Breakthroughs That May Redefine the Field – Hesperion insights

Autoimmunity 2023–2025: Breakthroughs That May Redefine the Field

Prepared by the Hesperion Research Team Autoimmunology is entering the era of precision therapies. Over the past two years, we have seen results that sounded like science fiction just a decade ago: CAR-T cells capable of “resetting” the immune system in autoimmune disease, inverse vaccines that teach the body to tolerate self-antigens, and single-cell atlases of the inflamed joint that break rheumatoid arthritis down into mechanistic endotypes. Here we summarize the most important directions, conclusions, and practical consequences.

1) CAR-T for Autoimmunity: From Oncology to Lupus, Myositis, and Scleroderma

The most widely discussed breakthrough is the use of CD19 CAR-T cells in severe B-cell–driven autoimmune conditions. In a multicenter case series published in 2024 in the NEJM, the therapy was feasible, safe, and induced deep remissions that allowed patients to discontinue immunosuppression. This is not yet therapy for the mainstream – controlled trials are ongoing – but the direction is clear: an “immune reset” rather than lifelong suppression.

• Who may benefit? B-cell–driven diseases (severe lupus, some inflammatory myopathies, systemic sclerosis with strong humoral activity).
• Risks and open questions: long-term safety (rare T-cell malignancies in oncology), cost, standardization of care after infusion.
• What it changes today: establishes referral pathways to clinical trials and specialized centers for refractory patients.

2) “Inverse Vaccines”: Antigen-Specific Tolerance Instead of Global Suppression

In parallel, a wave of therapies is emerging that reprogram immune responses against specific autoantigens. Studies from 2023–2025 demonstrated that nanoparticles mimicking apoptotic cells or mRNA/LNP platforms targeted to the liver and spleen can induce tolerance instead of inflammation. The most advanced is celiac disease: KAN-101 (Anokion), which delivers gluten peptides to the liver, showed favorable safety and early efficacy signals, with phase 2 now underway. For T1D and MS, preclinical and early clinical data suggest tolerogenic mRNA can suppress autoreactivity without global immune compromise.

• Why this matters: It represents a paradigm shift – antigen-targeted therapy that addresses the cause, with fewer infections and side effects than broad immunosuppression.
• Where we are: Celiac disease – phase 2 trials; MS and T1D – early stage or translational studies.
• Next steps: Standardizing biomarkers of functional tolerance and proving durability after therapy cessation.

3) Single-Cell Atlases and Endotypes: RA Is Not One Disease

Atlas projects are reshaping our view of autoimmunity. In 2023–2024, AMP RA/SLE consortia published single-cell maps of synovial tissue showing at least six mechanistically distinct inflammatory states, driven by different immune and stromal programs. This explains why two patients with “the same” diagnosis can respond completely differently to therapy – and it opens the door to endotype-driven treatment. New data also link pathogenic fibroblasts with aberrant innervation and pain in RA – a concrete therapeutic target.

• Clinical implication: Synovial biopsy plus transcriptomic profiling could become part of treatment stratification (matching the drug to the endotype).

4) Interferon Signature (IFN-I): From Phenomenon to Companion Diagnostic

In lupus, the IFN-I signature is moving from research to routine use as a biomarker for stratification and guiding anti-IFN therapy. Recent studies (2024–2025) standardized measurement and showed why some patients with a high signature respond to anifrolumab while others do not – heterogeneity in IFN pathways and overlapping inflammatory drivers.

• In practice: IFN-signature testing (gene panels) may soon become routine as a therapeutic compass and clinical trial stratifier.

5) EBV and MS: Vaccines and Targeted Immunotherapy

After establishing a causal link between EBV and MS, 2024–2025 brought EBV vaccine programs (e.g., mRNA-1195 in trials) and EBV-specific T-cell therapies. Not all trials have been positive, but the concept of preventing EBV infection or reactivation as a way to modify MS risk and progression is gaining traction.

6) Microbiome: From Association to First Interventions

In RA, converging data link gut dysbiosis with Th17-driven inflammation and more aggressive disease. Randomized trials of FMT (fecal microbiota transplant) and precise microbiome interventions are underway. While younger as a field compared to CAR-T or vaccines, it is moving from correlation to early therapeutic attempts.

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Practical Map for Patients and Clinicians

• Refractory B-cell autoimmunity: refer to CAR-T clinical trials where available.
• Celiac and well-defined autoantigen diseases: watch for tolerogenic vaccine trials (e.g., KAN-101) – potential disease modification.
• RA: consider endotype-driven care; synovial biopsy and molecular profiling where feasible.
• SLE: integrate IFN-signature testing into decision-making for anti-IFN therapies.
• MS: monitor EBV vaccine and immunotherapy trials – especially for early/preventive interventions.
• Microbiome: participation in clinical protocols; outside of trials, prioritize lifestyle, diet, and antibiotic stewardship.

12–36 Month Horizon

• Randomized CAR-T trials in autoimmunity with long-term outcomes (durability, safety, HTA assessment).
• Phase 2 tolerogenic vaccine results (celiac disease) and first human data in T1D/MS.
• Endotype validation in RA for routine treatment selection.
• IFN-signature standardization as a companion diagnostic in SLE.

Hesperion’s Perspective

• We are building an endotype atlas informed by literature and single-cell data, with RA as a model case.
• We embed biomarkers (IFN-signature, synovial panels) into our stratification protocols.
• We monitor CAR-T, inverse vaccines, and EBV-targeted approaches to provide guidance on trial eligibility.

Conclusion

The last two years have seen a shift from “firefighting” autoimmunity with blunt immunosuppression to precise immune modulation: reset (CAR-T), tolerance (inverse vaccines), endotype-driven care (single-cell atlases), and smarter biomarkers (IFN-signature). If these trends continue, the standard of care for many autoimmune diseases may look very different within the next 3–5 years.