Regulatory T cells (Tregs) are essential for preventing autoimmunity. They depend upon interleukin-2 (IL-2) for optimal function and due to high expression of the CD25 subunit of the IL-2 receptor, are 10-fold more sensitive to IL-2 than effector T cells (Teffs). Consequently low-dose IL-2 can be used to preferentially expand Tregs, a therapeutic strategy which has shown promise in a number of autoimmune and inflammatory conditions - including graft-versus-host disease and lupus, where IL-2 driven expansion correlates with improvements in some clinical markers of disease activity. Autoimmunity is a frequent delayed complication of treatment with the lymphocyte-depleting drug alemtuzumab in relapsing-remitting multiple sclerosis (RRMS). Here, using in vitro assays, a pre-clinical mouse model, and an experimental medicine study, we investigated whether low-dose IL-2 could selectively expand Tregs in alemtuzumab-treated RRMS patients. Six months after alemtuzumab treatment, the frequency of patient-derived naïve CD4+ Teffs expressing high-affinity IL-2 receptors increased from 30.11+/-5.09% to 72.88 +/-5.57%, and the density of receptors per cell increased, rendering them six times more sensitive to IL-2 in vitro, at concentrations that typically favour Tregs. Using a human CD52-expressing transgenic mouse model of alemtuzumab treatment, we found that IL-2 was still able to preferentially expand Tregs, but only when administered at a later time point, corresponding to more than 6 months post-treatment in patients. Guided by these findings, we evaluated low-dose IL-2 for Treg expansion in a prospective open-label mechanistic study of RRMS patients who had received alemtuzumab more than 6 months previously. IL-2, at a dose and frequency similar to that previously shown to expand Tregs in autoimmune diabetes (0.3 x 106 IU/m2 twice a week), was well tolerated and safe, but unexpectedly failed to expand Tregs. We discuss the potential reasons underlying this lack of response, ruling out sIL2RA-related neutralisation, and instead considering ceiling effects on Treg proliferation, Treg exhaustion and intrinsic Treg dysfunction in MS as possible contributors. Together, our findings demonstrate that low-dose IL-2 alone is not an effective strategy for promoting Treg expansion post-alemtuzumab, and is therefore not a viable approach by itself for preventing post-treatment autoimmune complications.

Multiple sclerosis (MS) is an incurable autoimmune disease marked by heterogeneous progression and a lack of reliable biomarkers, complicating prognosis and individualized care. This study introduces a novel trajectory-based statistical approach designed to identify patterns in patient histories within MS populations.

Monitoring donor-recipient chimerism following hematopoietic stem cell transplantation (HSCT) is essential for assessing engraftment success, early identification of graft failure and relapse, and guiding immunomodulating interventions. Recent advancements in molecular technologies, particularly digital droplet PCR (ddPCR) and next-generation sequencing (NGS), have markedly improved the sensitivity and precision of chimerism detection, allowing the identification of recipient cells at levels below 0.1%. These advancements enable more accurate and dynamic monitoring compared to traditional methods, which are limited in terms of sensitivity and specificity. In pediatric patients, the interpretation of chimerism results is complicated by unique factors, including thymic recovery, exposure to serotherapy agents such as ATG or alemtuzumab, and constraints related to small blood volume. These factors affect the kinetics of donor cell engraftment and the dynamics of mixed chimerism in different hematopoietic lineages. This review presents the current understanding of the biological basis of chimerism, compares traditional and advanced detection methodologies, and details lineage-specific chimerism kinetics in children. It also provides practical guidance for interpreting serial chimerism data to inform timely and preemptive clinical interventions. Owing to the limited pediatric-specific data, adult findings were integrated where appropriate, underscoring the urgent need for pediatric validation, assay harmonization, and standardized implementation protocols to optimize transplant outcomes in children.

Regimens combining calcineurin inhibitors with methotrexate or mycophenolate have been the backbone for graft-versus-host disease (GVHD) prophylaxis. Early studies highlighted a delicate dose-response balance. The inclusion criteria comprised randomized clinical trials of patients with hematologic malignancies undergoing sibling- or unrelated-donor transplants, adding a pharmacologic immunosuppressive agent to standard GVHD prophylaxis. This meta-analysis examined the impact of intensified GVHD prophylaxis strategies on relapse risk and included 16 randomized controlled trials among 26 eligible studies, with 1344 patients in the intervention group and 1260 in the control group. Few mismatched donors or children were included. The studies evaluated additions such as anti-thymocyte/lymphocyte globulin (ATG, ATLG), posttransplant cyclophosphamide (PTCy), sirolimus, abatacept, and alemtuzumab. Results showed no significant effect on relapse risk or progression-free survival overall, with HR = 1.12 (p = 0.16) for relapse and HR = 0.92 (p = 0.16) for progression-free survival. Sensitivity analysis identified one outlier study using alemtuzumab that reported higher relapse and indicated a modest increased risk with ATLG. The findings suggest that adding agents like ATG, sirolimus, abatacept, or PTCy does not increase relapse risk in matched sibling or unrelated transplants. While caution is advised with ATLG and alemtuzumab, the overall evidence supports the safety of modern prophylactic strategies, potentially improving transplant outcomes without compromising relapse risk.

