential in early-phase studies but require further validation. Most biomarkers exhibited high negative predictive value, though sensitivity and positive predictive values remained variable across platforms along with their applications in the early perioperative and late follow-up periods. None of the biomarker platforms distinguish ACR from antibody mediated rejection. Practical challenges including cost, assay standardization, and limited availability continue to impact widespread adoption. Conclusion: Non-invasive blood-based biomarkers show promise for improving acute cellular rejection surveillance in heart transplant recipients. While markers such as dd-cfDNA, extracellular vesicles, and microRNAs have demonstrated encouraging early results, their clinical use remains limited by variable inadequate sensitivity, low positive predictive value, inability to distinguish ACR from AMR, and lack of standardization. Ongoing investigations are expected to refine their diagnostic performance and guide their integration into routine clinical care.
Current therapies for antibody-mediated autoimmune diseases largely rely on broad immunosuppression or lineage-wide B-cell depletion. These approaches are associated with increased risks of infection and other adverse effects. This commentary focuses on Chimeric Autoantibody Receptor (CAAR) T-cell technology as a precision immunotherapy that selectively eliminates pathogenic autoreactive B-cell clones while preserving protective immunity. Using Pemphigus Vulgaris (PV) as a representative model, CAAR-T cells engineered to express desmoglein 3 (Dsg3) demonstrate antigen-specific targeting of B cells expressing anti-Dsg3 B cell receptors. Notably, these cells maintain cytolytic efficacy despite high circulating autoantibody titers and show tissue selectivity, sparing keratinocytes, potentially due to biophysical constraints governing immune synapse formation. We further discuss key translational challenges, including manufacturing complexity, the presence of additional pathogenic antibody populations (e.g., anti-Dsg1), and long-term cellular persistence. Collectively, CAAR-T technology represents a mechanistically distinct and potentially scalable therapeutic paradigm for antibody-mediated autoimmune disorders, emphasizing antigen-specific immune editing over global immune suppression.
The recently published review by Baeten et al. outlines the scientific and translational evidence supporting the role of cyclin dependent kinase (CDK) 4/6 in rheumatoid arthritis (RA) pathology, and it discusses how this stromal (synovial fibroblast) target provides the basis for a drug class with a novel non-immunosuppressive mechanism of action that could change the current immunosuppressive treatment paradigm in RA. The early clinical trial (phase 1b) of the next generation CDK4/6 inhibitor, ELV001, showed the rapid clinical improvement, and ELV001 was well tolerated with no clinically meaningful safety signals. This warrants further clinical evaluation of ELV001 in a larger group of patients with active RA, and the phase 2 study with ELV001 (START SYNERGY) is currently in progress. This commentary article on the published review by Baeten et al. describes additional perspectives, in particular, what is the next step in the clinical development of CDK4/6 inhibition for RA, as well as where CDK4/6 inhibition could be positioned in the RA treatment algorithm. A novel combination strategy that pairs systemic immunosuppression (current therapeutic options) with a synovial-targeted non-immunosuppressive anti-rheumatic therapy (with ELV001) is expected to leverage orthogonal mechanisms of action, and this approach would represent a distinct therapeutic paradigm for RA.
