Aug 2026· Brain : a journal of neurology· 0 citations
Medicine
TL;DR
This Update advances a disease-centred conceptual framework designed to reposition T-cell-based therapies within neurological practice, and delineates how adoptive T-cells may be differentially aligned with underlying disease biology, linking mechanistic insight to clinical strategy.
Abstract
Immune dysfunction, spanning pathogenic autoimmunity and impaired host defense, represents a convergent mechanism across neurological autoimmune and inflammatory diseases and opportunistic infections. Despite advances in immunomodulatory and anti-infective therapies, many patients remain treatment-refractory, reflecting limitations of conventional agents. Adoptive T-cell therapies introduce dynamic "living drugs" capable of in vivo expansion, adaptation, and persistence. These promising characteristics have led to a rapid proliferation of preliminary reports and clinical trials in inflammatory and infectious diseases of the nervous system, placing neurologists at the forefront of this evolving therapeutic landscape. In this Update, we advance a disease-centred conceptual framework designed to reposition T-cell-based therapies within neurological practice. Rather than adopting a technology-driven perspective, we organize disorders according to major patterns of immune dysfunction. Immune deficiency predisposing to opportunistic infection and immune dysregulation driving autoimmunity constitute the principal axes of neurological immune pathology. Within the autoimmune spectrum, distinct immunopathological archetypes (autoantibody-mediated, mixed B- and T-cell-driven, and disorders at the interface of inflammation and neurodegeneration) provide a pragmatic structure for therapeutic reasoning. Building on this classification, we delineate how adoptive T-cells (chimeric antigen receptor T-cells, virus-specific T-cells, and regulatory T-cells) may be differentially aligned with underlying disease biology, linking mechanistic insight to clinical strategy.
Neurodegenerative diseases, such as Parkinson’s disease, Alzheimer’s disease, and post-stroke sequelae, and rare disorders, including amyotrophic lateral sclerosis and multiple system atrophy, are characterized by complex neuroinflammatory processes and pathogenic protein aggregation. Natural killer and γδT cells, as pivotal immune effector cells, possess unique immunoregulatory and pathologic protein clearance capabilities, making these cells promising candidates for adoptive immunotherapy strategies. This review comprehensively discusses the synergistic mechanisms by which natural killer and γδT cells cross the blood-brain barrier and eliminate pathogenic proteins. Moreover, the mechanisms by which these cells modulate neuroinflammation and eliminate autoreactive T cells in the central nervous system are elucidated. The multifaceted roles across various neurodegenerative conditions are explored and the potential for clinical translation is evaluated. This review aims to provide theoretical and practical guidance for the development of innovative immune cell-based therapies targeting neurodegenerative diseases by integrating current research advances and identifying existing challenges.
Zhifeng Wu, Xiao-Lin Chen, Tingting Gan et al.· Neuropharmacology and Therap...· 0 citations
Current evidence on advances in clinical research and immunotherapy across the major autoimmune CNS disease groups is synthesized, with a particular focus on trial designs, endpoints, and the evolution from observational cohorts to randomized controlled trials.
Autoimmune diseases (ADs) are a group of inflammatory disorders triggered by aberrant immune responses against autoantigens and the breakdown of immune tolerance. Current therapeutic strategies, such as glucocorticoids and immunosuppressants, exert largely non-specific immunomodulation and are frequently associated with substantial adverse effects upon long-term administration. As such, these approaches are often insufficient to re-establish immune homeostasis. In recent years, regulatory T cell (Treg)-based therapeutics have undergone rapid advancement, with continuously updated therapeutic modalities broadening the application boundary of immune tolerance intervention. This review comprehensively outlines the progress of Treg-based therapeutics, spanning from fundamental biological research to translational applications in autoimmune diseases. We describe the developmental characteristics, suppressive machinery, and heterogeneity of Tregs, and highlight the preclinical and clinical advancements of diverse Treg therapeutic modalities, including polyclonal and antigen-specific Tregs, TCR-engineered Tregs, and CAR-Tregs. Furthermore, we emphasize current optimization strategies for enhancing Treg stability, antigen specificity, and in vivo fitness within inflammatory microenvironments. Additionally, we objectively address the major translational bottlenecks of Treg therapy and provide future perspectives to facilitate the clinical implementation of Treg-based immunotherapies for autoimmune diseases.
