Targeting the complement alternative pathway permits graft versus leukemia activity while preventing graft versus host disease

Hung Nguyen, Ali Alawieh, David Bastian, Sandeepkumar Kuril, Min Dai, Anusara Daenthanasanmak, Mengmeng Zhang, Supinya Iamsawat, Steven D. Schutt, Yongxia Wu, M. Mahdi Sleiman, Akshay Shetty, Carl Atkinson, Shaoli Sun, Juan Carlos Varela, Stephen Tomlinson, Xue Zhong Yu

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Purpose: Application of allogeneic hematopoietic cell transplantation (allo-HCT) for patients with hematologic disorders is limited by the development of GVHD. Separation of GVHD and graft-versus-leukemia (GVL) remains a great challenge in the field. We investigated the contribution of individual pathways involved in the complement cascade in GVH and GVL responses to identify specific targets by which to separate these two processes. Experimental Design: We used multiple preclinical murine and human-to-mouse xenograft models involving allo-HCT recipients lacking components of the alternative pathway (AP) or classical pathway (CP)/lectin pathway (LP) to dissect the role of each individual pathway in GVHD pathogenesis and the GVL effect. For translational purposes, we used the AP-specific complement inhibitor, CR2-fH, which localizes in injured target organs to allow specific blockade of complement activation at sites of inflammation. Results: Complement deposition was evident in intestines of mice and patients with GVHD. In a preclinical setting, ablation of the AP, but not the CP/LP, significantly improved GVHD outcomes. Complement activation through the AP in host hematopoietic cells, and specifically dendritic cells (DC), was required for GVHD progression. AP deficiency in recipients decreased donor T-cell migration and Th1/Th2 differentiation, while increasing the generation of regulatory T cells. This was because of decreased activation and stimulatory activity of recipient DCs in GVHD target organs. Treatment with CR2-fH effectively prevented GVHD while preserving GVL activity. Conclusions: This study highlights the AP as a new therapeutic target to prevent GVHD and tumor relapse after allo-HCT. Targeting the AP by CR2-fH represents a promising therapeutic approach for GVHD treatment.

Original languageEnglish (US)
Pages (from-to)3481-3490
Number of pages10
JournalClinical Cancer Research
Volume26
Issue number13
DOIs
StatePublished - Jul 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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