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Murine chronic graft-versus-host disease proteome profiling discovers CCL15 as a novel biomarker in patients

Jing Du, Ryan Flynn, Katelyn Paz, Hong-Gang Ren, Yuko Ogata, Qing Zhang, Philip R. Gafken, Barry E. Storer, Nathan H. Roy, Janis K. Burkhardt, Wendy Mathews, Jakub Tolar, Stephanie J. Lee, Bruce R. Blazar and Sophie Paczesny

Key points

  • Circulating levels of murine CCL9 and human homologue CCL15 are increased during chronic GVHD

  • Targeting CCL9 in vivo reverses murine chronic GVHD

Abstract

Improved diagnostic and treatment methods are needed for chronic graft-versus-host disease (cGVHD), the leading cause of late non-relapse mortality (NRM) in long-term survivors of allogenic hematopoietic cell transplantation (allo-HCT). Validated biomarkers that facilitate disease diagnosis, and classification generally are lacking in cGVHD. Here, we conducted whole serum proteomics analysis of a well-established murine multi-organ system cGVHD model. We discovered 4 up-regulated proteins during cGVHD that are targetable by genetic ablation or blocking antibodies, including the RAS and JUN kinase activator, CRKL, and CXCL7, CCL8 and CCL9 chemokines. Donor T cells lacking CRK/CRKL prevented the generation of cGVHD, germinal center reactions and macrophage infiltration seen with wild-type T cells. Whereas antibody blockade of CCL8 or CXCL7 was ineffective in treating cGVHD, CCL9 blockade reversed cGVHD clinical manifestations, histopathological changes and immunopathological hallmarks. Mechanistically, elevated CCL9 expression was present predominantly in vascular smooth muscle cells and uniquely seen in cGVHD mice. Plasma concentrations of CCL15, the human homologue of mouse CCL9, were elevated in a previously published cohort of 211 cGVHD patients compared to controls and associated with NRM. In a cohort of 792 patients, CCL15 measured at day +100 could not predict cGVHD occurring within the next 3 months with clinically relevant sensitivity/specificity. Our findings demonstrate for the first time the utility of preclinical proteomics screening to identify potential new targets for cGVHD and specifically CCL15 as a diagnosis marker for cGVHD. These data warrant prospective biomarker validation studies.

  • Submitted August 7, 2017.
  • Accepted January 11, 2018.