Effect of NOD2/CARD15 variants in T-cell depleted allogeneic stem cell transplantation.

BACKGROUND AND OBJECTIVES Three single nucleotide polymorphisms (SNP) in the NOD2/CARD15 gene have been associated with the incidence and the severity of acute graft-versus-host disease (GVHD) following allogeneic stem cell transplantation (SCT). We hypothesized that the clinical effect of SNP in NOD2/CARD15 might be different in patients submitted to T-cell-depleted allogeneic SCT, in which donor T cells, the main effectors of GVHD, are eliminated. DESIGN AND METHODS SNP 8, 12 and 13 in NOD2/CARD15 were studied using a Taqman protocol in 85 patients undergoing HLA-identical, T-cell-depleted SCT and in 71 of their sibling donors. RESULTS NOD2/CARD15 variants were present in nine (11%) patients and six (8%) donors. The incidences of acute GVHD and chronic GVHD were not associated with either the donors' or recipients' NOD2/CARD15 variants. In contrast, these genetic variants were associated with a lower disease-free survival (17% vs. 48%, p=0.03). Death due to pulmonary infection was more frequent in the group of patients with NOD2/CARD15 variants. In the multivariate analysis, only NOD2/CARD15 variants (RR 2.3, p=0.04) and older age (RR 2.2; p=0.04) were independent prognostic factors for disease-free survival. INTERPRETATION AND CONCLUSIONS NOD2/CARD15 variants have a deleterious effect on clinical outcome in T-cell-depleted allogeneic SCT, which is independent of GVHD. These results supports the hypothesis that the detrimental effect of NOD2/CARD15 variants in such a transplant setting might be produced by an alteration of the innate immune system more than by activation of the adaptive immune system.

[1]  G. Rogler,et al.  Prognostic significance of NOD2/CARD15 variants in HLA-identical sibling hematopoietic stem cell transplantation: effect on long-term outcome is confirmed in 2 independent cohorts and may be modulated by the type of gastrointestinal decontamination. , 2006, Blood.

[2]  G. Rogler,et al.  NOD2/CARD15 Variants of Donor and Recipient as Critical Risk Factors for the Development of Bronchiolitis Obliterans Syndrome after Allogeneic Stem Cell Transplantation. , 2005 .

[3]  E. Cario.  BACTERIAL INTERACTIONS WITH CELLS OF THE INTESTINAL MUCOSA: TOLL-LIKE RECEPTORS AND NOD2 , 2005, Gut.

[4]  M. Abreu,et al.  TLR Signaling in the Gut in Health and Disease1 , 2005, The Journal of Immunology.

[5]  Michael Karin,et al.  Nod2 Mutation in Crohn's Disease Potentiates NF-κB Activity and IL-1ß Processing , 2005, Science.

[6]  E. Holler,et al.  Genetic polymorphisms predicting the outcome of bone marrow transplants , 2004, British journal of haematology.

[7]  N. Suttorp,et al.  Nucleotide-binding Oligomerization Domain Proteins Are Innate Immune Receptors for Internalized Streptococcus pneumoniae* , 2004, Journal of Biological Chemistry.

[8]  G. Rogler,et al.  Both donor and recipient NOD2/CARD15 mutations associate with transplant-related mortality and GvHD following allogeneic stem cell transplantation. , 2004, Blood.

[9]  D. Philpott,et al.  Innate immune recognition of microbes through Nod1 and Nod2: implications for disease. , 2004, Microbes and infection.

[10]  A. Godzik,et al.  CARD6 Is a Modulator of NF-κB Activation by Nod1- and Cardiak-mediated Pathways* , 2003, Journal of Biological Chemistry.

[11]  D. Podolsky,et al.  CARD15/NOD2 functions as an antibacterial factor in human intestinal epithelial cells. , 2003, Gastroenterology.

[12]  E. G. de la Concha,et al.  Prevalence of mutations of the NOD2/CARD15 gene and relation to phenotype in Spanish patients with Crohn disease , 2003, Scandinavian journal of gastroenterology.

[13]  E. Lander,et al.  Human macrophage activation programs induced by bacterial pathogens , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[14]  Judy H. Cho,et al.  A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease , 2001, Nature.

[15]  M. Heinzelmann,et al.  Endotoxin and muramyl dipeptide modulate surface receptor expression on human mononuclear cells. , 2000, Immunopharmacology.

[16]  G. Hill,et al.  The primacy of the gastrointestinal tract as a target organ of acute graft-versus-host disease: rationale for the use of cytokine shields in allogeneic bone marrow transplantation. , 2000, Blood.

[17]  E. Montserrat,et al.  Immune reconstitution following allogeneic peripheral blood progenitor cell transplantation: comparison of recipients of positive CD34+ selected grafts with recipients of unmanipulated grafts. , 1999, Experimental hematology.

[18]  D. van der Waaij,et al.  Mitigation of secondary disease of allogeneic mouse radiation chimeras by modification of the intestinal microflora. , 1974, Journal of the National Cancer Institute.

[19]  E. Sgambato.  [Nosocomial sepsis and polymorphism of the NOD-2 gene]. , 2005, La Clinica terapeutica.