Th1/17 polarization and potential treatment by an anti-interferon-γ DNA aptamer in Hunner-type interstitial cystitis

Yoshiyuki Akiyama; Kaori Harada; Jimpei Miyakawa; Karl J Kreder; Michael A O'Donnell; Maeda Daichi; Hiroto Katoh; Miyuki Hori; Kensuke Owari; Kazunobu Futami; Shumpei Ishikawa; Tetsuo Ushiku; Haruki Kume; Yukio Homma; Yi Luo

doi:10.1016/j.isci.2023.108262

Th1/17 polarization and potential treatment by an anti-interferon-γ DNA aptamer in Hunner-type interstitial cystitis

iScience. 2023 Oct 21;26(11):108262. doi: 10.1016/j.isci.2023.108262. eCollection 2023 Nov 17.

Authors

Yoshiyuki Akiyama^{1

2}, Kaori Harada³, Jimpei Miyakawa¹, Karl J Kreder², Michael A O'Donnell², Maeda Daichi⁴, Hiroto Katoh⁵, Miyuki Hori³, Kensuke Owari³, Kazunobu Futami³, Shumpei Ishikawa⁵, Tetsuo Ushiku⁶, Haruki Kume¹, Yukio Homma^{1

7}, Yi Luo²

Affiliations

¹ Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
² Department of Urology, University of Iowa, Iowa City, IA, USA.
³ TAGCyx Biotechnologies Inc., Tokyo, Japan.
⁴ Department of Molecular and Cellular Pathology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
⁵ Department of Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
⁶ Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
⁷ Department of Interstitial Cystitis Medicine, Faculty of Medicine, Kyorin University, Tokyo, Japan.

Abstract

Hunner-type interstitial cystitis (HIC) is a rare, enigmatic inflammatory disease of the urinary bladder with no curative treatments. In this study, we aimed to characterize the unique cellular and immunological factors specifically involved in HIC by comparing with cystitis induced by Mycobacterium bovis bacillus Calmette-Guérin, which presents similar clinicopathological features to HIC. Here, we show that T helper 1/17 +polarized immune responses accompanied by prominent overexpression of interferon (IFN)-γ, enhanced cGAS-STING cytosolic DNA sensing pathway, and increased plasma cell infiltration are the characteristic inflammatory features in HIC bladder. Further, we developed a mouse anti-IFN-γ DNA aptamer and observed that the intravesical instillation of the aptamer significantly ameliorated bladder inflammation, pelvic pain and voiding dysfunction in a recently developed murine HIC model with little migration into the blood. Our study provides the plausible basis for the clinical translation of the anti-IFN-γ DNA aptamer in the treatment of human HIC.

Keywords: Disease; Immunology.

Grants and funding

R01 DK111396/DK/NIDDK NIH HHS/United States