Recipient NOD2/CARD15 status affects cellular infiltrates in human intestinal GvHD

Background: NOD2/CARD15 polymorphisms have been identified as risk factors of both, Crohn ́s disease and graft versus host disease (GvHD) following allogeneic stem cell transplantation. However, the role of these receptors of innate immunity in the pathophysiology of gastrointestinal GvHD is still poorly defined. Methods: Immunohistological features of intestinal GvHD were analyzed in gastrointestinal biopsies from 58 patients obtained at the time of first onset of intestinal symptoms and correlated the observed changes with concomitant risk factors and the presence of polymorphisms within the pathogen recognition receptor gene NOD2/CARD15. Results: Intestinal GvHD was associated with a stage dependent decrease in CD4-T cell infiltrates and an increase in CD8 T cells in the lamina propria; CD8 infiltrates correlated with extent of apoptosis and consecutive epithelial proliferation. Presence of NOD2/CARD15 variants in the recipient was associated with a significant loss of CD4 T cells: In a semiquantitative analysis, the median CD4 score for patients with wildtype NOD2/CARD15 was 1.1 (range 3), but only 0.4 (range 2) for patients with variants (p 0.002). This observation was independent from severity of GvHD in multivariate analyses and could not be explained by the loss of FoxP3+ T cells. Conclusions: Our results suggest a loss of protective CD4 T cells in intestinal GvHD which is further enhanced by the presence of NOD2/CARD15 variants. Our study might help to identify more selective therapeutic strategies in the future.