Modeling Chronic Graft-versus-Host Disease in MHC-Matched Mouse Strains: Genetics, Graft Composition, and Tissue...

Area of Science:

• Immunology
• Transplantation Biology
• Preclinical Models

Background:

• Graft-versus-host disease (GVHD) is a significant complication of allogeneic hematopoietic cell transplantation.
• Chronic GVHD (cGVHD) pathogenesis and autoimmune-like features are poorly understood due to limited preclinical models.

Purpose of the Study:

• To evaluate MHC-matched, minor antigen-mismatched mouse models for chronic GVHD (cGVHD) development.
• To identify a representative preclinical model for human cGVHD.

Main Methods:

• Examined 7 MHC-matched, minor antigen-mismatched mouse models over an extended period.
• Assessed cGVHD development based on MHC allele type and recipient strain.
• Utilized C57BL/6 into BALB.B strain combination for detailed analysis.

Main Results:

• The C57BL/6 into BALB.B model demonstrated moderate acute GVHD (aGVHD) and developed overt cGVHD in survivors, affecting eyes, skin, and liver.
• Naïve CD4+ T cells, but not hematopoietic stem cells or memory T cells, induced cGVHD.
• Donor CD4+ T cells injured medullary thymic epithelial cells, suggesting impaired thymic selection.

Conclusions:

• The C57BL/6 into BALB.B mouse model accurately represents human cGVHD.
• cGVHD evolves from early post-transplant immunologic events, particularly involving CD4+ T cells and thymic selection defects.