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  • 1
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    NOD2/CARD15 Mutations Associate with Transplant Related Mortality and GvHD in HLA-Identical Sibling Transplants: Detailed Analysis of Single SNPs in 211 Recipient/Donor Pairs.
    American Society of Hematology ; 2004
    In:  Blood Vol. 104, No. 11 ( 2004-11-16), p. 424-424
    Details
    In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 424-424
    Abstract: Recently, our group reported a strong association of the most frequent single nucleotide polymorphisms (SNPs) in the antibacterial defense gene NOD2/CARD15 with GvHD and outcome following allogeneic stem cell transplantation (SCT). We now extended our analysis in HLA-identical sibling transplants by adding a second cohort of 133 donor /recipient pairs collected in 3 centers to our previously analyzed group of 78 consecutive transplants. PCR analysis for major SNPs 8,12, and 13 of the NOD2/CARD15 gene was performed in DNA samples from recipients and their donors after receiving informed consent, and occurrence or absence of mutations was correlated with major outcome variables. Heterozygous NOD2/CARD15 mutations were observed in 54/211 (25,6%), whereas only 1 patient and 2 donors revealed homozygous mutations. Analysis of the second cohort confirmed the significant association of occurrence of any NOD2/CARD15 mutation with treatment related mortality (TRM) and graft-versus-host disease (GvHD): Incidence of severe GvHD rose from 13% (cohort1 + 2) to 48% (cohort1, p & lt;0.001) and 30% (cohort 2, p=0.02), and 6 months treatment related mortality (TRM) increased from 11% (cohort1) and 8% (cohort2) to 44% (cohort1, p =0.004) and 30% (cohort 2, p=0.002). By combining the data from both cohorts, we now were able to ask for the relevance of individual mutated SNPs: Detailed analysis of SNPs revealed an increased TRM in recipients bearing mutations for SNP8 or SNP12 (50% as compared to 15.6.% in wildtype recipients, p 0.005). Furthermore, our analyses showed an increased carriage of heterozygous mutations of SNP8 and 12 in healthy HLA-identical sibling donors resulting in a high number of pairs with simultaneous recipient and donor mutations for SNP8 and 12. As TRM was also strongly increased in these pairs (56%, p 0.001) but not at all in transplants with donor mutations alone, our data suggest a predominant role of recipient mutations in HLA-identical sibling transplants. This was also confirmed in a multivariate analysis of risk factors associated with TRM and overall survival where recipient and combined recipient and donor SNP8 or 12 mutations remained independent and highly significant (p 0.001) factors when compared with established risk factors such as age at Tx or stage at Tx. Even inclusion of possible interfering strategies such as use of in vivo/ex vivo T cell depletion or reduced intensity conditioning had no impact on the unique role of NOD2/CARD15 mutations. The strong association of recipient mutations points to a major role of NOD2/CARD15 mutations in intestinal inflammation, and otherwise asymptomatic heterozygous mutations might become symptomatic in the context of additional epithelial damage induced in the course of SCT.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V104.11.424.424
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
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  • 2
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    NOD2/CARD15 Variants of Donor and Recipient as Critical Risk Factors for the Development of Bronchiolitis Obliterans Syndrome after Allogeneic Stem Cell Transplantation.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 144-144
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 144-144
    Abstract: Bronchiolitis obliterans syndrome (BOS) is a life-threatening complication after allogeneic stem cell transplantation (SCT), that affects primarily small airways. BOS mortality is high and risk factors and pathophysiology have yet to be defined. Experimental data from BOS in heterotopic traecha transplant models suggest, that both bronchial epithelial cell (EC) integrity as well as an alloantigen-reactive T cell response are involved. We recently reported an association of single nucleotide polymorphisms (SNPs) of the NOD2/CARD15 gene resulting in a diminished NF- κB response to bacterial cell wall products with increased acute graft versus host disease (GVHD) severity and transplant-related mortality. As NOD2/CARD15 is expressed not only in monocytes/macrophages and intestinal EC but also in bronchial EC, we hypothesized that NOD2/CARD15 variants contribute to changes in host defense and alloreaction leading to BOS. We analyzed the association of NOD2/CARD15 SNPs (SNP 8, 12, 13) with the occurrence of BOS within 244 donor/recipient (D/R) pairs of patients (pts) receiving allogeneic SCT. Follow-up was performed for a mean of 1243±172 days (range: 327–2149). BOS was diagnosed by pathology or by functional airway obstruction (FEV1 & lt;/= 80% of predicted). 