The role of interleukin 27 in donor specific alloantibody responses

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Abstract There is a great clinical need for new approaches inhibiting pathogenic donor specific alloantibodies (DSA) and antibody-mediated rejection (AMR) in transplantation. Targeting interleukin-6 (IL-6) showed modest promise for AMR treatment. Interleukin-27 (IL-27) also belongs to IL-6 cytokine family, utilizes the same receptor signaling chain, gp130, and has many overlapping functions with IL-6. The current study tested the role of IL-27 in humoral immune responses using mouse transplant models. First, B6.WT and B6.IL-27R-/- recipients (H-2b) were transplanted with BALB/c heart allografts (H-2d). By d. 21 posttransplant, B6.WT recipients developed serum DSA against donor class I and class II MHC. In contrast, DSA responses were markedly reduced in B6.IL-27R-/- recipients. We next tested how IL-27 neutralization affects DSA using mAbs against p28 IL-27 subunit. B6.WT recipients transplanted with BALB/c skin allografts and treated with mAb against either p28, IL-6, or IL-6R or control IgG for the first two weeks posttransplant. While control recipients developed anti-H-Dd DSA, none of anti-p28 mAb treated recipients generated DSA, comparable to the effects of anti-IL-6 or anti-IL-6R therapies. Anti-IL-27 mAb resulted in a more profound decrease in the numbers of antibody secreting spleen plasma cells compared to anti-IL6 and anti-IL-6R treatments. Our data identify IL-27 as a novel therapeutic target to inhibit pathogenic DSA responses in transplant recipients.

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