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2.
Bone Marrow Transplant ; 50(4): 540-4, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25621806

ABSTRACT

We determined whether assessment of the immunogenicity of individual donor-recipient HLA mismatches based on differences in their amino-acid sequence and physiochemical properties predicts clinical outcome following haematopoietic SCT (HSCT). We examined patients transplanted with 9/10 single HLA class I-mismatched grafts (n=171) and 10/10 HLA-A-, -B-, -C-, -DRB1- and -DQB1-matched grafts (n=168). A computer algorithm was used to determine the physiochemical disparity (electrostatic mismatch score (EMS) and hydrophobic mismatch score (HMS)) of mismatched HLA class I specificities in the graft-versus-host direction. Patients transplanted with HLA-mismatched grafts with high EMS/HMS had increased incidence of ⩾grade II acute GVHD (aGVHD) compared with patients transplanted with low EMS/HMS grafts; patients transplanted with low and medium EMS/HMS grafts had similar incidence of aGVHD to patients transplanted with 10/10 HLA-matched grafts. Mortality was higher following single HLA-mismatched HSCT but was not correlated with HLA physiochemical disparity. Assessment of donor-recipient HLA incompatibility based on physiochemical HLA disparity may enable better selection of HLA-mismatched donors in HSCT.


Subject(s)
Databases, Factual , Graft vs Host Disease , HLA Antigens , Hematopoietic Stem Cell Transplantation , Unrelated Donors , Adolescent , Adult , Algorithms , Allografts , Child , Female , Graft vs Host Disease/etiology , Graft vs Host Disease/immunology , Graft vs Host Disease/mortality , HLA Antigens/chemistry , HLA Antigens/genetics , HLA Antigens/immunology , Humans , Incidence , Male , Netherlands , Risk Factors
3.
Transpl Immunol ; 30(2-3): 59-64, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24440708

ABSTRACT

INTRODUCTION: Previously we developed a weighted amino acid (AA) mismatch score predictive for cytotoxic T cell (CTL) alloreactivity (in vitro CTLp assay) based on the structure of the HLA class I molecule. The aim of this study is to confirm the clinical relevance of the CTLp assay and to validate the AA mismatch score as an alternative and easy to use tool to predict permissible mismatches in hematopoietic stem cell transplantation (HSCT). METHODS: We selected patients transplanted with a 9/10 single HLA class I mismatched graft (n=171) at three Dutch HSCT centers. A CTLp assay was performed in 73 donor-recipient pairs. As a control we selected 168 10/10 HLA matched pairs that were matched to the 9/10 single HLA class I mismatched pairs for HSCT year, donor type, patient age and diagnosis. RESULTS: We observed that pairs with negative a CTLp assay had statistically significant decreased incidence of mortality after HSCT comparable to that of 10/10 HLA matched pairs. However, the weighted AA mismatch score did not significantly predict any HSCT end point of interest. CONCLUSION: Further investigation is needed to unravel the mechanisms involved in causing the beneficial effect of a negative CTLp assay, before other alternative tools to predict HSCT outcome may be developed.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Hematopoietic Stem Cell Transplantation , Histocompatibility Antigens Class I/immunology , Translational Research, Biomedical , Unrelated Donors , Adolescent , Adult , Age Factors , Aged , Allografts , Child , Child, Preschool , Female , Humans , Infant , Male , Middle Aged , Netherlands , Predictive Value of Tests
4.
Bone Marrow Transplant ; 48(4): 483-90, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23064039

ABSTRACT

The MHC region on chromosome 6 contains a large number of non-HLA genes next to the HLA genes. Matching for HLA in unrelated hematopoietic SCT (HSCT) does not necessarily mean that these non-HLA genes are also matched. We selected 348 Northwest European patients transplanted with an HLA-A-, -B-, -C-, -DRB1-, -DQB1-matched unrelated donor (MUD) between 1987 and 2008. Patients' haplotypes were identified via descend. We were unable to determine the haplotypes of the donor; therefore we used frequent haplotypes (FH) in high linkage disequilibrium (LD) as a proxy for haplotype matching. Presence of a FH in a patient positively affected the probability and speed of identifying a matched unrelated donor. Competing risk survival analysis showed that patients with one or two FH have a statistically significantly decreased probability of developing ≥ grade II acute GVDH (aGVHD) without increased risk of relapse compared to patients without FH (HR (95% CI): 0.53 (0.31-0.91)). This association was strongest for those FH with the highest LD between both HLA-A and -C or -B, and HLA-C or -B and -DRB1 (HR (95% CI): 0.49 (0.26-0.92)). These results extend evidence that non-HLA allele coding regions have a significant impact on development of ≥ grade II aGVHD. We conclude that there is more to successful HSCT than matching for HLA genes.


