Littérature scientifique sur le sujet « Permissive mismatche »
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Articles de revues sur le sujet "Permissive mismatche"
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Buhler, Stéphane, Helen Baldomero, Sylvie Ferrari-Lacraz, Anne-Claire Mamez, Stavroula Masouridi-Levrat, Dominik Heim, Jörg Halter et al. « Analysis of biological models to predict clinical outcomes based on HLA-DPB1 disparities in unrelated transplantation ». Blood Advances 5, no 17 (3 septembre 2021) : 3377–86. http://dx.doi.org/10.1182/bloodadvances.2020003998.
Texte intégralRésumé :
Abstract HLA compatibility is a key factor for survival after unrelated hematopoietic stem cell transplantation (HSCT). HLA-A, -B, -C, -DRB1, and -DQB1 are usually matched between donor and recipient. By contrast, HLA-DPB1 mismatches are frequent, although it is feasible to optimize donor selection and DPB1 matching with prospective typing. Because classical DPB1 allele mismatches are often unavoidable, however, several biological models have been developed to predict the optimal DPB1 mismatch combination for less graft-versus-host disease (GVHD) and better overall survival. In 909 recipient/donor pairs, we analyzed the role of 3 biological models: T-cell epitopes (TCEs) based on the immunogenicity of DPB1, cell surface expression of DPB1 molecules based on a single-nucleotide polymorphism located in the 3′ untranslated region, and the Predicted Indirectly ReCognizable HLA Epitopes (PIRCHE) model based on the presentation of allogeneic peptides derived from mismatched HLA, compared with the classical allele mismatch. Matching for both DPB1 alleles remains the best option to prevent acute GVHD. In the situation of one DPB1 allele mismatch, the donor associated with the lowest acute GVHD risks is mismatched for an allele with a low expression profile in the recipient, followed by a permissive TCE3/4 mismatch and/or the absence of PIRCHE II potential against the recipient. In the context of 2 DPB1 mismatches, the same considerations apply for a permissive TCE3/4 mismatch and no PIRCHE II. By combining the biological models, the most favorable DPB1 constellation can be defined. This approach will help optimize donor selection and improve post-HSCT complications and patient prognosis.
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Chiusolo, Patrizia, Teresa Lamparelli, Giuseppe Sapienza, Alida Dominietto, Anna Maria Raiola, Carmen Di Grazia, Sabrina Giammarco et al. « The Impact of Aminoacid Substitution at Position 116 Class I HLA, in Unrelated Donor Transplants ». Blood 134, Supplement_1 (13 novembre 2019) : 4620. http://dx.doi.org/10.1182/blood-2019-130614.
Texte intégralRésumé :
Background : The role of aminoacid substitution at position 116 of class I HLA antigens, has been the subject of several contributions, suggesting the possibility of permissive or non permissive mismatches. Hypothesis. Permissive mismatched at position AA116, yield outcomes comparable to 10/10 matched grafts and superior to AA116 non permissive mismatches. Patients: We have analyzed 358 unrelated donor transplants (UD) to test this hypothesis. All donors were matched at class II for DRB1 and DQ alleles; 226 were also matched at high resolution for A,B and C alleles; 84 had 1 permissive AA116 mismatch (Pmm), and 48 had 1 non permissive mismatch (NPmm). The 3 groups were comparable for patients age (p=0.5), donors age (p=0.9), diagnosis (p=0.2) and intensity of the conditioning regimen (p=0.4); both NPmm and Pmm had more patients with advanced disease, as compared to matched patients. The stem cell source was peripjheral blood for the large majority of patients. Results. The cumulative incidence (CI) of acute GvHD grade II-IV (p=0.01) and III-IV (p=0.001) was greater in patients with 1 allele mismatch, compared to matched patients, irrespective of AA116 permissive substitution. The CI of non relapse mortality (NRM) at 5 years 29%, 35%, 50% respectively in patients grafted from 10/10 matched donors, 1 allele Pmm donors and 1 allele NPmm donors (p=0.005). GvHD with or without infections, as a cause of death was recorded in 19%, 23% and 33% of the three groups respectively (p=0.1). The CI of relapse was respectively 18%, 30%, 20% (p=0.1). The actuarial survival at 5 years was 68% for 10/10 matched patients, 63% for 1 allele Pmm patients and 47% for 1 allele NPmm patients. Conclusions. We confirm that aminoacid substitution at position 116 of class I HLA antigens, is a risk factor for non relapse mortality and survival. Patients with permissive mismatched AA116 donors have outcome comparable to patients grafted from matched donors. Figure Disclosures Angelucci: Novatis: Honoraria, Other: Chair Steering Committee TELESTO protocol; Celgene: Honoraria, Other: Participation in DMC; BlueBirdBio: Other: Local advisory board; Jazz Pharmaceuticals: Other: Local advisory board; Roche: Other: Local advisory board; Vertex Pharmaceuticals Incorp., and CRISPR Therapeutics: Other: Participation in DMC.
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Stevens, Cladd E., Carmelita Carrier, Carol Carpenter, Dorothy Sung et Andromachi Scaradavou. « HLA mismatch direction in cord blood transplantation : impact on outcome and implications for cord blood unit selection ». Blood 118, no 14 (6 octobre 2011) : 3969–78. http://dx.doi.org/10.1182/blood-2010-11-317271.
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AbstractDonor-recipient human leukocyte antigen mismatch level affects the outcome of unrelated cord blood (CB) transplantation. To identify possible “permissive” mismatches, we examined the relationship between direction of human leukocyte antigen mismatch (“vector”) and transplantation outcomes in 1202 recipients of single CB units from the New York Blood Center National Cord Blood Program treated in United States Centers from 1993-2006. Altogether, 98 donor/patient pairs had only unidirectional mismatches: 58 in the graft-versus-host (GVH) direction only (GVH-O) and 40 in the host-versus-graft or rejection direction only (R-O). Engraftment was faster in patients with GVH-O mismatches compared with those with 1 bidirectional mismatch (hazard ratio [HR] = 1.6, P = .003). In addition, patients with hematologic malignancies given GVH-O grafts had lower transplantation-related mortality (HR = 0.5, P = .062), overall mortality (HR = 0.5, P = .019), and treatment failure (HR = 0.5, P = .016), resulting in outcomes similar to those of matched CB grafts. In contrast, R-O mismatches had slower engraftment, higher graft failure, and higher relapse rates (HR = 2.4, P = .010). Based on our findings, CB search algorithms should be modified to identify unidirectional mismatches. We recommend that transplant centers give priority to GVH-O-mismatched units over other mismatches and avoid selecting R-O mismatches, if possible.
