Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Single nucleotide polymorphisms (SNPs) of the NOD2/CARD15 gene resulting in a diminished nuclear factor-kappaB (NF-kappaB) response to bacterial cell wall products have been associated with an increased incidence of Crohn disease. To assess a possible contribution of NOD2/CARD15 mutations to graft-versus-host disease (GvHD) and complications following allogeneic stem cell transplantation, we retrospectively typed DNA from donor/recipient pairs in 169 consecutive patients receiving transplants from related or unrelated donors. Mutated alleles were observed in 21% of patients and in 14% of donors. Cumulative incidence of 1-year, transplant-related mortality rose from 20% in donor/recipient pairs without mutated SNPs to 49% in pairs with recipient mutations (P =.03) and 59% in pairs with donor mutations (P <.005), and was highest in 12 pairs with mutated alleles in both donor and recipients (83%; P <.001). Similar associations were observed for severe overall and severe gastrointestinal GvHD. The impact of NOD2/CARD15 mutations was more prominent for HLA-identical sibling transplantations but was also observed in unrelated donor transplantation. Mutations proved to be independent risk factors for transplant-related mortality. Our findings indicate a major role of monocyte/macrophage dysfunction in the pathophysiology of GvHD and strongly suggest a future risk assessment or even donor selection through NOD2/CARD15 typing.
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PMID:Both donor and recipient NOD2/CARD15 mutations associate with transplant-related mortality and GvHD following allogeneic stem cell transplantation. 1509 Apr 55

Polymorphisms in NOD2 (CARD15) are associated with ileal and ileocolonic Crohn's disease, increased mortality from graft-versus-host disease, and Blau syndrome. NOD2 activation by peptidoglycan components initiates various signaling pathways and CD-associated NOD2 mutations are associated with decreased activation of NF-kappaB. NOD2 may be important for both initial defenses against commensal and pathogenic bacteria and tolerance mechanisms for maintaining controlled activation of the intestinal immune system. Significant progress has been made in defining NOD2 signaling partners and pathways and functional consequences of NOD2 mutations with respect to its activation, expression, signaling, synergistic effects with Toll-like receptor signaling, and antimicrobial effects. However, NOD2 contributions to human intestinal inflammation are complex and incompletely understood. Improved understanding of NOD2-mediated pathways may lead to identification of other molecules that can also contribute to the development of Crohn's disease in humans.
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PMID:Functional consequences of NOD2 (CARD15) mutations. 1680 2

At this moment, few confirmed associations between NOD2 mutations and diseases other than Crohn's disease (CD) and Blau syndrome (BS) have been reported, but research is ongoing in several fields where a genetic susceptibility factor and/or a role for the innate immune system is suspected. Whether the Crohn's-associated CARD15 mutations lead to a loss or gain of function of the NOD2 receptor is subject to controversy, and by which mechanisms this change in function might increase the susceptibility to CD is still under investigation. The possible involvement of NOD2/CARD15 in the pathogenesis of certain diseases with already (partially) unraveled pathophysiologic mechanisms might contribute to our further understanding of NOD2/CARD15 and its function in CD. We review studies on the association of CARD15 variants with diseases other than CD. The association of NOD2/CARD15 mutations with CD and BS, and possibly also early onset sarcoidosis, suggests a role for the gene in the development of granulomata and granulomatous diseases, possibly by inappropriate activation of the immune system. The data from the oncology field suggest that this inappropriate activation might even lead to uncontrolled proliferation of certain cell types. The studies in allergic diseases and atopy are the largest so far, and the association of NOD2/CARDI5 mutations with atopic phenotypes might be an indication that CARD15 also plays a role in the Th2 pathway. Finally, transplantation studies indicate that the genetic background of a patient should be taken into account when considering hematopoietic stem cell transplantation, given the increased risk of mortality and graft versus host disease observed. Whether NOD2 variants are also associated with an increased risk for infections and sepsis in patients receiving immunosuppressive therapies is unclear.
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PMID:NOD2/CARD15 disease associations other than Crohn's disease. 1720 82

Recent studies have pointed towards an association between certain single nucleotide polymorphisms (SNPs) in the NOD2/CARD15 gene, and negative outcome of Allo-SCT. In this study, 198 patients and their corresponding donors were analyzed retrospectively for the occurrence of NOD2/CARD15 mutations to evaluate the impact on clinical results after Allo-SCT. In all, 7.6% of the patients and 11% of the donors were heterozygous for one of three SNPs 8, 12 or 13. Contrary to earlier findings, we found no significant impact on incidence of acute GVHD or TRM following Allo-SCT. These differences in results could be due to a lower mutation frequency in the studied population and/or a lower overall incidence of severe GVHD. On the basis of these findings we conclude that a consideration to NOD2/CARD15 mutation status is not pertinent when selecting a donor for Allo-SCT at our centre.
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PMID:No impact of NOD2/CARD15 on outcome after SCT. 1869 58