Subject(s)
Donor Selection/methods , Graft vs Host Disease/mortality , HLA Antigens , Haplotypes , Hematopoietic Stem Cell Transplantation , Linkage Disequilibrium , Unrelated Donors , Acute Disease , Adolescent , Adult , Child , Child, Preschool , Disease-Free Survival , Female , Graft vs Host Disease/etiology , Graft vs Host Disease/pathology , Graft vs Host Disease/prevention & control , Histocompatibility Testing , Humans , Infant , Male , Retrospective Studies , Risk Factors , Survival Rate , Transplantation, Homologous
5.
Bone Marrow Transplant ; 47(5): 677-83, 2012 May.
Article in English | MEDLINE | ID: mdl-21860428

ABSTRACT

To investigate whether all patients in need of an allogeneic hematopoietic SCT (HSCT) are offered one, we retrospectively investigated the policy for all children diagnosed with myelodysplastic syndrome (n=90) or relapsed AML (n=75) between 1998 and 2008. These children are registered at diagnosis and treated according to protocols of the Dutch Childhood Oncology Group, which provides accurate disease incidence data and protocol-indicated appropriateness for HSCT. For 48 (30%) patients, a family donor was identified; for 90 (57%) patients, an unrelated donor (UD) search was performed; and for 21 (13%) patients, no UD search was initiated. Reasons for not initiating an UD search include: progressive disease (n=10), conserve quality of life (n=1), stable disease (n=3), immunosuppressive therapy (n=2), patient death (n=3), patient lives abroad (n=1) and second relapse (n=1). On the basis of the time interval between date of diagnosis and date of death/last follow-up, for eight (5%) patients, it may be questioned why an UD search was not performed. The fact that 95% of all children are given the option of an allogeneic HSCT is encouraging and reasons not to transplant seem fair in most cases.


Subject(s)
Health Services Accessibility , Hematopoietic Stem Cell Transplantation/statistics & numerical data , Leukemia, Myeloid, Acute/therapy , Myelodysplastic Syndromes/therapy , Adolescent , Child , Child, Preschool , Female , Humans , Netherlands , Recurrence , Retrospective Studies , Transplantation, Homologous , Unrelated Donors
7.
Bone Marrow Transplant ; 41(1): 1-9, 2008 Jan.
Article in English | MEDLINE | ID: mdl-17982505

ABSTRACT

On 16 November 2005, we celebrated the milestone when 10 million donors had been registered in Bone Marrow Donors Worldwide (BMDW). Since then another million donors have been added in little more than a year. It seems an appropriate time for reassessment and to ask whether we are on the right track or not. We will do so by discussing the strength, weaknesses, opportunities and threats of the unrelated stem cell donor operation.


Subject(s)
Bone Marrow Transplantation , Tissue Donors , Bone Marrow Transplantation/mortality , Graft vs Host Disease/etiology , Histocompatibility Testing , Humans , Registries , Time Factors , Tissue and Organ Procurement
8.
Bone Marrow Transplant ; 40(3): 193-200, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17529995

