Low-dose IL-2 therapy limits the reduction in absolute numbers of circulating regulatory T cells in rheumatoid arthritis

Abstract

Background: Circulating regulatory T cells (Tregs) are responsible for mediating immune tolerance and maintaining immunological homeostasis. Decreases in Tregs may be involved in the onset of rheumatoid arthritis (RA). Low-dose interleukin-2 (IL-2) has been considered for the treatment of inflammatory diseases mediated by T cells. This study focused on the status of circulating CD4+T subsets and the clinical feasibility of IL-2 therapies in patients with RA. Methods: The subjects included 888 patients with RA and 100 healthy controls (HCs); 233 RA patients received IL-2 treatment with 0.5 million international units (MIU)/day from days 1 through 5. The demographic features, disease activity, and levels of CD4+T cells measured by modified flow cytometry were collected in all RA patients before and after treatment. Results: RA patients had lower absolute Treg counts (but not Th17) compared with HCs, which was associated with disease activity; previously treated RA patients had the fewest circulating Tregs ( p < 0.05). Patients treated with low-dose IL-2 had a three-fold increase in absolute anti-inflammatory Treg counts, as well as a two-fold increase in the other CD4+T subsets. Moreover, post-treatment levels of markers of disease activity in RA patients treated with IL-2 were significantly lower than the baseline values ( p < 0.001), with no apparent side effects. Conclusion: Decreased absolute counts of circulating CD4+T lymphocyte subsets were observed in patients with RA. Circulating Tregs, which mediate immune tolerance, may be involved in the pathogenesis and progression of RA; however, this was ameliorated by low-dose IL-2, without obvious side effects. Plain language summary Low-dose IL-2 treatment for rheumatoid arthritis • Circulating Tregs may be involved in the pathogenesis and progression of RA. • The absolute count of Tregs was significantly correlated with disease activity measures. • Low-dose IL-2 was able to effectively expade Tregs and help for RA patients’ symptoms remission without evaluated side effects.

Characteristics of the Gut Microbiome and Its Relationship With Peripheral CD4+ T Cell Subpopulations and Cytokines in Rheumatoid Arthritis

“…All patients met the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for RA (Lee and Kim, 2017). Exclusion criteria were subjects who had another autoimmune-related or gastrointestinal tract or inflammatory bowel disease, take any probiotics or antibiotics within 1 month, serious infection, or a malignant tumor within the previous 6 months (Zhang et al, 2021). Each participant signed the consent form.…”

Low-Dose Interleukin-2 Altered Gut Microbiota and Ameliorated Collagen-Induced Arthritis

“…Based on the dose conversion between experimental animals and humans, two doses of IL-2 were used in this study. 1 , 11 , 20 , 31–33 There is currently no unified standard for the therapeutic dose of methotrexate in CIA model mice; thus, we referred to the literature and considered the dose of methotrexate administered to patients in our department (7.5–10 mg once weekly). Accordingly, the dose of methotrexate administered to mice in the experiment was converted from the dose of methotrexate administered to experimental animals and humans.…”

“…Rheumatoid arthritis (RA), a chronic inflammatory autoimmune disease that affects approximately 1% of the population worldwide, is characterized by synovial inflammation, and cartilage and bone destruction. 1–3 At present, immunosuppression is the main treatment strategy, but has some disadvantages including risk of infections and malignant tumors, difficulties in long-term disease suppression, and serious side effects. 4–7 Therefore, rheumatism research has focused on new treatment strategies.…”

Low-dose IL-2 improved clinical symptoms by restoring reduced regulatory T cells in patients with refractory rheumatoid arthritis: A randomized controlled trial

“…Treg cells are a distinct set of T cells responsible for suppressing autoreactive deleterious activities of effector T cells ( 15 ). Our previous study reported that reduced circulating Tregs (CD4 + CD25 + Foxp3 + Treg) might be involved in the pathogenesis and progression of RA ( 16 ). Although several studies ( 17 ) evaluated the proportion of Tregs in active RA and remission RA patients, the definition of Treg cells was different between these works.…”

“…However, high-dose IL-2 administration has been confirmed to enhance immune responses by activating effector T cells against cancer ( 19 , 20 ), while low-dose IL-2 was evidenced to mainly stimulate Treg cell survival and expansion and thereby control autoimmunity and inflammation. Low-dose IL-2 at 0.5 million IU was widely used in the treatment of several autoimmune diseases, such as systemic lupus erythematosus ( 20 , 21 ), psoriatic arthritis ( 22 ), and RA ( 16 ), but not refractory RA. However, due to the lack of evidence of decreased Treg cells in patients with refractory RA, the immune regulation therapy of IL-2 in these patients has not been examined.…”