Additive Therapeutic Effects of Mesenchymal Stem Cells and IL-37 for Systemic Lupus Erythematosus.

Abstract

Although mesenchymal stem cells (MSCs) might offer a promising strategy for treating SLE, their immunoregulatory plasticity makes their therapeutic effects unpredictable. Whether overexpressing IL-37, an IL-1 family member with immunosuppressive activity, might enhance the therapeutic effects of these cells for SLE is unknown. We genetically modified MSCs to overexpress IL-37 and assessed their effects on immune suppression <i>in vitro</i>. We also evaluated the effects of such cells versus effects of various controls after transplanting them into MRL/<i>lpr</i> mice (model of SLE). Stem cell characteristics did not appear altered in MSCs overexpressing IL-37. These cells had enhanced immunosuppression <i>in vitro</i> in terms of inhibiting splenocyte proliferation, reducing proinflammatory factors (IL-1<i>β</i>, TNF-<i>α</i>, IL-17, and IL-6), and suppressing autoantibodies (anti-dsDNA and anti-ANA). Compared with animals receiving control MSCs or IL-37 treatment alone, MRL/<i>lpr</i> mice transplanted with IL-37-overexpressing cells displayed improved survival and reduced signs of SLE (indicated by urine protein levels, spleen weight, and renal pathologic scores); they also had significantly lower expression of proinflammatory factors, lower total antibody levels in serum and urine, lower autoantibody production, and showed reduced T cell numbers in the serum and kidney. Expression of IL-37 by MSCs can maintain higher serum levels of IL-37, and MSCs had prolonged survival after transplantation, perhaps through IL-37 suppressing the inflammatory microenvironment. Mutually reinforcing interaction between MSCs and IL-37 appears to underlie their additive therapeutic effects. Genetic modification to overexpress IL-37 might offer a way to enhance the stability and effectiveness of MSCs in treating SLE.