ABSTRACT

A fully major histocompatilbility complex (MHC) matched donor is not available for the majority of patients in need of a haematopoietic stem cell transplantation (SCT), which illustrates the need for a tool to define acceptable MHC disparities. Previously, we noticed that a variety of single MHC class I mismatched allogeneic donor-recipient pairs did not elicit an allogeneic cytotoxic-lymphocyte (CTL) response in vitro if the MHC amino-acid sequences had five or more differences in the alpha-helices plus five or more differences in the beta-sheet (> or =5alpha5beta) (7). To address the clinical relevance of this observation, we analysed CTL precursor (CTLp) assay outcome and SCT outcome in 53 Dutch recipients of a single MHC class I mismatched graft from an unrelated donor. Overall patient survival was 44% after 4 years. In multivariate analysis, recipients of a > or =5alpha5beta mismatched graft with negative CTLp frequencies in vitro before transplantation demonstrated superior survival: survival at 4 years was 80% as compared to 47% in recipients of other mismatched grafts with negative CTLp frequencies (hazard ratio=0.131; 95% CI=(0.03-0.61); P=0.009). This option of acceptable mismatches may enlarge the pool of potentially acceptable stem cell donors.


Subject(s)
Hematopoietic Stem Cell Transplantation , Histocompatibility Antigens Class I , Histocompatibility , Living Donors , Adolescent , Adult , Aged , Autoimmune Diseases/immunology , Autoimmune Diseases/mortality , Autoimmune Diseases/therapy , CD8-Positive T-Lymphocytes/immunology , Child , Child, Preschool , Donor Selection , Female , Follow-Up Studies , Genetic Diseases, Inborn/mortality , Genetic Diseases, Inborn/therapy , Hematologic Diseases/immunology , Hematologic Diseases/mortality , Hematologic Diseases/therapy , Hematopoietic Stem Cell Transplantation/mortality , Histocompatibility/genetics , Histocompatibility Antigens Class I/genetics , Histocompatibility Antigens Class I/immunology , Humans , Infant , Male , Middle Aged , Netherlands , Protein Structure, Secondary , Survival Rate , Transplantation, Homologous
9.
Semin Hematol ; 42(2): 104-11, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15846576

ABSTRACT

Confrontation of the unborn child immune system with the noninherited maternal antigens (NIMAs) has a lifelong modulating impact on the immune response of the child against the NIMAs. In this review we summarize the clinical evidence for the existence of the NIMA effect, discuss the possible cellular and molecular basis of the phenomenon, and outline the necessity of further clinical research.


Subject(s)
Antigens/immunology , Graft vs Host Disease/immunology , Maternal-Fetal Exchange/immunology , Stem Cell Transplantation , Antigens/genetics , Female , Graft vs Host Disease/genetics , Humans , Male , Maternal-Fetal Exchange/genetics , Pregnancy , Siblings , Transplantation, Homologous
10.
Bone Marrow Transplant ; 35(7): 645-52, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15723086

ABSTRACT

Many patients do not reach haematopoietic stem cell transplantation. Shortage of unrelated donors (UDs) is still seen as the main cause. However, with a worldwide UD pool containing more than 8 million donors, it is possible that other impediments are becoming more important. We analysed 549 UD searches for Dutch patients, performed between 1987 and 2000, in order to find the reasons for failure or success to reach transplantation. Between 1996 and 2000, 59% of the patients of Northwest European origin received a graft from an UD with a median time span of 4.4 months from the start of the search. In all, 11% of the patients lacked a compatible donor, while 30% became medically unfit for transplantation. This is in contrast to the patients of non-Northwest European origin for whom UD shortage is still the most important impediment; only 32% were transplanted while 50% lacked a compatible donor. We conclude that the shortage of donors is no longer the biggest constraint in unrelated stem cell transplantation for patients of Northwest European origin. It may be more effective to optimize the chance on transplantation by making the search process more efficient.


Subject(s)
Hematopoietic Stem Cell Transplantation/statistics & numerical data , Registries , Tissue Donors/supply & distribution , Data Collection , Histocompatibility , Humans , Netherlands , Time Factors
11.
Bone Marrow Transplant ; 32(2): 121-4, 2003 Jul.
Article in English | MEDLINE | ID: mdl-12838274

ABSTRACT

The major goal of the World Marrow Donor Association (WMDA) is to facilitate the transfer of hematopoietic cells for transplantation purposes across international borders. It also has the goal of establishing guidelines on ethical, technical, medical, and financial aspects that concern the donor and donor-cell transfer. It has a Board and five Working Groups, namely the Donor Registry Working Group, the Quality Assurance Group, the Ethic Working Group, the Finance Working Group, and the Clinical Working Group. It has three types of membership, that is, full organizational membership, nonvoting organizational membership, and individual corresponding membership. Current important projects are speeding up the search process, accreditation of registries and collecting information about severe adverse effects in donors.