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Jucaud, Vadim. « The Immunogenicity of HLA Class II Mismatches : The Predicted Presentation of Nonself Allo-HLA-Derived Peptide by the HLA-DR Phenotype of the Recipient Is Associated with the Formation of DSA ». Journal of Immunology Research 2017 (2017) : 1–12. http://dx.doi.org/10.1155/2017/2748614.
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The identification of permissible HLA class II mismatches can prevent DSA in mismatched transplantation. The HLA-DR phenotype of recipients contributes to DSA formation by presenting allo-HLA-derived peptides to T-helper cells, which induces the differentiation of B cells into plasma cells. Comparing the binding affinity of self and nonself allo-HLA-derived peptides for recipients’ HLA class II antigens may distinguish immunogenic HLA mismatches from nonimmunogenic ones. The binding affinities of allo-HLA-derived peptides to recipients’ HLA-DR and HLA-DQ antigens were predicted using the NetMHCIIpan 3.1 server. HLA class II mismatches were classified based on whether they induced DSA and whether self or nonself peptide was predicted to bind with highest affinity to recipients’ HLA-DR and HLA-DQ. Other mismatch characteristics (eplet, hydrophobic, electrostatic, and amino acid mismatch scores and PIRCHE-II) were evaluated. A significant association occurred between DSA formation and the predicted HLA-DR presentation of nonself peptides (P=0.0169; accuracy = 80%; sensitivity = 88%; specificity = 63%). In contrast, mismatch characteristics did not differ significantly between mismatches that induced DSA and the ones that did not, except for PIRCHE-II (P=0.0094). This methodology predicts DSA formation based on HLA mismatches and recipients’ HLA-DR phenotype and may identify permissible HLA mismatches to help optimize HLA matching and guide donor selection.
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Shaw, Bronwen E., Katharina Fleischhauer, Mari Malkki, Theodore Gooley, Elisabetta Zino, Stephen Spellman, Yasuo Morishima et al. « Permissive HLA-DPB1 Mismatching Compared to a Non-Permissive Mismatching Significantly Improves Overall Survival Following Allogeneic Transplantation In Patients with Both 10/10 and 9/10 Matched Unrelated Donors ». Blood 116, no 21 (19 novembre 2010) : 227. http://dx.doi.org/10.1182/blood.v116.21.227.227.
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Abstract Abstract 227 It is well established that the use of a donor matched for 9–10/10 alleles at HLA-A,-B,-C,-DRB1,-DQB1 significantly improves overall survival (OS) after unrelated donor (UD) haematopoietic stem cell transplantation (HSCT). Whilst the matching status for HLA-DPB1 alleles has been shown to influence transplant complications (relapse and graft-versus-host disease (GVHD), its impact on survival has not been well defined. The current unmet need in clinical practice is an approach to stratify selection criteria when a clinician is confronted with the choice between several 10/10 or 9/10 matched unrelated donors. There is now considerable interest in exploring different types of matching criteria to define permissive HLA-DPB1 mismatches which may be associated with an improved outcome. We have previously shown that HLA-DPB1 permissiveness can be functionally defined by the characterization of shared T cell epitopes (TCE) recognized by alloreactive T cells. In this model, allelic HLA mismatches are classified as permissive if they do not involve TCE disparities, and as non-permissive if they do. Using this concept, we developed two overlapping algorithms of permissivity for allelic HLA-DPB1 mismatches, on the basis of 3 (TCE3) or 4 (TCE4) groups of DPB1 alleles encoding immunogenic TCE. Data from relatively small prospective studies has shown a worse outcome to be associated with non-permissive DPB1 TCE disparities. Here, we present outcomes in 9123 UD-HSCT pairs, collected through the International Histocompatibility Working Group (IHWG). The cohort was comprised of 5809 10/10 matched transplant pairs and 3314 9/10 matched pairs. Within the 10/10 and 9/10 matched pairs three groups of patients were identified: 1. Zero DPB1 mismatches (i.e. allele matched), 2. Permissive DPB1 mismatch, 3. Non-permissive DPB1 mismatch. The model was adjusted for disease severity, source of stem cells, conditioning regimen, use of T-cell depletion, patient/donor gender and patient age. In line with DPB1 allele frequencies in worldwide populations, the number of transplants scored as permissive was higher for TCE3 (4398/7270 [60.4%]) than for TCE4 (2577/7270 [35.4%]). Using the DPB1 permissive mismatch transplants as the reference group (either 10/10 or 9/10 matched), we showed that DPB1 allelic matches resulted in similar survivals to DPB1 permissive mismatches, both in the 10/10 (HR 0.96, p=0.498 for TCE3 and HR 0.99, p=0.85 for TCE4) and the 9/10 setting (HR 0.97, p=0.70 for TCE3 and HR 0.99, p=0.96 for TCE4). In contrast, survival was significantly worse in the presence of a non-permissive TCE3 or TCE4 mismatch, both in the 10/10 (HR 1.15, p=0.0005 for TCE3 and HR 1.13, p=0.0035 for TCE4) and in the 9/10 matched setting (HR 1.13, p=0.0140 for TCE3 and HR 1.11, p=0.0448 for TCE4). The survival detriment appeared to be due to a significantly increased non-relapse mortality (TCE3: 10/10 HR 1.27, p<0.001 and 9/10 HR 1.21, p=0.0001; TCE4: 10/10 HR 1.24, p<0.001 and 9/10 HR 1.13, p=0.0514), as well as an increase in grades II-IV acute GVHD (TCE3: 10/10 HR 1.17, p<0.001 and 9/10 HR 1.29, p<0.001; TCE4: 10/10 HR 1.12, p=0.0035 and 9/10 HR 1.19, p<0.0001). There was no significant difference in disease relapse between permissive and non-permissive mismatched pairs. Finally, using the 10/10 DPB1 permissive mismatched group as a reference, we found survival to be similar for 10/10 DPB1 non-permissive (HR 1.15) and 9/10 DPB1 permissive (HR 1.20) or DPB1 allele matched (HR 1.17) transplants. In conclusion, our results suggest that extending donor selection to include HLA-DPB1 both allelic and functional TCE matching may result in better prediction of survival for patients. These findings provide an attractive new algorithm to stratify donor choice when several well-matched UD are identified. Disclosures: No relevant conflicts of interest to declare.