12 pts developed BOS with a mean time point of diagnosis at 678±112 days after SCT (range: 186–1407). Incidence of BOS rose from 1.7% (3/174) in D/R pairs without mutated SNPs to 10.0% (6/60) in pairs with mutated alleles in either donor or recipient (p=0.01) and to 25.0% (3/12) in pairs with mutated alleles in both donor and recipient (p=0.009). In addition, in D/R pairs developing BOS, NOD2/CARD15 variants were observed at higher frequencies (donor: 60.0% vs. 12.9%, p=0.001; recipient: 50.0% vs. 15.0%; p=0.007). 50% of pts with BOS died between day +327 and day +1582 (mean: 844±195), whereas 6 pts are still alive (mean follow-up: 1642±170 days). Survival did not differ between pts with BOS in relation to the presence/absence of NOD2/CARD15 mutations. Finally, we analyzed whether other transplant-related parameters contributed to the incidence of BOS. Conditioning regimen intensity, stem cell source, donor type (matched unrelated donor vs. HLA-identical sibling), recipient age, donor or recipient gender, and acute GVHD were not associated with BOS development, whereas chronic GVHD was confirmed as a risk factor for BOS (p=0.01). Interestingly, NOD2/CARD15 mutations did not associate with chronic GVHD (p=0.19). Our data indicate that NOD2/CARD15 mutations of donor or recipient increase the risk of developing BOS after allogeneic SCT, which may be due to impaired macrophage function, to impaired defence mechanisms of bronchial epithelial cells, or to other pathways still unknown. Further, future risk assessment before SCT using NOD2/CARD15 typing may help identifying patients at higher risk for BOS and improve clinical outcome after allogeneic SCT.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.144.144
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
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    detail.hit.zdb_id: 80069-7
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  • 3
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    Both donor and recipient NOD2/CARD15 mutations associate with transplant-related mortality and GvHD following allogeneic stem cell transplantation
    American Society of Hematology ; 2004
    In:  Blood Vol. 104, No. 3 ( 2004-08-01), p. 889-894
    Details
    In: Blood, American Society of Hematology, Vol. 104, No. 3 ( 2004-08-01), p. 889-894
    Abstract: Single nucleotide polymorphisms (SNPs) of the NOD2/CARD15 gene resulting in a diminished nuclear factor-κB (NF-κB) 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 & lt; .005), and was highest in 12 pairs with mutated alleles in both donor and recipients (83%; P & lt; .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.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2003-10-3543
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
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    “ATG16 L1 a Additional Risk Factor for TRM After allogeneic Stem Cell Transplantation”.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 1155-1155
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 1155-1155
    Abstract: Abstract 1155 Poster Board I-177 Introduction A genome wide association scan of DNA polymorphisms identified association of a threonine-to-alanine substitution (T300A) in the autophagy-related 16-like gene ATG16 L1 as a new genetic risk factor of Crohn's disease. As our group had previously reported SNPs of another innate immunity receptor important in Crohn's disease, NOD2/CARD15, as a risk factor of severe graft-versus-host disease (GvHD) and treatment related mortality (TRM) following allogeneic stem cell transplantation (SCT), we now assessed the role of ATG16L in complications following SCT. Material and Methods A total of 127 HLAidentical sibling donor/recipient pairs were included. DNA from donors and recipients were analyzed for the ATG16L1 polymorphism and presence or absence of NOD2/CARD15 variants as previously published. Results of ATG16L1 and NOD2/CARD15 were correlated with clinical characteristics and outcome data, which were documented in a SPSS 17 database. The role of polymorphisms in GvHD III/IV was assessed by cross tabs, treatment related mortality (TRM) and overall survival were assessed by Kaplan Meier analysis. All patients and donors gave informed consent to analysis of genetic risk factors of GvHD. Results In 15 (12%) both recipient and donor were wildtype ATG16L1, in 25 (19%) either donor or recipient had the variant; and in 87 (69%) both donor and recipient had the variant. In 34 pairs, additional NOD2/CARD15 SNPs were observed. Severe GvHD occured in 6%, if both donor and recipient were ATG16L1 wildtype but increased to 22% if donor or recipient had the variant. Treatment related mortality increased in the presence of a donor variant (16% versus 46%, p 0.03) or if both; recipient and donor had variants (21% vs 48%, p 