Targeting the Complement Alternative Pathway Permits Graft Versus Leukemia Activity while Preventing Graft Versus...

Area of Science:

• Immunology
• Hematology
• Complement System Biology

Background:

• Allogeneic hematopoietic cell transplantation (allo-HCT) is limited by graft-versus-host disease (GVHD).
• Separating GVHD from graft-versus-leukemia (GVL) is a significant challenge.
• The role of individual complement cascade pathways in GVHD and GVL is not fully understood.

Purpose of the Study:

• To investigate the contribution of specific complement cascade pathways to GVH and GVL responses.
• To identify therapeutic targets for separating GVHD and GVL.

Main Methods:

• Utilized preclinical murine and human-to-mouse xenograft models of allo-HCT.
• Examined recipients lacking components of the alternative pathway (AP) or classical/lectin pathways (CP/LP).
• Employed the AP-specific complement inhibitor CR2-fH in translational studies.

Main Results:

• Complement deposition was observed in the intestines of GVHD patients and mice.
• Ablation of the AP, but not CP/LP, significantly improved GVHD outcomes.
• AP activation in host dendritic cells was crucial for GVHD; CR2-fH prevented GVHD while preserving GVL.

Conclusions:

• The AP is a novel therapeutic target for preventing GVHD post-allo-HCT.
• Targeting the AP with CR2-fH offers a promising strategy for GVHD treatment.
• This approach may help prevent tumor relapse after allo-HCT.