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Ruggeri, Annalisa, Carlheinz Mueller, Liesbeth C. de Wreede, Junfeng Wang, Lotte Wieten, Luca Vago, Jorinde Hoogenboom et al. « Association of Donor-Recipient HLA Matching with Outcome of Unrelated Donor Hematopoietic Stem Cell Transplantation : A Study from the Cellular Therapy and Immunobiology Working Party (CTIWP) of the European Society for Blood and Marrow Transplantation (EBMT) ». Blood 134, Supplement_1 (13 novembre 2019) : 3281. http://dx.doi.org/10.1182/blood-2019-125369.
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Introduction: Optimal HLA matching is associated with clinical outcome of unrelated donor (UD) hematopoietic cell transplantation (HCT)(Pidala, Blood2014, Morishima, Blood2015, Fürst, Blood2013), but a comprehensive analysis addressing this question in European transplant centers has not yet been performed. Within the CTIWP of EBMT, we have addressed this issue in adultsreceiving an UD-HCT from 2000 to 2015. Methods: All consecutive cases of UC-HCT with available 6-loci high resolution (2nd field) HLA-A, -B, -C, -DRB1, -DQB1, -DPB1 typing for both patient and donor and ARD-level matching for at least 7/8 HLA-A,B,C,DRB1 alleles reported to the EBMT were selected. Further inclusion criteria were first allogeneic HCT for hematological malignancies, patient age >=18 years, availability of donor age and use of either bone marrow or peripheral blood (PB) as stem cell source. Overall, 9575 patient-donor pairs were included from 29 countries and 198 transplant centers. Median follow-up was of 28.3 months, main diagnosis was acute leukemia (AL)(51.5%), disease stage was early in 44.1% of cases. UD-HCT were performed with PB in 84.7%, in vivo T cell depletion (TCD) in 64.4% and reduced intensity conditioning regimen in 57.3% of cases, and mostly standard graft-versus-host-disease (GvHD) prophylaxis with calcineurin inhibitors. HLA data were validated using the HLAcore library and a haplotype based probability check from the German Donor Registry. Pairs were stratified by: 1) In the overall cohort, according to HLA-A, -B, -C, -DRB1 matching status (8/8 N=7724 and 7/8 N=1851) and 2) in informative 8/8 matched pairs (N=7480), according to HLA-DPB1 matching status as identical (23.7%), permissive (26.6%) or non-permissive (32.9%) by the 3-group T Cell Epitope (TCE3) model, or by the 4-group TCE4 model (Fleischhauer, Blood2017). Primary endpoint was overall survival (OS), secondary endpoints were non-relapse mortality (NRM), relapse and acute GvHD grade II-IV, and relapse free survival (RFS). Results: At 5 years, OS and RFS in the entire cohort were 47% and 40.5%. The cumulative incidence of 5-y NRM, relapse and 1-y grade II-IV aGvHD was 28.1%, 31.4% and 19.4%, respectively. In multivariate analysis, a single mismatch at HLA-A, -B, -C, -DRB1 (7/8) was associated with a significantly higher risk of death compared to full match (8/8; HR 1.16, p<0.001). Other variables significantly associated with OS were patient (HR 1.14, p<0.001) and donor age (HR 1.08, p<0.001) per decade, CMV serostatus (HR 1.10, p=0.007), diagnosis of AL (HR 1.14, p<0.001), disease status (HR 1.22, p<0.001) and year of HCT (HR 0.98, p<0.001). The hazards of NRM, grade II-IV aGvHD and RFS were also significantly higher in 7/8 compared to 8/8 group (HR 1.34, p<0.001, HR 1.18, p<0.001 and HR 1.13, p<0.001, respectively) but not with lower risks of relapse (HR 0.96, p=0.51). In 8/8 matched HCT, when comparing with the HLA-DPB1 TCE3 permissive group, NRM were significantly higher in the non-permissive but not in the allele matched group (HR 1.17, p<0.001 and HR 0.90, p=0.15). Permissive HLA-DPB1 mismatches were associated with significantly lower relapse risks compared to allele matches but not compared to non-permissive mismatches (HR 0.85, p<0.01 and HR 0.96, p=0.433, respectively). OS was not significantly different between permissively HLA-DPB1 mismatched and allele matched pairs (HR 0.98, p=0.678.) or non-permissively mismatched pairs (HR 1.07, p=0.08). RFS was similar between the 3 groups. Stratification according to the TCE4 group model resulted in similar outcome associations. Conclusion: In this large independent cohort of UD-HCT from EBMT performed mostly from PB with in vivo TCD, a single allele mismatch at HLA-A, -B, -C, -DRB1 was independently associated with lower OS, and RFS, higher risk of NRM and aGvHD and no difference in relapse. The latter outcome was improved by permissive HLA-DPB1 mismatches in the 8/8 setting, which carried a significantly lower risk of NRM compared to non-permissive mismatches. The results from this new dataset validate current paradigms in donor selection and provide an important new platform for donor selection and HCT immunobiology. Figure: OS and RI relapse in UD-HCT. Pairs were stratified according to A) 8/8 (N=7724) and 7/8 (N=1851) HLA-A,B,C,DRB1 allele mismatches, or B) HLA-DPB1 allele matches (N=2045), TCE3 permissive mismatches (N=3743) and TCE3 non-permissive mismatches (N=2838) in the 8/8. Figure Disclosures Vago: Moderna Therapeutics: Research Funding; GenDx: Research Funding. Socie:Alexion: Consultancy. Kröger:Celgene: Honoraria, Research Funding; DKMS: Research Funding; JAZZ: Honoraria; Medac: Honoraria; Neovii: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Riemser: Research Funding; Sanofi-Aventis: Research Funding. Leleu:Takeda: Honoraria; Oncopeptide: Honoraria; Karyopharm: Honoraria; Amgen: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria; BMS: Honoraria; Merck: Honoraria; Sanofi: Honoraria. Bonini:Novartis: Consultancy; -: Patents & Royalties: Adoptive T cell therapy field; Intellia Therapeutics: Research Funding; Molmed: Consultancy; Intellia Therapeutics: Consultancy; TxCell: Consultancy; GSK: Consultancy; Allogene: Consultancy; Kite/Gilead: Consultancy. Chabannon:EBMT: Other: Working Party Chair, Board member; Fresenius Kabi: Other: research support; Miltenyi Biotech: Other: research support; Terumo BCT: Other: speaker's fees; Celgene: Other: speaker's fees; Novartis: Other: speaker's fees; Gilead: Other: speaker's fees, hospitalities; Sanofi SA: Other: research support, speaker's fees, hospitalities.