Jingchang Li, Jia Pang, Peipei Wu et al.· Frontiers in Immunology· 0 citations
Autoimmune diseases remain a major cause of chronic morbidity despite substantial advances in targeted immunomodulatory therapies. In many autoantibody-mediated conditions, disease refractoriness and relapse are driven by long-lived plasma cells, which are largely resistant to conventional immunosuppression and upstream B cell-directed strategies. CD38, a surface molecule highly expressed on plasmablasts and plasma cells and functionally involved in immunometabolic regulation, has emerged as a promising therapeutic target to overcome this limitation. Clinical interest in anti-CD38 therapy has been catalyzed by experience in plasma cell dyscrasias, where anti-CD38 monoclonal antibodies induce rapid and profound depletion of antibody-secreting cells. Over recent years, accumulating reports and early-phase studies have explored the repurposing of CD38-directed therapies in severe, treatment-refractory autoimmune diseases. The most compelling evidence has emerged in lupus nephritis and immune thrombocytopenia, with additional proof-of-concept data in autoimmune cytopenias and plasma cell-driven renal disorders such as immunoglobulin light chain (AL) amyloidosis. These experiences suggest that targeting CD38 can lead to meaningful clinical and immunological improvement, often accompanied by rapid reductions in pathogenic autoantibody production. However, the current evidence base remains heterogeneous and largely derived from small cohorts, case series, and early-phase trials, and important questions remain regarding durability of response, optimal treatment strategies, and long-term safety, particularly with respect to hypogammaglobulinemia and infection risk. We summarize the biological rationale for CD38 targeting in autoimmunity and plasma cell-driven immune-mediated diseases, critically appraise the emerging clinical evidence across disease settings, and discuss key challenges and future directions for integrating plasma cell-directed therapies into immunological disease management.
Dario Roccatello, S. Sciascia, D. Rossi et al.· BioDrugs· 0 citations
Immune-mediated demyelinating diseases of the central nervous system, including multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD), are unified by inflammatory injury to myelin and axons but differ fundamentally in their immunopathological mechanisms. Adaptive immune cells, particularly B cells and T cells, are central drivers of disease, contributing through both antibody-dependent and antibody-independent mechanisms. In MS, B cells exacerbate pathology via antigen presentation, cytokine secretion, and organization of ectopic lymphoid structures, consistent with the efficacy of anti-CD20 therapies despite largely preserved circulating immunoglobulin levels. In NMOSD, B cells and plasma cell progeny play a direct pathogenic role through aquaporin-4–specific (AQP-4) antibodies, establishing a model of antibody-mediated astrocytopathy. MOGAD occupies an intermediate immunopathological niche, with pathogenic antibodies targeting myelin oligodendrocyte glycoprotein (MOG) coexisting with additional, incompletely defined immune mechanisms. Recent advances from single-cell profiling, high-resolution imaging, and experimental models suggest substantial heterogeneity in B-cell developmental states, tolerance checkpoints, and tissue residency, challenging uniform approaches to B-cell–directed therapy. This review synthesizes current understanding of B-cell biology across demyelinating diseases, highlighting mechanisms of pathogenicity, immune regulation, and tolerance failure, and discusses implications for precision immunomodulatory strategies.
Yawei Liu, Henrik Hasseldam· Frontiers in Immunology· 0 citations
Autoimmune diseases are heterogeneous disorders marked by immune dysregulation, loss of self-tolerance, autoantibody production, and chronic inflammation. Although immunosuppressants and biologics have improved disease control, incomplete remission, relapse after withdrawal, cumulative toxicity, and failure to restore immune homeostasis remain common. Chimeric antigen receptor T-cell (CAR-T) therapy offers a potential strategy for refractory autoimmune diseases by selectively eliminating pathogenic immune compartments and providing a theoretical pathway toward target-dependent immune remodeling and immune resetting. This review summarizes immunopathogenesis and therapeutic gaps in representative autoimmune diseases, compares CAR-T applications in malignancies and autoimmunity, and evaluates emerging response endpoints, target-selection strategies, and safety considerations in autoimmune settings. Early clinical evidence suggests rapid disease control, autoantibody reduction, and immunosuppression-free remission in selected B-cell- or autoantibody-driven diseases. However, reported remission duration and response proportions remain limited by small cohorts, short follow-up, and disease-specific heterogeneity. The central unresolved question is whether durable remission can be achieved without persistent immune deficiency. Cytokine release syndrome, infection, hypogammaglobulinemia, relapse, impaired vaccine responses, T-cell fitness, manufacturing barriers, and cost remain key challenges. Future studies should define optimal targets, standardized remission endpoints, durable remission biomarkers, long-term safety, and the role of T-cell engagers.
Mengting Zhang, Lianfeng Zhao, Tianyu Chen et al.· International Immunopharmaco...· 0 citations
