Programmed death-1 pathway in host tissues ameliorates Th17/Th1-mediated experimental chronic graft-versus-host...

Area of Science:

• Immunology
• Transplantation Biology
• Oncology

Background:

• Chronic graft-versus-host disease (GVHD) is a significant complication following allogeneic hematopoietic cell transplantation.
• The exact mechanisms driving chronic GVHD pathogenesis are not fully understood.

Purpose of the Study:

• To investigate the role of the programmed death-1 (PD-1) pathway in the development of chronic GVHD.
• To explore potential therapeutic strategies targeting the PD-1 pathway for chronic GVHD.

Main Methods:

• Utilized a well-defined mouse model of allogeneic hematopoietic cell transplantation.
• Analyzed PD-1 and PD-L1 expression on immune cells and tissues.
• Investigated the effects of PD-1 pathway blockade and stimulation using monoclonal antibodies (mAbs) and a synthetic retinoid (Am80).
• Employed chimeric mice to delineate the cellular sources of PD-L1 function.

Main Results:

• PD-1 expression on donor T cells was consistently upregulated during chronic GVHD.
• Blockade of the PD-1 pathway (using anti-PD-1, anti-PD-L1, or anti-PD-L2 mAbs) exacerbated chronic GVHD.
• PD-L1 expression in host tissues suppressed the expansion of IL-17(+)IFN-γ(+) T cells, a key driver of GVHD.
• Am80 treatment reduced GVHD severity in PD-L1 deficient recipients by mitigating IL-17(+)IFN-γ(+) T cell expansion.
• Stimulating the PD-1 pathway alleviated chronic GVHD.

Conclusions:

• The PD-1 pathway plays a crucial suppressive role in chronic GVHD, particularly against Th17/Th1-mediated responses.
• Targeting the PD-1 pathway presents a promising therapeutic avenue for preventing or treating chronic GVHD.