Purchase this article with an account.
Yoko Ogawa, Mio Yamane, Eisuke Shimizu, Shinsuke Shibata, Motoshi Hayano, Takanori Suzuki, Shin Mukai, Shigeto Shimmura, Hideyuki Okano, Tsutomu Takeuchi, Yutaka Kawakami, Kazuo Tsubota; Stress-induced senescence in chronic ocular graft-versus-host disease in mice. Invest. Ophthalmol. Vis. Sci. 2019;60(9):1743.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Chronic graft-versus-host disease (cGVHD) is a multi-step inflammatory and fibrotic disease after hematopoietic stem cell transplantation. Lacrimal glands including other target organs can be affected by cGVHD and lose their function. An abnormal immune response and dysregulated cytokine production are major factors in the development of cGVHD. Although several treatments include immunosuppressive therapies have been reported, they are still unsatisfactory, and other interventions are required. To meet the unmet medical needs, we explored one of the other additional pathways for stress-induced senescence in chronic ocular GVHD.
To produce the cGVHD mouse model, allogeneic bone marrow transplantation (BMT) was performed with 8-week-old male B10.D2 and female BALB/c mice as transplant donors and recipients, respectively. This is an MHC-identical and minor histocompatible antigen-mismatched transplantation. BALB/c into BALB/c transplant mice were used as the syngeneic controls. Four weeks after BMT, we collected lacrimal gland tissue from the cGVHD mice and the controls for analyzing tissues by immunohistochemistry and electoron microscopy and gene expression, and serum for cytokines and chemokines by enzyme-linked immunosorbent assay to examine senescence-related molecules.
Our findings suggested an association between the pathology of chronic ocular GVHD and stress-induced cellular senescence, through the production of the senescence-associated secretory phenotype (SASP) including IL-6 (p<0.01) and CXCL9 (p<0.01) in the lacrimal glands affected by cGVHD compared to the control samples (N≥5, each group) both protein and mRNA level. Senescent cells including macrophages and endothelia produce cytokines and chemokines, such as IL-6 and CXCL9. An accumulation of senescent cells was associated with the development of lacrimal gland cGVHD, as evidenced by the fact that the selective elimination of senescent cells (senolysis) using ABT-263 reduces lacrimal gland cGVHD. Here, this study suggested that a senolytic therapy which inhibited major components of SASP including IL-6 and CXCL9 could be a novel therapeutic intervention for cGVHD pathology in mice.
Collectively, our results have suggested that the SASP plays some roles for the development of lacrimal gland cGVHD and that targeted senolytic treatment contribute a new additional therapeutic intervention for cGVHD-related dry eye disease.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
This PDF is available to Subscribers Only