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Michallet, Mauricette, Mohamad Sobh, Hélène Labussière-wallet, Marie Balsat, Caroline Lejeune, Sophie Ducastelle-Leprêtre, Xavier Thomas et al. « Allogeneic Hematopoietic Stem Cell Transplantation from Unrelated Peripheral Blood or Bone Marrow Donors : The Impact of HLA Matching Including HLA-DPB1 Allele in a Multivariable Risk Model ». Blood 126, no 23 (3 décembre 2015) : 3213. http://dx.doi.org/10.1182/blood.v126.23.3213.3213.
Texte intégralRésumé :
Abstract Introduction Allogeneic hematopoietic stem cell transplantation (allo-HSCT) from unrelated donors has been increasingly used worldwide in the last decade in patients with hematological malignancies when HLA-identical sibling donors are unavailable. Identification of the HLA locus matching at the allele level is important in optimizing transplantation outcomes by minimizing non-relapse mortality (NRM) as well as in enhancing the graft-versus-leukemia effect. It has been demonstrated that patients with HSC donors matched on HLA-A, -B, -C, -DRB1, and -DQB1 alleles can have different outcomes if considering matching on HLA-DPB1 allele. HLA-DPB1 mismatches based on T-cell-epitope groups could identify mismatches that might be tolerated (permissive) and those that would negatively impact transplantation outcomes (non-permissive). We conducted this study to evaluate the impact of HLA matching degree between patient and HSC donor including HLA-DPB1, taking into account the other impacting variables in the allo-HSCT settings. Material and methods A total of 235 patients who received allo-HSCT at our center between January 2005 and December 2014 with a full donor/recipient HLA class I and II locus available data were included, 131 (56%) were males, the median age at allo-HSCT was 50 years (range: 18-69). There was 123 (53%) acute leukemia (93 AML, 30 ALL), 24 (10%) MDS, 35 (15%) multiple myeloma, 20 (8%) NHL, 7 (3%) Hodgkin's disease, 10 (4%) myeloproliferative neoplasms, 13 (6%) CML, and 3 (1%) CLL. One hundred and nineteen patients (51%) received myeloablative conditioning (MAC) and 116 (49%) received reduced intensity conditioning (RIC). Disease status at allo-HSCT was complete remission (CR) in 144 (61%) patients and less than CR in 91 (39%). HSC donor was 10/10 HLA matched unrelated (MUD) for 162 (69%) (80 PBSC and 93 BM), among them 21 (9%) were matched for HLA-DPB1, 41 (18%) had permissive mismatch and 100 (42%) had non-permissive mismatch; while 73 (31%) had 9/10 HLA mismatched donor MMUD (48 PBSC and 25 BM), among them, 7 (3%) were matched for HLA-DPB1, 12 (5%) had permissive mismatch and 54 (23%) had non-permissive mismatch; 110 (47%) were ABO compatible, 58 (24%) had minor incompatibility and 67 (29%) had major incompatibility. For sex mismatching, in 33 (14%) cases, it was female donor to a male patient. Results After a median follow-up for surviving patients of 29 months (range: 4-108), patients with 10/10 HLA MUD had better overall survival (OS) than those with 9/10 MMUD without considering the HLA-DPB1 matching, with 2 years OS probability of 51% vs 35% respectively (p=0.09), which was reflected by a lower NRM at 2 years of 29% vs 42% (p=0.07). When considering the HLA-DPB1 matching, we found comparable outcomes in terms of OS and NRM for: 1) 10/10 HLA MUD - DPB1 matched vs 10/10 HLA MUD - DPB1 permissive mismatched, 2) 10/10 HLA MUD - non-permissive DPB1 mismatched vs 9/10 HLA MMUD - DPB1 matched, 3) 9/10 HLA MMUD - DPB1 matched vs 9/10 HLA MMUD - DPB1 permissive mismatched; all these 3 groups were not significantly different between each other expect for a last group which included 9/10 HLA MMUD with non-permissive DPB1 mismatch, this group had worse OS and NRM compared to all others with 2 years rates of 34% vs 49% (p=0.05) and 47% vs 29% (p=0.04) respectively. In multivariate analysis, patient age (>50 years), disease status (less than CR), HLA matching (9/10 HLA MUD non-permissive DPB1) and sex mismatching (female donor to male patient) were significantly impacting OS and NRM. We included all these variables in a risk score: age < 50 years= 0, > 50 years= 1; CR= 0, less than CR= 1; HLA 10/10 (matched on DPB1) or HLA 10/10 with permissive MM on DPB1= 0; HLA 10/10 with non-permissive MM on DPB1 or HLA 9/10 (matched on DPB1 or with permissive MM on DPB1)=1; HLA 9/10 with non-permissive MM on DPB1=2; for sex matching, female donor to male patient=1, all other= 0. The risk score distinguished low risk patients (total score=0), intermediate (total score=1 or 2) and high risk (total score >2) with 2 years OS and NRM rates of 66%, 52%, 30% (p=0.003) and 22%, 29% 48% (p=0.004) respectively. Conclusion MMUD with non-permissive T-cell-epitope mismatch at HLA-DPB1 should be avoided due to increased rates of NRM. The risk score combining HLA matching with age, disease status and sex matching is very helpful for daily clinical practice offering patients better treatment strategy. Figure 1. Figure 1. Disclosures Nicolini: Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.
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Oran, Betul, Rima M. Saliba, Yudith Carmazzi, Elizabeth J. Shpall, Katayoun Rezvani, Marcos De Lima, Marcelo Fernández-Viña, Richard E. Champlin et Kai Cao. « Increased Disease Progression in HLA-a, -B, -C, -DRB1 and -DBP1 Matched Recipients of Unrelated Donor Transplants with Peripheral Blood Is Independent of Risk Groups By Disease Risk Index ». Blood 126, no 23 (3 décembre 2015) : 2005. http://dx.doi.org/10.1182/blood.v126.23.2005.2005.
