title: Recipient NOD2/CARD15 status affects cellular infiltrates in human intestinal graft-versus-host disease.
abstract: Nucleotide-binding oligomerization domain 2/caspase recruitment domain 15 (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. Immunohistological features of intestinal GVHD were analysed in gastrointestinal biopsies from 58 patients obtained at the time of first onset of intestinal symptoms. The observed changes were correlated with concomitant risk factors and the presence of polymorphisms within the pathogen recognition receptor gene NOD2/CARD15. 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. The 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 wild-type 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 forkhead box P3(+) T cells. Our results suggest a loss of protective CD4 T cells in intestinal GVHD which is enhanced further by the presence of NOD2/CARD15 variants. Our study might help to identify more selective therapeutic strategies in the future.
authors.affiliation: Department of Haematology/Oncology, University Medical Centre, Regensburg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Landfried
authors.forename: F
authors.initials: F
authors.lastname: Bataille
authors.forename: G
authors.initials: G
authors.lastname: Rogler
authors.forename: J
authors.initials: J
authors.lastname: Brenmoehl
authors.forename: K
authors.initials: K
authors.lastname: Kosovac
authors.forename: D
authors.initials: D
authors.lastname: Wolff
authors.forename: I
authors.initials: I
authors.lastname: Hilgendorf
authors.forename: J
authors.initials: J
authors.lastname: Hahn
authors.forename: M
authors.initials: M
authors.lastname: Edinger
authors.forename: P
authors.initials: P
authors.lastname: Hoffmann
authors.forename: F
authors.initials: F
authors.lastname: Obermeier
authors.forename: J
authors.initials: J
authors.lastname: Schoelmerich
authors.forename: R
authors.initials: R
authors.lastname: Andreesen
authors.forename: E
authors.initials: E
authors.lastname: Holler
mesh_terms: D000305:Adrenal Cortex Hormones / Q000494:pharmacology / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002452:Cell Count; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006086:Graft vs Host Disease / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D007413:Intestinal Mucosa / Q000473:pathology; D007422:Intestines / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008875:Middle Aged; D009092:Mucous Membrane / Q000473:pathology; D009504:Neutrophils / Q000473:pathology; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D036102:Peripheral Blood Stem Cell Transplantation; D011110:Polymorphism, Genetic / Q000276:immunology*; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D000305:Adrenal Cortex Hormones; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007166:Immunosuppressive Agents; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein