Purpose Tocilizumab®, a monoclonal antibody to the IL-6R was recently approved by the FDA for treatment of rheumatoid arthritis. Although anti-IL-6R antibodies can reduce autoantibody levels in human diseases, the use of anti-IL-6R for alloantibody suppression has not been examined. This pre-clinical study evaluated the efficacy of a mousenized rat-anti-mouse IL-6R mAb, mMR16-1, in suppressing anti-HLA-A2 antibody responses to skin allograft.

Method C57BL/6 mice were sensitized with skin allografts from a HLA.A2 transgenic mouse, and treated with intraperitoneal injections of mMR16-1 or control antibody. Donor specific antibody (DSA) responses were monitored weekly for 5 weeks by measurement of serum anti-HLA.A2 antibodies in a flow cytometric antibody binding assay.

Results mMR16-1 significantly reduced DSA responses to skin allograft, resulting in significant decreases of anti-HLA.A2 IgM (treated vs. control: 12.7+2.3 MFI vs. 22.9+3.2 MFI at day 14, p=0.00022), IgG2a (99.41 +35.31 MFI vs. 300.6+53.04 MFI at day 28, p=6.621E-05) and IgG1 (25.6+9.8 MFI vs. 40.01+7.7 MFI at day 28, p=0.029), respectively. Anti-IL6R treatments also normalized serum amyloid A (SAA), an acute phase reactant induced by IL-6 (p<0.01 vs. control). In addition, mMR16-1 treatment caused accumulation of soluble IL-6R as well as IL-6 in the blood. Thus, the alternation in IL-6/IL-6R homeostasis likely impairs both the classic signaling and trans-signaling pathways, which would interfere with a wide range of IL-6 dependent immune activation events.

Conclusion The data indicate that antibody therapy targeting the IL-6/IL-6R pathway may serve as a strategy to suppress DSA generation. Future mechanistic studies to dissect various cellular compartments targeted by anti-IL-6R in the alloimmunity will shed more light on our understanding of the therapeutic properties of anti-IL-6R on rejection suppression.

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