Texte intégralRésumé :
Abstract The use of unrelated donors matched in all alleles of HLA-A, -B, -C, and -DRB1 loci has been associated with superior outcomes compared with those having 1 or more mismatches. Recent studies showed increased transplant-related mortality (TRM) with the use of HLA-DPB1 mismatched donors supporting the notion that the ideal volunteer unrelated donor should fully match at HLA-A, -B, -C, and -DRB1 and lack -DPB1 mismatches. The issue of the effect of HLA-DPB1 mismatch on the disease progression rate is still controversial and we aimed to investigate the impact of HLA-DPB1 mismatch in the graft versus host direction on transplant outcomes in patients categorized according to the recently defined disease risk index (DRI) for disease risk classification. Our study cohort included 1,211 transplant patients with hematological malignancies whohave received an hematopoietic stem cell transplant (HSCT) from an unrelated HLA-A, -B, -C,-DRB1 matched donor by high resolution typing (8/8 matched) after 2005 through 2014. The study cohort had a median age of 55 (range, 19-77); the hematopoietic stem cell source was peripheral blood (PB) in 698 and bone marrow (BM) in 513 patients. Disease risk index (DRI) at HSCT was high or very high in 382 (33%), intermediate in 598 (51%), low in 185 (16%) patients. Of the pairs, 1,154 (95%) were matched atHLA-DQB1 and 1,116 (92%) at HLA- DRB3/4/5 by high resolution testing. However, 633 (52%) had mismatch at one of the DPB1 alleles and 208 (17%) had two mismatches. There was association between matching for DPB1and matching for DRB3/4/5 (p=0.002) but not with DQB1. In PB recipients, there was a highly significant decreaseof disease progression in DPB1 mismatched pairs (one and two allele; HR=0.7, p=0.01 and HR=0.6, p=0.01 respectively) as compared tothose pairs with DPB1 matched. The impact of mismatches at one or two alleles were not different on disease progression (HR=1.2, p=0.4). However, the impact of DPB1 mismatch on disease progression was not uniform in different disease risk groups by DRI. Mismatch at DPB1 significantly decreased disease progression only in the intermediate risk group (HR=0.5, p=0.002) but not in low risk and high/very high disease groups by DRI (HR=0.9, p=0.8 and HR=0.7, p=0.1 respectively) (Figure 1a-c). In BM recipients, increasing number of DPB1 incompatibilities decreased disease progression (HR=0.9, p=0.4 and HR=0.6, p=0.1 for 1 and 2 allele mismatches respectively) but did not reach significance. Mismatches at HLA-DQB1 and -DRB3/4/5 had no impact on disease progression in both PB and BM recipients. Pairs with one or two allele-level DPB1 mismatches increased TRM compared with DPB1 matched pairs in PB (HR=1.5, p=0.04 and HR=1.9, p=0.006 respectively) and BM recipients (HR=1.8, p=0.03 and HR=1.9, p=0.05). There was no difference between two and one allele DPB1 mismatched for TRM in PB and BM recipients. Multivariate analyses revealed that the negative impact of DPB1 mismatch on TRM was not uniform in younger or (?) older patients. Interestingly, DPB1 mismatches increased TRM only in younger (aged<55) patients (HR=2.3, p=0.02) if they were PB recipients but only in older patients (HR=2.03, p=0.046) if they were BM recipients. We next analyzed the impact of DPB1 matching on progression free survival (PFS) and did not observe any impact of DPB1 mismatches on PFS in PB (HR=0.9, p=0.9) and BM (HR=1.12, p=0.6) recipients. Subgroup analyses by DRI to identify a specific risk group that the use of HLA-A, -B, -C and -DRB1 matched but DPB1 mismatched unrelated donor might lead to improved PFS did not reveal any particular risk group in both PB and BM recipients. Thus, in recipients of HLA-A, -B-C and DRB1 allele-level matched unrelated donors a mismatch for DPB1 is associated with a significantlydecreased risk of disease progression with no impact on PFS in intermediate risk group by DRI. Further analysis permissive vs. non-permissive DPB1 mismatches would be warranted. Figure 1. The cumulative incidence of disease progression by DPB1 mismatch and Disease Risk Index in peripheral blood recipients. Figure 1. The cumulative incidence of disease progression by DPB1 mismatch and Disease Risk Index in peripheral blood recipients. Disclosures No relevant conflicts of interest to declare.
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Arrieta-Bolanos, Esteban, Pietro Crivello, Meilun He, Tao Wang, Shahinaz M. Gadalla, Sophie Paczesny, Steven G. E. Marsh et al. « A Refined Model of HLA-DP Permissiveness Improves Stratification of Acute Graft-Versus-Host Disease Risks after Unrelated Hematopoietic Cell Transplantation : A Retrospective Study from the CIBMTR ». Blood 138, Supplement 1 (5 novembre 2021) : 2890. http://dx.doi.org/10.1182/blood-2021-146957.
