New Directions in the Genomics of Allogeneic Hematopoietic Stem Cell Transplantation

The 3-stage pathogenesis of aGVHD. In stage 1, conditioning causes damage and activation of host tissues. Bacterial LPS translocates from the intestinal lumen to the circulation, resulting in stimulation of inflammatory cytokine secretion and upregulated expression of MHC antigens and adhesion molecules on host tissues, which in turn enhance the recognition of MHC and miHAs by mature donor T cells. In stage 2, T_H1 T cells proliferate in the presence of IL-12 and secrete IL-2 and IFN-γ. IL-2 and IFN-γ induce further T cell expansion and CTL and NK cell responses, and activate mononuclear phagocytes. CTL and NK effectors damage tissue by perforin/granzyme, FasL, and TNF. In phase 3, effector functions of activated mononuclear phagocytes are triggered by LPS and other stimulatory molecules that leak through the intestinal mucosa damaged during phases 1 and 2. This amplifies local tissue injury and further drives an inflammatory response. Gut damage amplifies LPS release and leads to the “cytokine storm” of aGVHD. Reproduced with permission from Hill and Ferrara [39].

Genomic polymorphism of TNF. TNF and the adjacent LTA gene lie on the short arm of chromosome 6 separated by 1 kb. HLA-DRB1 and TNF are separated by approximately 850 kb, and LTA and HLA-B by 250 kb. Locations of commonly studied TNF and flanking SNPs and microsatellites (variable number tandem repeats) are shown. TNFd and e microsatellites lie in the LST1 gene. Exons are represented by shaded boxes, and translated regions of the gene by black boxes. Arrows represent direction of transcription.