T Cell Priming and Allograft Rejection
In the lymph nodes, activated dendritic cells stimulate naïve T cells that recognize antigens from the allograft. The primed T cells proliferate and enter the circulation, and react strongly when they encounter the allograft. T cells express two genes used in AlloMap® testing that are increased in rejection: ITGA4, associated with T-cell infiltration at the site of inflammation, and PDCD1, which limits potential autoreactivity.
Heart Tissue Infiltration and Inflammation
When transplant recipient T cells detect donor antigens, they activate and infiltrate the heart tissue, creating localized inflammation. Inflammation induces platelet activation, a process seen in patients with rejection. The AlloMap test measures the expression of two genes associated with rejection and expressed by platelets: PF4 and G6b. The inflammation process also produces inflammatory mediators which activate dendritic cells, causing them to gather antigens and migrate to the lymph nodes.
Proliferation and Mobilization of Hematopoeitic Precursors
Inflammatory mediators from the rejecting heart, such as IL-6, can induce proliferation and mobilization of hematopoeitic precursors. Three genes used in the AlloMap test are expressed by immature blood cells–MIR, WDR40A (erythrocytes), and SEMA7A (granulocytes)–and are elevated in rejection.
Impact of Steroids
Three genes used in the AlloMap test–IL1R2, ITGAM, and FLT3–are expressed in monocytes, and the level of expression correlates with increasing steroid doses.