Subject(s)
Hematopoietic Stem Cell Transplantation , Registries , Tissue Donors , Biological Specimen Banks/organization & administration , Hematopoietic Stem Cell Transplantation/ethics , Hematopoietic Stem Cell Transplantation/standards , Hematopoietic Stem Cell Transplantation/statistics & numerical data , Humans , International Cooperation
12.
Transfus Clin Biol ; 8(3): 315-7, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11499985

ABSTRACT

Blood transfusions can induce both immune activation and immunosuppression. The former is expressed by the induction of HLA alloantibodies and T cell activation, while the latter is accompanied by enhanced graft survival in transfused versus non-transfused recipients. The immunological mechanism leading to downregulation of the alloimmune response has not yet been elucidated. Possible explanations include the induction of a Th2 response by non-professional antigen presentation by the transfused blood cells and blockage of alloreactive T cell reactivity by soluble HLA and soluble FasL in the supernatant of blood components. These mechanisms, however, do not explain the observations which have shown that the degree of HLA compatibility between the transfusion donor and patient is a determining factor. Transfusions in which the donor blood shares at least one HLA-DR antigen with the recipient induce tolerance, while fully HLA-DR mismatched transfusions lead to immunization. The importance of HLA-DR sharing suggests a central role for CD4+ regulatory T cells. In this case, indirect recognition of an allopeptide in the context of self-HLA-DR on the transfusion donor by CD4+ T cells of the recipient might be the clue to the induction of tolerance. Recent data from our laboratory in fact show that CD4+ T cells specific for an allopeptide in the context of self HLA-DR are able to downregulate the alloimmune response of autologous T cells. As these regulatory T cells produce IL-10, they may also be involved in the extension of tolerance via their modulatory effect on dendritic cells. It remains to be established whether these regulatory T cells are indeed responsible for the 'blood transfusion effect' in organ transplantation.


Subject(s)
Blood Transfusion , CD4-Positive T-Lymphocytes/immunology , Disease Susceptibility , HLA Antigens/immunology , Histocompatibility , Humans , Immune Tolerance , Immunization , Immunosuppression Therapy , Infections/etiology , Isoantibodies/biosynthesis , Lymphocyte Activation , Neoplasm Recurrence, Local/etiology , T-Lymphocyte Subsets/immunology , Transfusion Reaction , Transplantation Immunology
13.
Proc Natl Acad Sci U S A ; 98(12): 6806-11, 2001 Jun 05.
Article in English | MEDLINE | ID: mdl-11381117

ABSTRACT

The alloreactive human T cell clone MBM15 was found to exhibit dual specificity recognizing both an antigen in the context of the HLA class I A2 molecule and an antigen in the context of the HLA class II DR1. We demonstrated that the dual reactivity that was mediated via a single clonal T cell population depended on specific peptide binding. For complete recognition of the HLA-A2-restricted specificity the interaction of CD8 with HLA class I is essential. Interestingly, interaction of the CD8 molecule with HLA class I contributed to the HLA-DR1-restricted specificity. T cell clone MBM15 expressed two in-frame T cell receptor (TCR) Valpha transcripts (Valpha1 and Valpha2) and one TCR Vbeta transcript (Vbeta13). To elucidate whether two TCR complexes were responsible for the dual recognition or one complex, cytotoxic T cells were transduced with retroviral vectors encoding the different TCR chains. Only T cells transduced with the TCR Valpha1Vbeta13 combination specifically recognized both the HLA-A2(+) and HLA-DR1(+) target cells, whereas the Valpha2Vbeta13 combination did not result in a TCR on the cell surface. Thus a single TCRalphabeta complex can have dual specificity, recognizing both a peptide in the context of HLA class I as well as a peptide in the context of HLA class II. Transactivation of T cells by an unrelated antigen in the context of HLA class II may evoke an HLA class I-specific T cell response. We propose that this finding may have major implications for immunotherapeutic interventions and insight into the development of autoimmune diseases.


