The therapeutic potential of natural killer cells in treating systemic lupus erythematosus.

Abstract

Abstract Systemic lupus erythematosus (SLE) is a chronic disease defined by rampant autoantibody production and multi-organ pathology. Standard treatments for SLE are broadly immunosuppressive and often ineffective, as ~38% of patients develop lupus nephritis (LN) that can result in kidney failure and death. Current therapeutics may lack efficacy because they do not target the specific immune processes underlying SLE. For example, lupus autoantibodies can arise from aberrant germinal centers (GCs) driven by dysregulated follicular helper T cells (TFH). We have shown that natural killer (NK) cells suppress activated TFH during immunization, resulting in blunted GCs and antibody production. We hypothesize that an effective new strategy to treat SLE would involve harnessing of this NK cell-mediated humoral regulation. To assess whether therapeutic elevation of NK cell numbers can ameliorate disease, we used IL-2/αIL-2 complexes to expand endogenous populations of NK cells in the bm12 cGVHD mouse model of SLE-like disease. We also evaluated ex vivo activation, expansion, and infusion of NK cells as an immunotherapeutic means to ameliorate disease in mouse models of SLE. Finally, we are engineering human NK cells expressing a programmed death-ligand 1 (PD-L1)-based chimeric antigen receptor (CAR) that will facilitate cytolytic elimination of TFH and B cells that highly express programmed cell death protein 1 (PD-1). We plan to evaluate the capacity of these CAR NK cells to selectively kill PD-1+ targets and to reduce autoantibody-mediated LN in humanized mouse models of SLE. These CAR NK cells represent an innovative means to curtail autoantibody production, particularly during disease flares, and thereby promote disease remission in SLE.