IL-2/anti-IL-2 complexes ameliorate lupus nephritis by expansion of CD4+CD25+Foxp3+ regulatory T cells

Adoptive transfer of regulatory T cells (Tregs) can delay disease progression and reduce mortality in lupus-prone mice. Here, we tested whether complex (IL-2C) consisting of IL-2 and anti -IL-2 monoclonal antibody (JES6-1) ameliorates lupus nephritis by expanding Tregs as an alternative to problematic Treg infusion therapy. IL-2C treatment of NZB/W Fl mice induced an effective and sustained expansion of CD4(+)CD25(+)Foxp3(+) Tregs in both the kidneys and spleen along with decreased renal infiltration of T cells, B cells, and innate immune cells. Compared with controls, mice treated with IL-2C showed reduced proteinuria and fewer acute and chronic renal pathological lesions with improved renal function and survival. IL-2C significantly attenuated glomerular and tubular injury, vasculitis scores, and renal deposition of IgG and C3. Disease activity markers, such as high levels of anti-dsDNA antibodies and immunoglobulin levels, and low levels of complement were improved in sera of IL-2C-treated mice. IL-2C treatment decreased renal expression of TNF-alpha and IL-6, and the frequencies of IFN-gamma(+)CD4(+) and IL-17A(+)CD4(+) T cells in both the kidneys and spleen. Depletion of Tregs by anti-CD25 antibodies abrogated the beneficial effects of IL-2C. When compared with combination therapy of steroid and mycophenolate mofetil, IL-2C treatment showed similar or better outcomes. Thus, IL-2C protected lupus-prone mice against lupus nephritis by expanding Tregs. Hence, IL-2C could have therapeutic potential in lupus nephritis.