Subject(s)
HLA-A2 Antigen/immunology , HLA-DR1 Antigen/immunology , Receptors, Antigen, T-Cell, alpha-beta/physiology , T-Lymphocytes/immunology , CD8 Antigens/physiology , Cross Reactions , Humans
14.
Proc Natl Acad Sci U S A ; 98(7): 3988-91, 2001 Mar 27.
Article in English | MEDLINE | ID: mdl-11274421

ABSTRACT

Antigens of pathogenic microbes that mimic autoantigens are thought to be responsible for the activation of autoreactive T cells. Viral infections have been associated with the development of the neuroendocrine autoimmune diseases type 1 diabetes and stiff-man syndrome, but the mechanism is unknown. These diseases share glutamic acid decarboxylase (GAD65) as a major autoantigen. We screened synthetic peptide libraries dedicated to bind to HLA-DR3, which predisposes to both diseases, using clonal CD4(+) T cells reactive to GAD65 isolated from a prediabetic stiff-man syndrome patient. Here we show that these GAD65-specific T cells crossreact with a peptide of the human cytomegalovirus (hCMV) major DNA-binding protein. This peptide was identified after database searching with a recognition pattern that had been deduced from the library studies. Furthermore, we showed that hCMV-derived epitope can be naturally processed by dendritic cells and recognized by GAD65 reactive T cells. Thus, hCMV may be involved in the loss of T cell tolerance to autoantigen GAD65 by a mechanism of molecular mimicry leading to autoimmunity.


Subject(s)
Antigens, Viral/immunology , Cytomegalovirus/immunology , Glutamate Decarboxylase/immunology , T-Lymphocytes/immunology , Autoantibodies/immunology , Autoantigens/immunology , Autoimmunity , Cross Reactions , Epitopes/immunology , Humans , In Vitro Techniques
15.
Vox Sang ; 78 Suppl 2: 273-5, 2000.
Article in English | MEDLINE | ID: mdl-10938968

ABSTRACT

Blood transfusions can affect the immune response in two opposite ways. They may either lead to immunization or to tolerance induction. Immunization is reflected by the induction of HLA alloantibodies and T cell activation while the induction of tolerance is suggested by the enhanced graft survival in transfused versus non-transfused recipients. The immunological mechanism leading to downregulation of the alloimmune response is not clear. One possible explanation is the induction of a Th2 response by non-professional antigen presentation by the transfused blood cells. On the other hand, evidence is accumulating that the degree of HLA compatibility between transfusion donor and patient is a determining factor. Transfusions sharing at least one HLA-DR antigen with the recipient induce tolerance while fully HLA-DR mismatched transfusions lead to immunization. The importance of the degree of HLA-DR sharing suggests a central role for CD4+ regulatory T cells. We hypothesize that indirect recognition of an allopeptide in the context of self-HLA-DR on the transfusion donor by CD4+ T cells of the recipient might be the clue to tolerance induction. Preliminary data show indeed that CD4+ T cells specific for an allopeptide in the context of self HLA-DR are able to downregulate the alloimmune response of autologous T cells. Further analysis of transplanted patients, who have received an HLA-DR shared transfusion, should reveal whether such CD4+ regulatory T cells are indeed responsible for the beneficial effect of pretransplant blood transfusions.


Subject(s)
Blood Transfusion , Immunity , Animals , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/immunology , Histocompatibility Testing , Humans , Immune Tolerance , Immunization , Isoantigens/blood , Isoantigens/immunology
16.
World J Surg ; 24(7): 823-7, 2000 Jul.
Article in English | MEDLINE | ID: mdl-10833250

ABSTRACT

Although HLA matching can improve organ graft survival, well matched grafts fail and poorly matched ones survive. Recently evidence has been found that perinatal exposure to noninherited antigens (NIMAs) has a lifelong impact on the immune repertoire of the individual. The state of the art of the influence of NIMAs on graft survival is summarized. These findings could lead to a better understanding of the allograft reaction.


