- This study investigated if low-dose interleukin-2 could expand regulatory T cells in alemtuzumab-treated relapsing-remitting multiple sclerosis patients.
- Researchers used in vitro assays, a preclinical mouse model, and a prospective open-label mechanistic study in alemtuzumab-treated patients.
- Low-dose IL-2 (0.3 x 106 IU/m2 twice weekly) unexpectedly failed to expand Tregs in patients.
- The authors concluded that low-dose IL-2 alone is not an effective strategy for promoting Treg expansion post-alemtuzumab.
- This finding suggests low-dose IL-2 by itself is not a viable approach for preventing post-alemtuzumab autoimmune complications.
Navigating Autoimmunity After Alemtuzumab in Multiple Sclerosis
Alemtuzumab is a potent lymphocyte-depleting monoclonal antibody used as a high-efficacy therapy for relapsing-remitting multiple sclerosis (RRMS) [1, 2]. While effective, its use is complicated by the delayed onset of secondary autoimmune diseases, which can affect up to 47.92% of patients [3, 4]. These conditions, most often autoimmune thyroid disease or immune thrombocytopenia, typically emerge months to years after treatment, creating a substantial monitoring burden [5, 6, 7, 8]. This has prompted a search for strategies to restore immune tolerance in the post-alemtuzumab setting. Because regulatory T cells (Tregs) are essential for preventing autoimmunity, a recent study investigated whether their numbers could be augmented to mitigate this risk [9].
The Promise of IL-2 and Treg Modulation
The rationale for using interleukin-2 (IL-2) to prevent autoimmunity is rooted in basic T-cell biology. Regulatory T cells (Tregs), which suppress autoimmune responses, depend on IL-2 for their survival and function. Critically, Tregs express high levels of the CD25 subunit of the IL-2 receptor, making them 10-fold more sensitive to IL-2 than the effector T cells (Teffs) that can drive autoimmune pathology. This differential sensitivity allows low doses of IL-2 to preferentially expand the Treg population without significantly activating Teffs. This strategy has been explored in other conditions, such as graft-versus-host disease and lupus, where IL-2-driven Treg expansion correlated with improvements in clinical disease markers. Based on this precedent, researchers hypothesized that low-dose IL-2 could be a viable strategy to bolster the Treg population in RRMS patients after alemtuzumab-induced lymphodepletion.
Unexpected Immune Shifts Post-Alemtuzumab
The immune environment following alemtuzumab treatment, however, presents a unique challenge to the low-dose interleukin-2 (IL-2) strategy. An investigation of patient-derived immune cells revealed a significant shift in the T-cell landscape six months after therapy. In vitro assays showed that the frequency of naïve CD4+ Teffs expressing high-affinity IL-2 receptors increased dramatically, from a baseline of 30.11+/-5.09% to 72.88 +/-5.57%. Furthermore, the density of these receptors on each cell also increased. The combined effect of these changes rendered the pro-inflammatory Teffs six times more sensitive to IL-2 in vitro. This finding is clinically significant because it erodes the therapeutic window for low-dose IL-2; at concentrations intended to selectively stimulate Tregs, the newly sensitive Teffs would also become activated, potentially counteracting the intended therapeutic effect.
Preclinical Insights and Clinical Trial Design
To further explore this complex interaction, the researchers used a preclinical model involving transgenic mice that express human CD52, the target of alemtuzumab. In this model, IL-2 administration was still capable of preferentially expanding regulatory T cells (Tregs), but with a critical caveat: the effect was observed only when IL-2 was given at a later time point, corresponding to more than 6 months after alemtuzumab treatment in humans. This preclinical observation directly informed the design of a subsequent prospective, open-label mechanistic study in humans. The trial enrolled RRMS patients who had received alemtuzumab more than six months prior, aligning with the optimal therapeutic window identified in the mouse model. Patients received IL-2 at a dose and frequency previously shown to be effective in autoimmune diabetes: 0.3 x 10^6 IU/m^2 administered twice a week.
Clinical Outcome: No Treg Expansion
Despite the careful trial design informed by preclinical data, the clinical study did not achieve its primary objective. The low-dose interleukin-2 (IL-2) regimen was well tolerated and safe, but it unexpectedly failed to expand the regulatory T cell (Treg) population in alemtuzumab-treated RRMS patients. In seeking an explanation, the authors ruled out neutralization by soluble IL-2 receptor alpha. Instead, they proposed several non-mutually exclusive biological possibilities. These include a potential ceiling effect, where post-alemtuzumab Tregs are already proliferating at a maximal rate; Treg exhaustion, a state of functional unresponsiveness to stimulation; or an intrinsic Treg dysfunction specific to multiple sclerosis that impairs the cells' ability to respond to IL-2. The study's conclusion is direct: low-dose IL-2 as a monotherapy is not an effective strategy for promoting Treg expansion after alemtuzumab treatment and is therefore not a viable approach by itself for preventing secondary autoimmune complications in this patient population.
References
1. Samjoo IA, Drudge C, Walsh S, et al. Comparative efficacy of therapies for relapsing multiple sclerosis: a systematic review and network meta-analysis.. Journal of comparative effectiveness research. 2023. doi:10.57264/cer-2023-0016
2. Rae‐Grant A, Day GS, Marrie RA, et al. Comprehensive systematic review summary: Disease-modifying therapies for adults with multiple sclerosis. Neurology. 2018. doi:10.1212/wnl.0000000000005345
3. Yang J, Sun Y, Zhou P, et al. Risk of secondary autoimmune diseases with alemtuzumab treatment for multiple sclerosis: a systematic review and meta-analysis.. Frontiers in Immunology. 2024. doi:10.37766/inplasy2024.4.0048
4. Jimenez-Sanchez S, Maksoud R, Eaton-Fitch N, Marshall-Gradisnik S, Broadley SA. The role of alemtuzumab in the development of secondary autoimmunity in multiple Sclerosis: a systematic review.. Journal of neuroinflammation. 2024. doi:10.1186/s12974-024-03263-9
5. Patera B, Zaffaroni A, Louka S, Gallo D, Piantanida E, Tanda M. Graves’ orbitopathy following Alemtuzumab treatment for multiple sclerosis: a systematic review and real-world insights. Thyroid Research. 2025. doi:10.1186/s13044-025-00276-1
6. Sun Y, Liu Z, Yang J, et al. Risk of secondary immune thrombocytopenia following alemtuzumab treatment for multiple sclerosis: a systematic review and meta-analysis.. Frontiers in neurology. 2024. doi:10.3389/fneur.2024.1375615
7. Scappaticcio L, Castellana M, Virili C, et al. Alemtuzumab-induced thyroid events in multiple sclerosis: a systematic review and meta-analysis.. Journal of endocrinological investigation. 2020. doi:10.1007/s40618-019-01105-7
8. Makkawi S, Abulaban A, Malik YA, et al. Administration and Monitoring Burden of High-Efficacy Disease-Modifying Therapies for Multiple Sclerosis: A Delphi Consensus of Clinical Experts from Saudi Arabia. Neurological Therapeutics. 2025. doi:10.1007/s40120-024-00707-5
9. Georgieva ZG, Howlett SK, Rainbow DB, et al. Low-dose IL-2 fails to expand Tregs after alemtuzumab: insight into impaired immune tolerance in multiple sclerosis.. Brain : a journal of neurology. 2026. doi:10.1093/brain/awag171