Faculty Collaboration Database

Targeting the Complement Alternative Pathway Permits Graft Versus Leukemia Activity while Preventing Graft Versus Host Disease. Clin Cancer Res 2020 Jul 01;26(13):3481-3490

Date

01/11/2020

Pubmed ID

31919135

Pubmed Central ID

PMC7334060

DOI

10.1158/1078-0432.CCR-19-1717

Scopus ID

2-s2.0-85087469837 (requires institutional sign-in at Scopus site)   7 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.

Author List

Nguyen H, Alawieh A, Bastian D, Kuril S, Dai M, Daenthanasanmak A, Zhang M, Iamsawat S, Schutt SD, Wu Y, Sleiman MM, Shetty A, Atkinson C, Sun S, Varela JC, Tomlinson S, Yu XZ

Authors

Yongxia Wu PhD Assistant Professor in the Microbiology and Immunology department at Medical College of Wisconsin
Xue-Zhong Yu MD Professor in the Microbiology and Immunology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Complement Activation
Complement Pathway, Classical
Complement System Proteins
Dendritic Cells
Disease Models, Animal
Disease Susceptibility
Graft vs Host Disease
Hematopoietic Stem Cell Transplantation
Humans
Immunophenotyping
Leukemia
Mice
Mice, Knockout
Prognosis
T-Lymphocyte Subsets
Transplantation, Homologous