Is It Time to Reconsider the Lipopolysaccharide Paradigm in Acute Graft-Versus-Host Disease?

The curative efficiency of allogeneic hematopoietic cell transplantation (HCT) is considerably dampened by the graft-versus-host disease (GVHD) that leads to significant mortality and morbidity. Donor T cell subsets are recognized as the main cellular mediators and effectors of acute GVHD (aGVHD). T cell interactions with antigen-presenting cells (APC) of both host and donor origin are required to achieve the status of “alloreactive activated T cell” generating the cytotoxic attack against target organs. However, a preliminary awakening of APC by exogenous or endogenous alarm signals from distressed/injured cells is critical to recruit and drive an efficient T cell activation. Endogenous signals are known to be released after the conditioning regimen (1). They consist in “damageassociated molecular patterns” (DAMP) that are not discussed here. Exogenous signals are a group of widespread natural microbial patterns called “pathogen-associated molecular patterns” (PAMP) and are supposed to be translocated from the microbiota in case of body natural barrier weakness, especially gut mucosa. We will focus here on the role of a major component of the Gram-negative bacteria, the lipopolysaccharide (LPS), which is one of the most studied PAMP in immunology and in the aGVHD pathophysiology.