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). The selection of a suitable donor is the most critical issue in preventing severe GVHD. Recent data suggest that the risk of GVHD does not only depend on human leukocyte antigens (HLA) but also on polymorphisms of genes that influence immune responses. We analyzed the 1142 G>A single-nucleotide polymorphism (SNP) in the interleukin-23 receptor gene (IL23R) and 3 SNPs in the NOD2/CARD15 gene in a cohort of 231 children who underwent allogeneic stem cell transplantation and/or their respective donors. No association was observed between any of the NOD2/CARD15 polymorphisms and GVHD in either donor or recipient. Likewise, the IL23R polymorphism in the recipient was not significantly associated with GVHD. We found a significantly reduced incidence of acute GVHD (aGVHD) grade II-IV in patients who were transplanted from a donor with the IL23R polymorphism (5.0% versus 33.3%; P=.009). There was no case of aGVHD grade III-IV if this polymorphism occurred in the donor. These findings could be particularly relevant for children with inborn metabolic or immunologic disorders who do not benefit from a graft-versus-tumor effect, and therefore, selection of a donor with the IL23R polymorphism might be beneficial.
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PMID:Polymorphism of interleukin-23 receptor gene but not of NOD2/CARD15 is associated with graft-versus-host disease after hematopoietic stem cell transplantation in children. 1989 81

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.
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PMID:Recipient NOD2/CARD15 status affects cellular infiltrates in human intestinal graft-versus-host disease. 1991 54

Previous European studies suggest NOD2/CARD15 and interleukin-23 receptor (IL-23R) donor or recipient variants are associated with adverse clinical outcomes in allogeneic hematopoietic stem cell transplantation. We reexamined these findings as well as the role of another inflammatory bowel disease (IBD) susceptibility gene (immunity-related GTPase family, M [IRGM]) on transplantation outcomes in 390 US patients and their matched unrelated donors, accrued between 1995 and 2004. Patients received T-replete grafts with mostly myeloablative conditioning regimens. Multivariate analyses were performed for overall survival, disease-free survival, transplantation-related mortality, relapse, and acute and chronic graft-versus-host disease. Of 390 pairs, NOD2/CARD15 variant single nucleotide polymorphisms (SNPs) were found in 14% of donors and 17% of recipients. In 3% both donor and recipient had a mutant SNP. Thirteen percent of donors and 16% of recipients had variant IL23R SNPs, with 3% having both donor and recipient variants. Twenty-three percent of both donors and recipients had variant IRGM SNPs. None of the 3 IBD-associated alleles showed a statistically significant association with any adverse clinical outcomes. Our results do not support an association between the 3 IBD-associated SNPs and adverse outcomes after matched unrelated donor hematopoietic cell transplantations in US patients.
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PMID:Insufficient evidence for association of NOD2/CARD15 or other inflammatory bowel disease-associated markers on GVHD incidence or other adverse outcomes in T-replete, unrelated donor transplantation. 2017 49

Single nucleotide polymorphisms (SNPs) in the innate immunity receptor NOD2/CARD15 have been demonstrated to modulate the outcome of allogeneic hematopoietic stem cell transplantation (SCT). The effect of NOD2/CARD15 polymorphism is reported to be associated with type of donor (sibling or matched unrelated donor) as well as type of conditioning regimen. We reviewed NOD2/CARD15 SNPs in all donor/recipient pairs of 192 consecutive patients who received nonmyeloablative allogeneic SCT at our institution between 2002 and 2006. All patients were treated with fludarabine 30 mg/m(2)/day for 3 days followed by 200 cGy total-body irradiation (TBI) (n = 154) or TBI alone (n = 38) and received grafts from HLA-matched related (n = 132) or unrelated (n = 61) donors. NOD2/CARD15 polymorphisms were observed in 36 of 192 (19%) patients and in 35 of 192 (18%) donors. The incidences of acute and chronic graft-versus-host disease (aGVHD, cGVHD) were 39% and 49%, respectively, in patients with NOD2/CARD15 variants versus 51% and 61% in patients with wild type. The relapse rate at 3 years was 38% in patients with variants and 36% in patients with wild type. The incidence of transplant-related mortality was 22% for patients with variants and 21% for patients with wild type. Overall survival (OS) at 3 years was 56% in patients with variants and 64% in patients with wild-type NOD2/CARD15. There was no significant impact of NOD2/CARD15 mutations on clinical outcome (all P > .05, Kaplan-Meier and Fine and Gray's tests). These data indicate that mutations in the NOD2/CARD15 gene are not a risk factor for clinical outcome in nonmyeloablative allogeneic SCT. Therefore, screening for NOD2/CARD15 polymorphisms in patients or donors does not have additional value in patients undergoing nonmyeloablative SCT.
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PMID:NOD2/CARD15 variants are not a risk factor for clinical outcome after nonmyeloablative allogeneic stem cell transplantation. 2160 Feb 96

Graft versus host disease (GVHD) is the major limitation of allogeneic hematopoietic stem cell transplantation (HSCT) presenting high mortality and morbidity rates. However, the exact cause of death is not completely understood and does not correlate with specific clinical and histological parameters of disease. Here we show, by using a semi-allogeneic mouse model of GVHD, that mortality and morbidity can be experimentally separated. We injected bone marrow-derived dendritic cells (BMDC) from NOD2/CARD15-deficient donors into semi-allogeneic irradiated chimaeras and observed that recipients were protected from death. However, no protection was observed regarding clinical or pathological scores up to 20 days after transplantation. Protection from death was associated with decreased bacterial translocation, faster hematologic recovery and epithelial integrity maintenance despite mononuclear infiltration at day 20 post-GVHD induction with no skew towards different T helper phenotypes. The protected mice recovered from aGVHD and progressively reached scores compatible with healthy animals. Altogether, our data indicate that severity and mortality can be separate events providing a model to study transplant-related mortality.
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PMID:Disease severity and mortality can be independently regulated in a mouse model of experimental graft versus host disease. 2564 48