Texte intégralRésumé :
Abstract Introduction: Permissive HLA-DPB1 mismatches defined by the T-cell epitope (TCE) model are an established selection criterion for unrelated donors in allogeneic hematopoietic cell transplantation (alloHCT) (Dehn et al. Blood 2019). Based on biological evidence, the TCE model has classified HLA-DPB1 alleles into at least three functional groups, one of which (TCE group 3; TCE3) houses a large number of alleles with different structural and functional characteristics. We have recently shown that structurally close HLA-DP allotypes have similar peptide-binding motifs and share a significant proportion of their immunopeptidomes, the latter being fundamental for permissiveness (Meurer & Crivello et al. Blood 2021). Hence, we hypothesized that HLA-DPB1 mismatches involving alleles that encode structurally distant allotypes within TCE3 could be less permissive than those involving alleles that encode structurally closer allotypes, and thus have a differential impact on clinical outcomes. Methods: Multidimensional scaling techniques were used to compare 28 polymorphic positions (amino acids 8-215) among 51 alleles present in a cohort of 5,140 10/10 matched patient-donor pairs who received a first alloHCT for AML, ALL, or MDS between 2008-2017. Based on these analyses, TCE3-permissive mismatches (N=2,216) were further stratified into those involving structurally close or more distant combinations and compared with HLA-DPB1-matched (N=785) and non-permissively mismatched (N=2,023) pairs. These models were tested in parallel to the "classical" TCE model considering permissive mismatches (N=2,332) as a whole, to determine their association with overall survival (OS), disease-free survival (DFS), treatment-related mortality (TRM), primary disease relapse, and acute (a) and chronic (c)GVHD. Kaplan-Meier analysis and log-rank testing were used to compare the median OS and DFS. The incidences of GVHD, relapse and TRM were compared using competing risks and Gray's test. The effect of HLA-DPB1 mismatch on time-to-event outcomes was modelled by Cox regression after adjusting for confounders and testing for the proportional hazards assumption. Results: Within TCE3, we identified a subgroup of 4 frequent and structurally as well as functionally closely related alleles (i.e. DPB1*02:01, 04:01, 04:02, 23:01) that form a separate cluster (Figure 1A). These "core" alleles have similar bound-peptide motifs (van Balen et al. J Immunol 2020) and can be distinguished from other alleles in TCE3 in terms of the strength of in vitro alloreactive responses elicited from permissive responders (Meurer et al. Front Immunol 2018). Moreover, principal component analysis identified the HLA-DP 84-87 DEAV/GGMP motif as a major factor driving structural variability among TCE3 alleles (not shown). We used these observations to stratify TCE3 permissive mismatches in the allo-HCT cohort into "core" (N=930) and "non-core" (N=1,286) or into DEAV/GGPM-matched (N=1,209) and mismatched (N=1,007) pairs (Figure 1B). Multivariable analysis confirmed the association of aGVHD2-4 for the classical TCE model of non-permissive mismatching (p<.0001) and revealed a trend in DEAV/GGPM and "core"/"non-core" TCE3-permissive models. When compared to HLA-DPB1 allele matched pairs the risks of aGVHD2-4 increased progressively with "core" TCE3-permissive (HR 1.12 [0.98-1.28]; p=0.1012), "non-core" TCE3-permissive (HR 1.24 [1.06-1.46]; p= 0.0082), and non-permissive mismatches (HR 1.32 [1.16-1.50]; p<.0001) (Figure 1C, "core" vs. "non-core" HR 0.90 [0.80-1.01]; p=0.062). Similar albeit less significant results were obtained with the DEAV/GGPM model. The "core"/"non-core" TCE3 model was also associated with TRM with alloHCT from "core" TCE3-permissive donors showing lower risks of TRM than "non-core" TCE3-permissive (HR 0.82 [0.70-0.96]; p=0.0118) and non-permissive donors (HR 0.78 [0.68-0.88]; p=0.0002). Conclusion: Our results suggest that structural differences within TCE3 that reflect functional divergence and differential immunogenicity of alleles in this group associate with the risks of aGVHD and TRM after alloHCT. Hence, within the population of 10/10 matched donors, selection of "core" TCE3-permissive donors might reduce patient morbidity after transplantation. Figure 1 Figure 1. Disclosures Paczesny: Medical University of South Carolina: Patents & Royalties: inventor on the ST2 bispecific antibody patent application. Lee: AstraZeneca: Research Funding; Incyte: Research Funding; Janssen: Other; Kadmon: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Syndax: Research Funding; Takeda: Research Funding; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding.
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Metzing, Maximilian, Pietro Crivello, Thuja Meurer, Michel G. D. Kester, Dominik Megger, Weiqiang Chen, Peter Van Balen et al. « HLA-DM Mediates Permissiveness of HLA-DPB1 T Cell Epitope Mismatches in Unrelated HCT ». Blood 134, Supplement_1 (13 novembre 2019) : 3211. http://dx.doi.org/10.1182/blood-2019-129921.
Texte intégralRésumé :
Introduction: In 8/8 matched unrelated donor (UD) hematopoietic cell transplantation (HCT), permissive HLA-DPB1 (DP) mismatches within the same functional T Cell Epitope (TCE) group are associated with better outcomes compared to non-permissive mismatches across different TCE groups (Fleischhauer, Blood 2017). This clinical advantage has been shown to be associated with limited in vitro T cell alloreactivity (Meurer, Front Immunol 2019), which in turn is dependent on polymorphic peptide contact amino acids in the DP molecule (Crivello, Biol Blood Marrow Transplant 2015). The HLA class II immunopeptidome is shaped by the peptide editor HLA-DM (DM), and its natural antagonist HLA-DO (DO). Here we investigated the effect of DM/DO activity on the DP immunopeptidome, the breadth of the overall alloresponse to and immunogenicity of permissive and non-permissive DP mismatches, in healthy individuals and in patients after UD-HCT. Methods: HeLa cells expressing single DP alleles in the presence or absence of DM, or in the presence of DM and DO (Rutten, BBMT 2008), were generated for HLA-DPB1*04:02 (DP4) and *10:01 (DP10) as prototypes for 2 distinct TCE groups. The DP immunopeptidomes were analyzed by mass spectrometry. Alloresponses against DP were quantified by CD137 up-regulation assays after co-culture of irradiated HeLa cells with CD4+ responder T cells from 14 healthy blood donors permissive to DP4 and non-permissive to DP10, or from 2 patients referring to the University Hospital Essen, Germany, the latter alive and well >9 months after 8/8 matched UD-HCT with a permissive DP4 or a non-permissive DP10 mismatch, respectively. The breadth of the responding T cell receptor beta (TCRb) repertoire was determined by immunosequencing (Adaptive Biotechnologies, Seattle, USA). The study was performed under informed consent according to the declaration of Helsinki. Results: Reflecting their association with different TCE groups, DP4 and DP10 presented peptidomes with limited (<4%) overlap and different peptide motifs. These features were not changed by the presence or absence of DM. In contrast, the presence of DM resulted in a significant (>50%) shrinking of the peptide repertoire displayed by the same DP antigen in the absence of DM, with approximately 30% peptides shared by the same allele in the two conditions, both for DP4 and for DP10 (Figure 1A). In the presence of DM, the magnitude of the T cell alloresponse to non-permissive DP10 was significantly higher than to permissive DP4, both in healthy individuals (40.7% vs 16.3%, respectively, p<0.0001) and in the informative transplanted patients (Figure 1B). Neither the absence of DM (40.7% vs 45.3%, p=ns) nor the presence of DM with DO (71.6% vs 77.4%, p=ns) altered the magnitude of the non-permissive alloresponse to DP10. Compellingly, both the absence of DM (16.3% vs 39.0%, p<0.001) and the co-expression of DM and DO (21.6% vs 59.5%, p<0.001) significantly increased the response to permissive DP4, again both in healthy individuals and in the informative transplanted patients. The strength of the overall alloresponse was associated with the breadth of the corresponding TCRb repertoire, with significantly higher diversity (1-clonality) in response to non-permissive DP10 (mean 0.68) compared to permissive DP4 (mean 0.48) in the presence of DM, and similar high diversity against both DP antigens in its absence (mean 0.74 vs 0.75 against DP4 and DP10, respectively) in healthy individuals. In the transplanted patients, the permissive alloresponse to DP4 was dominated by a single TCRb that could be retrieved at high frequency also in ex-vivo follow-up samples from the same patient from day +195 and +363, while the non-permissive alloresponse to DP10 was polyclonal (mean 0.62 and 0.61 in the presence and absence of DM, respectively) (Figure 1C). Conclusion: Permissiveness of HLA-DPB1 TCE mismatches is dependent on the peptide editing by DM, and converted into non-permissiveness in its absence or in the presence of its antagonist DO. Permissiveness is associated with the immunopeptidomes of mismatched HLA-DP alloantigens on the MHC side, and with TCRb diversity on the alloreactive T cell side, both in healthy individuals and in patients after UD-HCT. These new mechanistic insights suggest that expression of DM and DO by leukemia or healthy tissues might modulate graft-versus-leukemia and graft-versus-host disease after permissively DP mismatched UD HCT. Disclosures No relevant conflicts of interest to declare.
