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

• Published in: Thyroid (New York, N.Y.) Vol. 29; no. 2; p. 258
• Main Authors: Faßbender, Julia, Holthoff, Hans-Peter, Li, Zhongmin, Ungerer, Martin
• Format: Journal Article
• Language: English
• Published: United States 01.02.2019
• Subjects: Adenoviridae; Animals; Disease Models, Animal; Epitopes - chemistry; Female; Fibrosis; Graves Ophthalmopathy - immunology; Graves Ophthalmopathy - therapy; HEK293 Cells; Humans; Immunoglobulins, Thyroid-Stimulating; Mice; Mice, Inbred BALB C; Orbit - physiopathology; Peptides, Cyclic - therapeutic use; Receptors, Thyrotropin - genetics; Tachycardia - genetics; Thyroxine - blood; peptides; autoimmunity; thyroid; Graves' disease
• ISSN: 1557-9077
• DOI: 10.1089/thy.2018.0326

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). 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. 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. 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.