TY - JOUR
T1 - Targeting the complement alternative pathway permits graft versus leukemia activity while preventing graft versus host disease
AU - Nguyen, Hung
AU - Alawieh, Ali
AU - Bastian, David
AU - Kuril, Sandeepkumar
AU - Dai, Min
AU - Daenthanasanmak, Anusara
AU - Zhang, Mengmeng
AU - Iamsawat, Supinya
AU - Schutt, Steven D.
AU - Wu, Yongxia
AU - Mahdi Sleiman, M.
AU - Shetty, Akshay
AU - Atkinson, Carl
AU - Sun, Shaoli
AU - Varela, Juan Carlos
AU - Tomlinson, Stephen
AU - Yu, Xue Zhong
N1 - Funding Information:
This work was supported by NIH grants R01s HL140953 and R01HL137373 to X.-Z. Yu, University of Central Florida (UCF) Start-up Grant no. 2540-0715 to H. Nguyen. Institutional resources at the Medical University of South Carolina were supported by NIH support C06 RR15455 and P30 CA138313 grants (to Hollings Cancer Center). We thank cell and molecular imaging, flow cytometry, and pathology cores at the Medical University of South Carolina (MUSC) for their valuable services. We also thank Dr. Angie Duong at MUSC for her coordination in obtaining patient biopsies.
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/7
Y1 - 2020/7
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-19-1717
DO - 10.1158/1078-0432.CCR-19-1717
M3 - Article
C2 - 31919135
AN - SCOPUS:85087469837
VL - 26
SP - 3481
EP - 3490
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 13
ER -