Interleukin-15 receptor-directed immunotoxins atteunuate disease severity in rat adjuvant arthritis

We previously constructed two Pseudomonas exotoxin (PE)-based immunotoxins, IL15-PEΔ293 (IT1) and IL15M-PEΔ293 (IT2), for eliminating interleukin-15 receptor (IL-15R)-overexpressing cells. These two immunotoxins were generated by fusing either wild-type human IL-15 or an antagonist mutant IL-15 (IL-15M) to a modified form of PE. In this study the anti-arthritic effect of IT1 and IT2 was investigated using the rat model of adjuvant arthritis (AA). We found that both IT1 and IT2 could specifically target IL-15R-positive cells and induce apoptosis. After AA induction, treatment with either IT1 or IT2 resulted in profound improvement of the disease, with reductions in levels of synovial mononuclear leukocytes and certain inflammatory factors. Clinical and histological comparisons, together with the analyses of mRNA expression and the signal transducer and activator of transcription-3 (STAT-3) phosphorylation, revealed that the two immunotoxins decreased joint inflammation in AA rats to a similar extent. These data suggest that eliminating IL-15R-bearing cells via immunotoxins may be a promising approach for RA treatment. In addition, wild-type IL-15-based immunotoxins can be as effective as antagonist mutant IL-15-based immunotoxins in preventing joint inflammation associated with rheumatoid arthritis.