Augmented CD47 expression impairs alloreactive T-cell clearance after allo-HCT

Area of Science:

• Immunology
• Transplantation Biology
• Oncology

Background:

• Graft-versus-Host disease (GvHD) is a major complication of allogeneic hematopoietic cell transplantation (allo-HCT).
• Controlling inflammation is key to managing GvHD, with phagocytosis playing a role in resolving inflammation.
• The specific role of phagocytosis in GvHD pathogenesis remains unclear.

Purpose of the Study:

• To investigate the role of the "don't eat me" signal CD47 in GvHD.
• To explore CD47 as a therapeutic target for eradicating alloreactive T-cells post-allo-HCT.
• To assess the impact of modulating CD47 on T-cell phagocytosis and GvHD outcomes.

Main Methods:

• Analysis of global datasets to assess CD47 expression on T-cells in inflamed tissues.
• Examination of CD47 levels in the gastrointestinal tract (GIT) of GvHD patients and mice post-allo-HCT.
• In vitro studies using anti-CD47 antibodies to assess antibody-dependent cellular phagocytosis (ADCP) of T-cells.
• In vivo studies administering anti-CD47 antibodies or CD47-deficient T-cells to GvHD mouse models.

Main Results:

• CD47 expression is significantly upregulated on T-cells in the inflamed ileum of GvHD patients and mice.
• Activated donor T-cells suppress ADCP via CD47 signaling, leading to impaired phagocytosis.
• Treatment with anti-CD47 antibodies restored ADCP, enhanced T-cell phagocytosis in the GIT, and improved survival in mice.
• Transplantation of CD47-deficient donor T-cells improved clinical GvHD scores and survival.

Conclusions:

• CD47 upregulation is a critical mechanism in GvHD, causing impaired phagocytic clearance of alloreactive T-cells.
• Targeting CD47 with antibodies represents a promising therapeutic strategy to enhance phagocytosis of alloreactive T-cells.
• Anti-CD47 therapy could facilitate inflammation resolution and improve outcomes after allo-HCT.