Therapeutic Effects of Short Cyclic and Combined Epitope Peptides in a Long-Term Model of Graves' Disease and Orbitopathy

Abstract

BACKGROUND: Cyclic peptides derived from some cylindrical loops of the leucine-rich repeat domain (LRD) of the thyrotropin receptor (TSHR) have been shown to treat disease manifestations in a mouse model of Graves' disease during a long-term protocol of four-weekly immunizations with adenovirus coding for the TSHR A-subunit (Ad-TSHR289). METHODS: In a follow-up study, two additional cyclic peptides were tested, which were shortened in order to obtain additional information on the minimally involved epitopes and to enable easier production conditions. In addition, a linear peptide was tested, which mimics parts of three loops of the native TSHR LRD structure, and is potentially able to block the discontinuous epitopes of anti-TSHR antibodies. RESULTS: The novel peptides markedly reduced thyroid size, serum thyroxine levels, retro-orbital fibrosis, and tachycardia in Ad-TSHR289-immunized mice. In immunologically naïve mice, administration of the peptides did not induce any immune response. CONCLUSIONS: In summary, novel cyclic peptides mitigate many clinical findings in a mouse model of established Graves' disease and orbitopathy, and may therefore provide an additional therapeutic option compared to existing drugs or interventions.