Intravenous Methylprednisolone Enhances CD46-Mediated Tr1 Cells in Lupus Nephritis Remission

Treatment with intravenous methylprednisolone (ivMP) pulse therapy in patients with active lupus nephritis (LN) has been shown to induce remission by targeting CD46-mediated type 1 regulatory (Tr1) T cells, thus inhibiting inflammatory activity and increasing interleukin (IL)-10 production, according to study results published in Pediatric Research.  

In a prospective cohort study conducted in Taiwan, researchers sought to elucidate the molecular changes in Tr1 cells via CD46 cytoplasmic tails Cyt1 and Cyt2 in patients with LN who received ivMP therapy.

Patients with active class 3 or 4 LN and prominent proteinuria, along with a healthy control participants, were enrolled in the study. Clinical characteristics and peripheral blood mononuclear cells were collected prior to and 3 days following the administration of ivMP. Kidney specimens were obtained from 5 patients with LN and 5 patients with minimal-change nephrotic syndrome.

A total of 40 patients (32 women) aged between 10 and 18 years were included in the study; 30 healthy control participants were also included. Eligible participants met the 2019 European Alliance of Associations for Rheumatology/american College of Rheumatology (EULAR/ACR) criteria, with the onset of LN prior to age 10 years and nephrotic-range proteinuria (ie, >40 mg/m²/hour or >1 g/day/m²).

Patients received ivMP pulse therapy (15 mg/kg/day at a maximum of 1/g/day for 3 days), which was followed by oral prednisolone 1 mg/kg of body weight. Clinical responses and disease activity were based on the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score and SLEDAI-2k score, validated for use in children. The SLEDAI and SLEDAI-2k scores were calculated both before and 14 days after ivMP therapy in patients with LN.

Results of the study showed that all patients with LN who received treatment with ivMP therapy had significantly better SLEDAI/SLEDAI-2k scores and complement levels, as well as decreased daily protein levels (P <.05). Microscopic analysis of kidney tissue showed that the number of CD4+CD46+ T cells was lower in patients with class 3 or 4 active LN than in control participants with minimal disease changes (n=5 in both groups). The proportion of blood-circulating CD4+CD46+ cells decreased significantly prior to treatment with ivMP in patients with active LN compared with healthy control participants (P <.05).

Treatment with ivMP enhanced LN remission; restored production of IL-10; increased the CD46-cyt1/cyt2 ratio, AKT, and cAMP-responsive element-binding protein phosphorylation; and induced migration with expression of chemokine receptor molecules CCR4, CCR6, and CCR7 of CD3/CD46-activated Tr1 cells.

The researchers concluded, “Enhancing the expression of functional CD4+ CD46+ Tr1 cells may be a useful therapeutic approach for LN.” They added that though the expression levels of CD46 isoforms Cyt1 and Cyt2 in CD4+CD46+ Tr1 cells differed in patients with active LN, these levels can be corrected using corticosteroid treatment.

Reference

Tsai YG, Chien JW, Chiu YM, et al. Lupus nephritis with corticosteroid responsiveness: molecular changes of CD46-mediated type 1 regulatory T cells. Pediatr Res.
Published online December 24, 2021. doi:10.1038/s41390-021-01882-z