Thèses sur le sujet "Permissive mismatche"
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CRIVELLO, PIETRO. « New molecular insights into HLA immunogenicity ». Doctoral thesis, Università degli Studi di Milano-Bicocca, 2012. http://hdl.handle.net/10281/29854.
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Alloreactivity is the major barrier to solid organ and hematopoietic stem cell transplantation (HSCT), determining important clinical events such as graft rejection and graft versus host disease. This biological phenomenon is due to the immunogenicity of allogeneic Human Leukocyte Antigens (HLA) expressed in transplanted tissues and recognized by T cell receptor (TCR) on the surface of alloreactive T cells. In the past, the hosting laboratory identified an immunogenic T cell epitope (TCE) encoded by a subset of HLA-DPB1 alleles, thereby defining permissive and non-permissive DPB1 mismatches between donor and recipient associated with different clinical outcomes after HSCT. Aim of this thesis is to elucidate the molecular basis underlying the different clinical impact of DPB1 mismatches in order to improve our understanding of HLA immunogenicity in the context of transplantation. To achieve this aim, we investigated if the clinical effect of DPB1 mismatches was reflected by the strength of their in vitro alloreactive T cell response and, subsequently, we characterized the alloreactive response to one of the most immunogenic DPB1 alleles, HLA-DPB1*09:01 (HLA-DP9), at the molecular level by homology modeling driven site directed mutagenesis.
The strength of the alloreactive T cell response to HLA-DP was assessed in Mixed Lymphocyte Reactions between healthy responder/stimulator pairs mismatched only at the DPB1 locus, followed by quantitative assessment of responder T cells upregulating the cell surface activation marker CD137. We observed significantly higher frequencies of activated T cells against non-permissive mismatches (n=9; mean 10.13% ± 7.51%) compared to permissive mismatches (n=15; mean 2.34% ± 2.82% p<0.05).
SDM of HLA-DP9 was performed on 6 polymorphic amino acid residues predicted to be crucial for interaction with bound peptide (positions 9, 35, 55, 69, 76 and 84), and on 2 amino acid residues putatively involved in direct interaction with the TCR (positions 56 and 57). These residues were mutated into amino acids naturally occurring in other HLA-DP variants. A lentiviral vector expression platform was used to express the wild type or mutant HLA-DP in 2 HLA homozygous reporter B lymphoblastoid Cell lines. A panel of 8 alloreactive T cell effectors, specific for wild type HLA-DPB1*09:01 (n=6) or for DPB1*10:01 and DPB1*1701, respectively, but crossreactive to DPB1*09:01 (n=2), was used to evaluate the impact of mutagenesis on T cell recognition by gIFN ELISpot or CD107a degranulation assay. For T cells specifically alloreactive to HLA-DPB1*09:01, recognition was influenced by a complex pattern of residues, which was different for each of the 6 effectors studied. In contrast, for the 2 T cells cross-reactive to HLA-DPB1*09:01, only 2 amino acids (positions 69 and 76) had an influence on allorecognition, suggesting the presence of a more restricted set of T cell epitopes in the context of cross-reactivity rather than nominal specificity. These results are consistent with the peptide involvement in alloreactivity to HLA-DPB1*09:01, and underline the complexity of allorecognition which may be one of the mechanisms underlying the immunogenicity of this molecule.
Finally, an additional collaborative study with the North Italian Program for Solid Organ Transplantation was aimed at predicting the functional role of amino acid point mutations in newly described naturally occurring variants of HLA-A3 and A32, respectively, by homology modeling. These studies confirmed data from the literature suggesting a relevant putative role of amino acid substitutions at positions 114 and 116, present in a variant of HLA-A3, on the molecular shape and charge of the peptide binding groove. In contrast, point mutations at position 151 and 258 found in two variants of HLA-A32 and A3, respectively, were not predicted to have important functional impacts, due to limited structural or biochemical changes of the groove.
In conclusion, our results shed new light on the molecular basis of T cell alloreactivity. In particular, we showed that the stronger immunogenicity of non-permissive DPB1 mismatches is reflected by a divergent and complex T cell epitope repertoire with a putative involvement of the peptide repertoire presented to the alloreactive TCRs. Identification of specific allopeptides associated with these responses will allow to further dissect their molecular basis.
Livres sur le sujet "Permissive mismatche"
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Korsgaard, Christine M. The Animal Antinomy, Part 2. Oxford University Press, 2018. http://dx.doi.org/10.1093/oso/9780198753858.003.0012.
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The intractable problems of animal ethics arise from a fundamental mismatch between morality and nature: nature resists moral reorganization. This chapter argues that we should reject the principle that “ought implies can” and do the best that we can for animals. It asks what is involved in treating animals as ends in themselves and rejects apartheid—the abolitionist’s ban on interaction between people and animals. It then examines specific practical questions. It argues that we should not eat animals, even if they come from “humane” farms, that we should not experiment on them, that there are limits on what kinds of work we may make them do. Finally, it argues that human beings need the company of animals and holds out the hope that we might achieve conditions, very different from the ones we live in now, in which keeping animals as pets and companions would be permissible.
Chapitres de livres sur le sujet "Permissive mismatche"
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Wujciak, T., et G. Opelz. « Evaluation of the permissible mismatch concept ». Dans Transplant International, 8–10. Berlin, Heidelberg : Springer Berlin Heidelberg, 1996. http://dx.doi.org/10.1007/978-3-662-00818-8_3.
