Deciphering the role of the major histocompatibility complex, the intestinal microbiome and metabolites in the pathogenesis of acute graft-versus-host disease

Allogeneic hematologic stem cell transplantation is a cornerstone in modern hematological treatment, yet its efficacy is compromised by acute Graft-versus-Host Disease. In acute Graftversus-Host Disease, conditioning regimen induced epithelial damage leads to release of damage and pathogen associated molecular patters which in turns triggers activation of alloreactive donor T cells, ultimately resulting in destruction of healthy tissue. Advances in major histocompatibility complex typing and preclinical studies using tissue specific major histocompatibility complex deletion have illuminated the contributions of both, hematopoietic and nonhematopoietic cells to acute Graft-versus-Host Disease pathophysiology. Concurrently, highthroughput sequencing techniques have enabled researchers to recognize the significant impact of the intestinal microbiome and newly discovered metabolites in the pathophysiology of acute Graft-versus-Host Disease. In this review, we discuss the implications of major histocompatibility complex expression on hematopoietic and non-hematopoietic cells, the effect on the intestinal microbiome and the metabolic alterations that contribute to acute Graft-versus-Host Disease. By combining these findings, we hope to untangle the complexity of acute Graft-versus-Host Disease, ultimately paving the way for the development of novel and more effective treatmen options in patients.