Cord blood represents an alternative source of hematopoietic progenitor cells. A wide spread of cord blood banks has occurred worldwide providing repositories where cord blood units are cryopreserved and maintained ready for use. By the means of national donors registries, candidate units can be selected for a patient in need using a set of minimum essential data, mainly: HLA match categories and cell dose. The HLA system plays a primary role in immunity and consequently represents a major barrier in allografts. Due to the tolerogenic properties of cord blood, current HLA definition in cord blood banking programs is based on serological/low resolution antigenic typing for HLA–A and – B and high resolution allelic typing for -DRB1, where until 1-2 mismatches are permitted. Recently, the importance of allele-level definition of cord blood donor/recipient HLA match is modifying the current donor selection algorithm and cord blood banking programs strategies. Furthermore, the impact of non-HLA genetic factors on the clinical outcome is still debated. Finally, due to the extensive polymorphism and linkage disequilibrium, the HLA system display patterns of genetic variation worldwide that could be informative in regard to human geographic expansion, demographic history and cultural diversification. In this scenario, the cord blood banks may take part by making available their DNA archives and donors’ data collections, that include ethnic and geographical origin extended back to grandparents for both the maternal and paternal lineage. During these three years of doctoral studies, I mainly focused my research activity on three projects aimed to investigate the genetics of cord blood transplantation. The first project I worked on aimed to validate a platform that enables to achieve high definition HLA typing of cord blood units at time of banking in a quick, accurate and cost-effective manner, in response to the increasing importance of allele-level donor-recipient match on the outcome after cord blood transplantation. The second research project aimed at evaluating the impact of non-HLA genetics on clinical outcome after cord blood transplantation. In a multicentric retrospective analysis we demonstrated the association of CTLA-4 GG of the cord with lower survival and higher non–relapse mortality, suggesting that this polymorphism might be considered for cord blood donor selection. The third study was carried out on 48 cord blood donors with maternal or paternal geographical origin documented to be from Central and South America aiming to investigate the contribution of HLA polymorphisms in human population genetics, in parallel to mitochondrial DNA and Y-chromosome analysis. The high resolution definition of class II HLA alleles, confirmed to be able to provide complementary information, in particular if the maternal HLA typing is available, enabling the definition of the maternal (and indirectly the paternal) inherited haplotype. Moreover the samples from Ecuador and Peru contributed to a study on mitogenomes analysis aimed to shed light on the Paleo-Indian entry into South America. Taken together, the data reported in this thesis remark the fact that the genetics of cord blood transplantation is still an evolving field of endeavour, where multidisciplinary approaches may contribute to the progresses achieved in many areas of investigation, involving also other apparently not related spheres of interest such as the study of human migrations.

Cord blood represents an alternative source of hematopoietic progenitor cells. A wide spread of cord blood banks has occurred worldwide providing repositories where cord blood units are cryopreserved and maintained ready for use. By the means of national donors registries, candidate units can be selected for a patient in need using a set of minimum essential data, mainly: HLA match categories and cell dose. The HLA system plays a primary role in immunity and consequently represents a major barrier in allografts. Due to the tolerogenic properties of cord blood, current HLA definition in cord blood banking programs is based on serological/low resolution antigenic typing for HLA–A and – B and high resolution allelic typing for -DRB1, where until 1-2 mismatches are permitted. Recently, the importance of allele-level definition of cord blood donor/recipient HLA match is modifying the current donor selection algorithm and cord blood banking programs strategies. Furthermore, the impact of non-HLA genetic factors on the clinical outcome is still debated. Finally, due to the extensive polymorphism and linkage disequilibrium, the HLA system display patterns of genetic variation worldwide that could be informative in regard to human geographic expansion, demographic history and cultural diversification. In this scenario, the cord blood banks may take part by making available their DNA archives and donors’ data collections, that include ethnic and geographical origin extended back to grandparents for both the maternal and paternal lineage. During these three years of doctoral studies, I mainly focused my research activity on three projects aimed to investigate the genetics of cord blood transplantation. The first project I worked on aimed to validate a platform that enables to achieve high definition HLA typing of cord blood units at time of banking in a quick, accurate and cost-effective manner, in response to the increasing importance of allele-level donor-recipient match on the outcome after cord blood transplantation. The second research project aimed at evaluating the impact of non-HLA genetics on clinical outcome after cord blood transplantation. In a multicentric retrospective analysis we demonstrated the association of CTLA-4 GG of the cord with lower survival and higher non–relapse mortality, suggesting that this polymorphism might be considered for cord blood donor selection. The third study was carried out on 48 cord blood donors with maternal or paternal geographical origin documented to be from Central and South America aiming to investigate the contribution of HLA polymorphisms in human population genetics, in parallel to mitochondrial DNA and Y-chromosome analysis. The high resolution definition of class II HLA alleles, confirmed to be able to provide complementary information, in particular if the maternal HLA typing is available, enabling the definition of the maternal (and indirectly the paternal) inherited haplotype. Moreover the samples from Ecuador and Peru contributed to a study on mitogenomes analysis aimed to shed light on the Paleo-Indian entry into South America. Taken together, the data reported in this thesis remark the fact that the genetics of cord blood transplantation is still an evolving field of endeavour, where multidisciplinary approaches may contribute to the progresses achieved in many areas of investigation, involving also other apparently not related spheres of interest such as the study of human migrations.