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Rood, J. J., E. L. Lagaaij, I. Doxiadis, D. Roelen, G. G. Persijn et F. H. J. Claas. « Permissible Mismatches, Acceptable Mismatches and Tolerance : New Trends in Decision Making ». Dans Immunogenetics : Advances and Education, 109–20. Dordrecht : Springer Netherlands, 1997. http://dx.doi.org/10.1007/978-94-011-5486-4_13.
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Liberto, Hallie. « A Limited-Scope Analysis of Misinformation, Deception, and Permissive Consent ». Dans Green Light Ethics, 177—C7.P130. Oxford University PressOxford, 2022. http://dx.doi.org/10.1093/oso/9780192846464.003.0007.
Texte intégralRésumé :
Abstract Chapter 7 describes a variety of existing views about the effects of misinformation and deception on permissive consent. Most of these explanations appeal to the mismatch generated between one person’s actions—which are only permissible if undertaken with a right-holder’s consent—and the intended scope of the right-holder’s consent. It explains that much of the disagreement in this literature has to do with what intentions and beliefs play a role in shaping the scope of consent. The chapter investigates two broad categories of consent under misinformation: (i) the active deception of a prospective consent-giver in cases wherein the consent-recipient is morally responsible for that deception; (ii) misinformation or missing information suffered by a prospective consent-giver for which the consent-recipient is not morally responsible. The analysis is tied directly to the processes required to prevent a Divergence Strike and a Standing Strike, as they are described in Chapter 4.
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Lixinski, Lucas. « Temporalities of International Heritage Law ». Dans International Heritage Law for Communities, 106–26. Oxford University Press, 2019. http://dx.doi.org/10.1093/oso/9780198843306.003.0004.
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This chapter focuses on the way international heritage law applies across time, and the mismatch between community and state expectations of these relationships between heritage and time. While it often relies on time as a means to define heritage, international heritage law has in many respects a difficult relationship with Chronos. From the age of heritage down to the non-retroactivity of treaties which essentially resets the clock on a number of heritage disputes and injustices, the temporal application of international heritage law plays a significant role in shaping what is permissible heritage, and how the law addresses heritage. The chapter uses genocide’s relationship to cultural heritage as a means to examine how heritage plays roles before, during, and after major events, in ways that the law does not always capture constructively. Lastly, it queries the potential of international human rights law to address international heritage law’s shortcomings in this area.
Actes de conférences sur le sujet "Permissive mismatche"
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Mujahid, Suhaib. « Detecting wearable app permission mismatches : a case study on Android wear ». Dans ESEC/FSE'17 : Joint Meeting of the European Software Engineering Conference and the ACM SIGSOFT Symposium on the Foundations of Software Engineering. New York, NY, USA : ACM, 2017. http://dx.doi.org/10.1145/3106237.3121279.
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Snyder, Harold T. « Variable Speed Drives ». Dans ASME 1995 Citrus Engineering Conference. American Society of Mechanical Engineers, 1995. http://dx.doi.org/10.1115/cec1995-4101.
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The 3 C’s Cash - Control - and Coordination based on the use of variable speed drives in the Citrus Industry is covered in this paper. Proper use of variable speed drives results in more money (CASH) from Energy Savings, Reduced Maintenance cost, and Improved Efficiencies. By regulating the speed of pumps and conveyor belts, less problems from mismatched speeds occur (CONTROL). The timing of the material reaching the correct location through proper speeds of equipment means improved COORDINATION. The various types of variable speed drives and their manufacturers are discussed. The type of drives covered range from simple eddy current, with minimum control features, to electronic AC and DC drives with unlimited control functions. Paper published with permission.
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Baik, K. H., P. S. Grant, A. R. Bhatti et R. A. Shatwell. « Fabrication of SiC Fibre Reinforced MoSi2 Based Composites by Low Pressure Plasm a Spraying ». Dans ITSC 2000, sous la direction de Christopher C. Berndt. ASM International, 2000. http://dx.doi.org/10.31399/asm.cp.itsc2000p0821.
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Abstract SiC fibre reinforced SiAlON-MoSi2 composites have been manufactured by concurrent fibre winding and low pressure plasma spraying (LPPS), producing multi-layer, circumferentially fibre-reinforced composite rings. LPPS parameters for the powder used were optimised by a two-level experimental design method followed by additional tuning, achieving smooth sprayed surfaces with low matrix porosity and good deposition efficiency. The microstructure of the SiAlON-MoSi2 matrix consisted of a lamellar structure and uniformly distributed SiAlON splats throughout the MoSi2 matrix. The spray/wind composites exhibited 2% porosity and well controlled fibre distribution. Matrix cracking occurred after heat treatment at 1500°C and was attributed to the development of large tensile residual stresses during cooling due to CTE mismatch. Increasing the SiAlON to MoSi2 ratio in the composite solved the problem. Simulations based on residual stresses showed that the maximum permissible fibre volume fraction to avoid matrix cracking was 0.06 for SiC/MoSi2 and 0.23 for SiC/SiAlON(40v/o)-MoSi2.
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Alexander, Chris, et Ron Scrivner. « Analysis of Girth Welds in Pipelines Subjected to Lifting Loads ». Dans 2006 International Pipeline Conference. ASMEDC, 2006. http://dx.doi.org/10.1115/ipc2006-10480.
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Williams Gas Pipeline requested that Stress Engineering Services provide engineering services to analytically assess issues that occurred in a 30-inch pipeline due to cracked girth welds. The focus of the analytical effort was to simulate the lifting during the pipeline construction process. Using finite element methods, nominal bending stresses were calculated considering a specific set of criteria including 80-foot pipe joints, skid locations, and a given root pass weld thickness. These bending stresses were used to calculate a total stress that included stress concentration factors (SCFs) due to hi-low weld mismatch and weld profile geometry. For conservatism, residual stresses were also included in computing the total stress. As an example, the results showed that if a residual stress of 50 percent yield and a total SCF of 4.5 are assumed, the lift height should be limited to approximately 9 inches for a root pass weld thickness of 0.0625 inches. In this calculation, a stress limit of two times yield was used. Once the final stress was computed considering the range of variables, a closed-form equation was developed that integrated the variables of interest for the 30-inch pipe. This equation was used to compute data points to guide Williams in establishing permissible lift heights for a range of SCFs for the welds. A stress limit of two times the yield strength was selected as the limiting value. The details of the work presented in this paper will assist pipeline operators in developing a protocol that balances the need for rapid construction and ensuring that proper girth welds are fabricated.