Immune reconstitution and tolerance-inducing therapies as promising therapeutic approaches in multiple sclerosis

Interferon-γ-induced tolerogenic dendritic cells ameliorate autoimmune neuroinflammation and suppress T-cell responses in multiple sclerosis

Background Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system characterized by immune-mediated demyelination and neuroinflammation resulting from the breakdown of self-tolerance. Tolerogenic dendritic cells (tolDC) have emerged as a promising therapeutic strategy to restore antigen-specific immune tolerance; however, generating stable tolDC under inflammatory conditions remains challenging. Although interferon (IFN)-γ is traditionally regarded as a pro-inflammatory cytokine, accumulating evidence indicates that it can also exert protective and immunoregulatory functions in specific cellular and disease contexts. Here, we investigated whether low-dose IFN-γ directly programs dendritic cells (DC) toward a stable tolerogenic phenotype with therapeutic relevance for MS. Methods Murine bone marrow-derived DC were differentiated in the presence of IFN-γ and evaluated for phenotype, cytokine production, and T-cell modulatory capacity. Therapeutic efficacy was assessed in experimental autoimmune encephalomyelitis (EAE). Translational relevance was examined using monocyte-derived DC from treatment-naïve MS patients and healthy donors (HD). Results IFN-γ-conditioned DC displayed reduced expression of co-stimulatory molecules and MHC-II, increased PD-L1 expression, and diminished pro-inflammatory cytokine production. Functionally, these cells suppressed myelin antigen-driven CD4+ T-cell proliferation and activation while promoting FoxP3+ regulatory T-cell differentiation. Adoptive transfer of myelin-derived peptide-loaded IFN-γ-conditioned DC significantly ameliorated established EAE and induced sustained clinical improvement, even after inflammatory challenge, demonstrating phenotypic and functional stability. In human studies, IFN-γ induced comparable tolerogenic phenotypes in DC from MS patients and HD; however, only MS-derived IFN-γ-conditioned DC effectively suppressed CD4+ and CD8+ T-cell responses. Residual CD80 expression correlated with T1 lesion burden. Conclusion Collectively, these findings uncover a previously underappreciated context-dependent immunoregulatory role of IFN-γ in DC biology and immune tolerance. Furthermore, IFN-γ-induced DC emerge as a promising therapeutic strategy to restore immune tolerance in MS.

CAR-T cell therapy for autoimmune diseases: from immune suppression to immune resetting.

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.

Immune Profiling after treatment with an Anti-CD19 Chimeric Antigen Receptor T Cell Therapy in Treatment-Refractory Progressive Multiple Sclerosis

Regulatory T cells in autoimmune diseases: biological mechanisms, clinical translation, and translational challenges

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.

Restoring Immune Tolerance in Rheumatic Disease

Autoimmune rheumatic diseases are still treated predominantly through broad or targeted suppression of inflammatory pathways, yet durable restoration of self-tolerance remains a central unmet therapeutic goal. This narrative review examines restoration of immune tolerance as an emerging translational framework in rheumatology, integrating checkpoint agonism, antigen-specific immunotherapy, regulatory cell-based strategies, and immune-reset approaches within a unified therapeutic perspective. Rather than treating these strategies as isolated innovations, the review evaluates how each attempts to restore, reinforce, or reconfigure immune restraint at distinct biological levels, spanning inhibitory receptor signaling, antigen-selective non-responsiveness, dominant regulatory control, and deeper reconfiguration of pathogenic immune architecture. Their relevance is considered across rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s disease, and systemic sclerosis, with emphasis on mechanistic rationale, translational maturity, disease-specific therapeutic fit, biomarkers, therapeutic timing, and major barriers to clinical implementation. Collectively, these approaches suggest a shift in rheumatology from repeated control of inflammatory consequences toward more selective and potentially durable recalibration of autoreactive immunity. Although the field remains biologically and clinically immature, restoration of immune tolerance is emerging as an important organizing principle for the development of more precise and potentially disease-modifying therapies in autoimmune rheumatic disease.

Activating Inflammation Resolution Programs Improves Immunosuppressive Therapy and Prevents Toxicity in Autoimmune Bone Marrow Failure 2267406

Chronic inflammatory and autoimmune diseases are among the leading causes of morbidity and mortality worldwide, yet immunosuppressive therapy (IST) often fails to achieve durable remission and induces toxicity. Severe aplastic anemia (SAA) is a lethal bone marrow failure driven by autoreactive T cells. Patients treated with cyclosporine A (CsA) exhibit sustained inflammation, frequent relapse, and secondary complications. Specialized pro-resolving lipid mediators, such as Resolvin E1 (RvE1), promote resolution of inflammation and restore tissue homeostasis. Using a preclinical murine model, we examined how immunosuppressive and resolution-targeted therapies shape disease outcomes, and whether their combination improves recovery. SAA was induced in sub-lethally irradiated mice via MHC-mismatched splenocyte transfer. Mice were treated with 10 mg/kg CsA and/or 0.0125 mg/kg RvE1 after disease onset. Long-term recovery was assessed 30-90 days post-withdrawal. scRNAseq, ligand-receptor analyses, receptor knockouts, and reciprocal chimeras were used to determine cell-specific mechanisms. CsA improved survival (75%), but caused persistent T cell activation, Th17 expansion, granulocytic skewing, and renal toxicity. Conversely, RvE1 (50% survival) normalized T cells and restored hematopoietic output without organ injury. Combination therapy achieved 100% survival, restored immune profiles, and prevented systemic toxicity. ChemR23 on immune cells was required for RvE1 protection. scRNAseq revealed CsA-induced transcriptional dysregulation, inflammatory cell-cell crosstalk, and aberrant histone gene expression, consistent with durable immune remodeling. RvE1 co-therapy normalized these transcriptional networks. CsA impairs inflammation resolution and long-term organ function. Co-treatment with RvE1 restores immune and hematopoietic homeostasis, supporting integration of pro-resolving therapy with IST for safer, durable remission for autoimmune and inflammatory diseases. CDMRP Bone Marrow Failure Research Program-IDA (BM190079 and BM220031) and NHLBI R01HL159411 Therapeutic Approaches to Autoimmunity (THER)