Investigating the genetics of cord blood transplantation: from classical and non-classical HLA towards non-HLA genetics and more

BERGAMASCHI, PAOLA
2018-01-16

Abstract

Cord blood represents an alternative source of hematopoietic progenitor cells. A wide spread of cord blood banks has occurred worldwide providing repositories where cord blood units are cryopreserved and maintained ready for use. By the means of national donors registries, candidate units can be selected for a patient in need using a set of minimum essential data, mainly: HLA match categories and cell dose. The HLA system plays a primary role in immunity and consequently represents a major barrier in allografts. Due to the tolerogenic properties of cord blood, current HLA definition in cord blood banking programs is based on serological/low resolution antigenic typing for HLA–A and – B and high resolution allelic typing for -DRB1, where until 1-2 mismatches are permitted. Recently, the importance of allele-level definition of cord blood donor/recipient HLA match is modifying the current donor selection algorithm and cord blood banking programs strategies. Furthermore, the impact of non-HLA genetic factors on the clinical outcome is still debated. Finally, due to the extensive polymorphism and linkage disequilibrium, the HLA system display patterns of genetic variation worldwide that could be informative in regard to human geographic expansion, demographic history and cultural diversification. In this scenario, the cord blood banks may take part by making available their DNA archives and donors’ data collections, that include ethnic and geographical origin extended back to grandparents for both the maternal and paternal lineage. During these three years of doctoral studies, I mainly focused my research activity on three projects aimed to investigate the genetics of cord blood transplantation. The first project I worked on aimed to validate a platform that enables to achieve high definition HLA typing of cord blood units at time of banking in a quick, accurate and cost-effective manner, in response to the increasing importance of allele-level donor-recipient match on the outcome after cord blood transplantation. The second research project aimed at evaluating the impact of non-HLA genetics on clinical outcome after cord blood transplantation. In a multicentric retrospective analysis we demonstrated the association of CTLA-4 GG of the cord with lower survival and higher non–relapse mortality, suggesting that this polymorphism might be considered for cord blood donor selection. The third study was carried out on 48 cord blood donors with maternal or paternal geographical origin documented to be from Central and South America aiming to investigate the contribution of HLA polymorphisms in human population genetics, in parallel to mitochondrial DNA and Y-chromosome analysis. The high resolution definition of class II HLA alleles, confirmed to be able to provide complementary information, in particular if the maternal HLA typing is available, enabling the definition of the maternal (and indirectly the paternal) inherited haplotype. Moreover the samples from Ecuador and Peru contributed to a study on mitogenomes analysis aimed to shed light on the Paleo-Indian entry into South America. Taken together, the data reported in this thesis remark the fact that the genetics of cord blood transplantation is still an evolving field of endeavour, where multidisciplinary approaches may contribute to the progresses achieved in many areas of investigation, involving also other apparently not related spheres of interest such as the study of human migrations.
16-gen-2018
Cord blood represents an alternative source of hematopoietic progenitor cells. A wide spread of cord blood banks has occurred worldwide providing repositories where cord blood units are cryopreserved and maintained ready for use. By the means of national donors registries, candidate units can be selected for a patient in need using a set of minimum essential data, mainly: HLA match categories and cell dose. The HLA system plays a primary role in immunity and consequently represents a major barrier in allografts. Due to the tolerogenic properties of cord blood, current HLA definition in cord blood banking programs is based on serological/low resolution antigenic typing for HLA–A and – B and high resolution allelic typing for -DRB1, where until 1-2 mismatches are permitted. Recently, the importance of allele-level definition of cord blood donor/recipient HLA match is modifying the current donor selection algorithm and cord blood banking programs strategies. Furthermore, the impact of non-HLA genetic factors on the clinical outcome is still debated. Finally, due to the extensive polymorphism and linkage disequilibrium, the HLA system display patterns of genetic variation worldwide that could be informative in regard to human geographic expansion, demographic history and cultural diversification. In this scenario, the cord blood banks may take part by making available their DNA archives and donors’ data collections, that include ethnic and geographical origin extended back to grandparents for both the maternal and paternal lineage. During these three years of doctoral studies, I mainly focused my research activity on three projects aimed to investigate the genetics of cord blood transplantation. The first project I worked on aimed to validate a platform that enables to achieve high definition HLA typing of cord blood units at time of banking in a quick, accurate and cost-effective manner, in response to the increasing importance of allele-level donor-recipient match on the outcome after cord blood transplantation. The second research project aimed at evaluating the impact of non-HLA genetics on clinical outcome after cord blood transplantation. In a multicentric retrospective analysis we demonstrated the association of CTLA-4 GG of the cord with lower survival and higher non–relapse mortality, suggesting that this polymorphism might be considered for cord blood donor selection. The third study was carried out on 48 cord blood donors with maternal or paternal geographical origin documented to be from Central and South America aiming to investigate the contribution of HLA polymorphisms in human population genetics, in parallel to mitochondrial DNA and Y-chromosome analysis. The high resolution definition of class II HLA alleles, confirmed to be able to provide complementary information, in particular if the maternal HLA typing is available, enabling the definition of the maternal (and indirectly the paternal) inherited haplotype. Moreover the samples from Ecuador and Peru contributed to a study on mitogenomes analysis aimed to shed light on the Paleo-Indian entry into South America. Taken together, the data reported in this thesis remark the fact that the genetics of cord blood transplantation is still an evolving field of endeavour, where multidisciplinary approaches may contribute to the progresses achieved in many areas of investigation, involving also other apparently not related spheres of interest such as the study of human migrations.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11571/1214800
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