Subject(s)
HLA Antigens/physiology , Organ Transplantation , Animals , Graft Rejection/immunology , Graft Survival/immunology , Histocompatibility Testing , Humans , Phenotype
17.
World J Surg ; 24(7): 834-43, 2000 Jul.
Article in English | MEDLINE | ID: mdl-10833252

ABSTRACT

The transplantation of organs, cells, and tissues has burgeoned during the last quarter century, with the development of multiple new specialty fields. However, the basic principles that made this possible were established over a three-decade period, beginning during World War II and ending in 1974. At the historical consensus conference held at UCLA in March 1999, 11 early workers in the basic science or clinical practice of transplantation (or both) reached agreement on the most significant contributions of this era that ultimately made transplantation the robust clinical discipline it is today. These discoveries and achievements are summarized here in six tables and annotated with references.


Subject(s)
Organ Transplantation/history , Transplantation Immunology , Animals , History, 20th Century , Humans , Los Angeles , Organ Transplantation/trends , Universities
18.
Immunol Today ; 21(6): 269-73, 2000 Jun.
Article in English | MEDLINE | ID: mdl-10825738

ABSTRACT

Recent studies suggest that exposure of the fetus and newborn to non-inherited maternal major histocompatibility complex HLA antigens (NIMA) has a life-long effect on allograft recognition that could influence tolerance of organ grafts. NIMA also appear to influence disease susceptibility. Here, Jon van Rood and Frans Claas discuss evidence that three HLA haplotypes, those inherited from the parents plus NIMA, shape the immune response.


Subject(s)
Autoantigens/immunology , Fetus/immunology , HLA Antigens/immunology , Immune Tolerance/immunology , Isoantigens/immunology , Kidney Transplantation/immunology , Maternal-Fetal Exchange , Tissue Donors , Transplantation Immunology , Age Factors , Animals , Blood Transfusion , Chimera/immunology , Dogs , Fathers , Female , Graft Enhancement, Immunologic , Graft Rejection/immunology , Graft Rejection/prevention & control , HLA Antigens/genetics , Haplotypes/immunology , Histocompatibility , Humans , Lymphocyte Culture Test, Mixed , Male , Mice , Mothers , Nuclear Family , Pregnancy , Prenatal Exposure Delayed Effects , Transplantation, Homologous/immunology
20.
Transplantation ; 69(3): 411-7, 2000 Feb 15.
Article in English | MEDLINE | ID: mdl-10706052

ABSTRACT

BACKGROUND: The beneficial effect on graft survival achieved by pretransplant blood transfusions is well established. Previous studies have shown that the degree of major histocompatibility complex (MHC) (mis)-match between the transfusion donor and the recipient plays a determining role. However, other factors are also involved. In this study, we explored the hypothesis that, in addition to sharing of MHC antigens between the transfusion donor and the recipient, the MHC type of the organ donor is also of importance. METHODS: To mimic the human situation, F1 mice, rather than inbred strains, were pretreated with haplotype-shared allogeneic whole blood transfusions and transplanted with hearts of organ donors with different matched or mismatched H2 haplotypes. RESULTS: When a heart was transplanted 1 week after donor-specific transfusion (DST; blood transfusion donor=organ donor), an excellent prolongation of graft survival was obtained (median survival time: 77 days vs. 9 days in untreated mice). However, this was only the case when a haplotype was shared with the recipient; a DST given with no match between organ donor (=BT donor) and recipient did not induce any prolongation. Furthermore, in order to obtain the optimal beneficial effect of a haplotype-shared blood transfusion, the other haplotype of the transfusion donor had to be mismatched with the recipient. The immunogenetic studies showed that haplotype-shared blood transfusions in combinations where the H2 type of the organ donor differed from that of the transfusion donor are less efficient in inducing prolongation of graft survival. CONCLUSIONS: These results demonstrate that haplotype-shared blood transfusions can induce a significantly prolonged survival of cardiac allografts in F1 mice. The immunogenetic studies suggest that presentation of alloantigen-derived peptides in the context of self MHC (the indirect pathway of allorecognition) is essential for the beneficial effect of haplotype-shared blood transfusions.


Subject(s)
Blood Transfusion , Graft Survival , Heart Transplantation , Transplantation Immunology , Animals , Graft Survival/immunology , H-2 Antigens/immunology , Haplotypes , Humans , Mice , Transplantation, Homologous
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