Multiple sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system and the leading cause of non-traumatic disability in young adults. In Poland, MS represents a significant neurological and public health challenge. Although treatment principles for MS are largely based on international guidelines, their implementation varies across countries due to differences in healthcare organization and access to therapies. Current treatment algorithms in Poland include both platform agents, such as interferon beta, glatiramer acetate, fumarates, and teriflunomide, as well as high-efficacy therapies, including monoclonal antibodies (e.g., ocrelizumab, ofatumumab, ublituximab, alemtuzumab, natalizumab) and oral agents (e.g., fingolimod, cladribine, ozanimod, ponesimod). Therapeutic decisions typically follow either an escalation strategy or an early intensive approach, depending on disease activity, prognostic factors, and reimbursement criteria. In addition, treatment priorities vary depending on the disease phenotype: in relapsing-remitting MS (RRMS), the aim is to reduce relapse rates and delay disability progression, whereas in progressive forms, such as primary progressive MS (PPMS) and secondary progressive MS (SPMS), the goal is to slow disease progression and preserve daily functioning. With an expanding range of therapeutic options, European clinical experience in the management of different MS phenotypes, particularly RRMS, reflects an individualized treatment approach. In routine practice, therapeutic decisions are primarily guided by disease activity, with high-efficacy therapies considered early in selected patients; similar principles inform real-world clinical practice in Poland. This review offers practical guidance for clinicians and provides therapeutic algorithms designed to support the management of patients with MS. The future development of MS management in Poland will depend on expanding access to innovative therapies, advancing biomarker research, and implementing the latest diagnostic criteria for MS. European treatment recommendations will continue to provide an important framework supporting high-quality care and early intervention for people with MS.

Alemtuzumab is a humanized monoclonal antibody targeting CD52, a glycosylphosphatidylinositol-anchored surface antigen broadly expressed on lymphocytes and other immune cells. Although currently approved for multiple sclerosis and used in selected transplantation settings, alemtuzumab was among the earliest lymphocyte-depleting biologics explored across a wide spectrum of autoimmune rheumatic diseases. With renewed interest in deep immune-depleting strategies, including CAR-T cells and bispecific T-cell engagers, revisiting the immunobiology and clinical experience of alemtuzumab is timely. This review summarizes current knowledge of CD52 structure, expression, and immunological function, highlighting its dual role as both a co-stimulatory and immunoregulatory molecule. We examine the mechanisms underlying alemtuzumab-induced lymphocyte depletion, subsequent immune reconstitution, and the paradoxical development of secondary autoimmunity. Clinical evidence for alemtuzumab use in rheumatic diseases, including rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, vasculitis, idiopathic inflammatory myopathies, ocular inflammatory disease, and Behçet's syndrome, is reviewed, with emphasis on efficacy, durability of response, and safety outcomes. Across multiple refractory disease settings, alemtuzumab has demonstrated the capacity to induce rapid clinical improvement and, in some cases, prolonged drug-free remission. However, treatment is limited by risks of infection, delayed immune reconstitution, and immune dysregulation. We conclude that alemtuzumab remains a potent immunomodulatory option in selected refractory rheumatic diseases, provided that careful patient selection, cautious monitoring, and long-term follow-up are implemented.

HLA-identical sibling donor hematopoietic cell transplant (HCT) is an established curative therapy for sickle cell disease (SCD). While myeloablative HCT conditioning achieves a high event-free survival (EFS) in children, it carries substantial toxicity, including risks of graft-versus-host disease (GVHD), transplant-related mortality, and infertility. Nonmyeloablative conditioning with alemtuzumab, 300 cGy total body irradiation, and sirolimus has demonstrated tolerability as a curative approach in adults with SCD. We conducted a multicenter, prospective clinical trial to evaluate this regimen in children and adolescents with SCD. Thirty-eight patients (age 2.9-21.9 years, median 13.5) underwent HCT. All achieved initial engraftment; however, 7 patients (18.4%) experienced secondary graft failure between day +39 and day +391 with autologous hematologic reconstitution. One additional patient received an unconditioned second HCT. At 2 years post-HCT, overall survival was 100% and EFS was 78.9%. Among engrafted patients, 2-year median donor myeloid chimerism was 95% and T-cell chimerism was 75%. No patients developed acute or chronic GVHD. The median number of platelet transfusions received was 0 (interquartile range 0-3). Patient-reported health-related quality of life remained stable early post-HCT and significantly improved at 1 year. After year 2, three additional patients received a reduced intensity second HCT to prevent secondary graft failure. While regimen modifications are needed to reduce graft failure risk, this nonmyeloablative approach offers a relatively low-toxicity curative option for children with SCD who have an HLA-identical sibling donor. This trial was registered at www.clinicaltrials.gov as #NCT03587272.