0.03). There seemed to be a gene dose effect for TRM, which was 13% if both were wildtype, 27% in the presence of either a donor or recipeint varaint and 48% if both had the variant (p≤ 0.05). Overall survival was not significantly different between these groups. In multivariate analysis, presence of ATG16L1 variant in both, donor and recipient was an independent risk factor for treatment related mortality when compared with age and stage of underlying disease (Hazard ratio 2.5, 95% confidence interval 1.1 – 6.1). Additional presence of NOD2/CARD15 variants seemed to be additive: TRM rose from 36% in recipients with ATG16L1 variant to 59% in the presence of additional recipient NOD2/CARD15 variants and from 34% in donors with ATG16L1 variants to 64%, if donors had additional NOD2/CARD15 SNPs. Conclusions As reported ATG16L1 polymorphism is a genetic risk factor for inflammatory bowel disease. In our work ATG16L1 polymorphism seems also to contribute to increased TRM in patients receiving allogeneic SCT. An accurate analysis of the causes of death is still accomplished. Altogether the data underline the role of the innate immunity and the disturbed antibacterial defense in the pathophysiology of transplant-associated complications. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.1155.1155
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 5
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    Intestinal Microbiota: From Inflammatory Bowel Disease to Bone Marrow Transplantation
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. SCI-50-SCI-50
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. SCI-50-SCI-50
    Abstract: Abstract SCI-50 A dysregulated interaction of the intestinal microbiome with the patient's innate and adaptive immune response seems to contribute to both inflammatory bowel disease (IBD) and intestinal graft-versus-host disease (GVHD). In IBD, polymorphisms within genes involved in antibacterial defense have been identified as genetic risk factors, such as in NOD2, a gene coding for an intracytoplasmatic receptor for muramyldipeptide, a bacterial cell wall compound, or in ATG16L1, a gene involved in autophagy of bacteria. Disruption of these genes results in dysfunction of Paneth cells, which are the major producers of antimicrobial peptides such as defensins. They thereby protect epithelial stem cells from invasion and destruction by intestinal bacteria and contribute to homeostasis of the intestinal microbiota. Based on van Bekkum's finding of the absence of intestinal GVHD in germ-free mice and the central role of TNF-α release in intestinal GVHD, our group focused on the microbiome/host interactions in GVHD. In prospective studies on genetic risk factors of GVHD, single-nucleotide polymorphisms (SNPs) of NOD2 and also ATG16L1 turned out to be predictive for severe intestinal GVHD and IBD. In addition, however, pulmonary complications revealed an altered production of antibacterial peptides in the presence of NOD2 SNPs. We therefore speculated that human intestinal GVHD similar to IBD might be associated with disruption of the bacterial diversity. We applied metabolomic analyses of metabolites processed in the presence of intestinal bacteria as well as 16s rRNA sequencing to serial urine and stool samples from patients receiving allogeneic stem cell transplantation. Urinary indoxylsulfate (IS) levels dropped during the period of decontamination and use of antibiotics during the neutropenic period but recovered to pretransplant levels in patients with uneventful courses. In contrast, patients developing intestinal GVHD had significantly lower IS levels, suggesting suppression of bacterial diversity in intestinal GVHD. Analysis of 16s rRNA confirmed a major shift from an almost normal distribution pretransplant toward a loss of Firmicutes and an increase in enterococci in the neutropenic period. Although this shift may be partially explained by antibiotic decontamination or treatment during this period that was given to all patients, those patients with subsequent development of intestinal GVHD showed a significantly stronger shift toward enterococci in this period (p=0.002). Whereas patients without intestinal GVHD returned to pretransplant diversity thereafter, predominance of enteroccal flora persisted in patients with intestinal GVHD. These data indicate early microbiome changes in patients with intestinal GVHD. We are currently addressing potential Paneth cell damage and loss of antimicrobial peptides as an underlying mechanism. In summary, our data confirm the relevance of the close interaction of microbiome and host defense in GVHD patients, similar to what has been described in IBD, and raise new options for immune system modulation by restoration of intestinal tolerance. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.SCI-50.SCI-50
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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