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Investigating the Genetics of Cord Blood Transplantation: from Classical and Non-Classical HLA Towards Non-HLA Genetics and More

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Investigating the Genetics of Cord Blood Transplantation: from Classical and Non-Classical HLA Towards Non-HLA Genetics and More å UNIVERSITÀ DEGLI STUDI DI PAVIA Dipartimento di Biologia e Biotecnologie “Lazzaro Spallanzani” Investigating the genetics of cord blood transplantation: from classical and non-classical HLA towards non-HLA genetics and more Paola Bergamaschi Dottorato di Ricerca in Genetica, Biologia Molecolare e Cellulare XXX Ciclo – A.A. 2014-2017 UNIVERSITÀ DEGLI STUDI DI PAVIA Dipartimento di Biologia e Biotecnologie “Lazzaro Spallanzani” Investigating the genetics of cord blood transplantation: from classical and non-classical HLA towards non-HLA genetics and more Paola Bergamaschi Supervised by Prof. Laura Salvaneschi and Prof. Antonio Torroni Dottorato di Ricerca in Genetica, Biologia Molecolare e Cellulare XXX Ciclo – A.A. 2014-2017 This thesis is dedicated to my beloved grandmothers, Piera and Maria. May their force be with me. ∞ «...os homini sublime dedit caelumque videre iussit et erectos ad sidera tollere vultus». (P.Ovidii Nasonis, Met., I, 85-86) ___________________________________________________________________ On the cover: a group of women carrying their products to the Chimbote market, Chimborazo region, Ecuador, 1998 (modified from a photograph by Sebastião Salgado). On the background: the schematic representation of the HLA region, low right, mitochondrial DNA (mtDNA), up left, and Y chromosome (Y-chr), up right. Abstract Cord blood represents an alternative source of hematopoietic progenitor cells for transplantation in patients with both hematological and inborn disorders. Thus cord blood banks have become common worldwide providing repositories for cryopreserved cord blood units that are 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 required for the search procedure, mainly relying on HLA match categories and cell dose. The HLA system plays a primary role in immunity and consequently represents, in allografts between non HLA identical individuals, a major barrier that need to be overcome to contrast the occurrence of immunological complications such as graft rejection and Graft versus Host Disease. Due to the tolerogenic properties of cord blood, donor/recipient HLA match is less stringent in this setting. Therefore 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 up to 1-2 mismatches are permitted. Recently, the impact of allele-level definition of cord blood donor/recipient HLA match has been reported as increasingly relevant and is modifying not only the current donor selection algorithm but also cord blood banking programs strategies. Furthermore, the impact of non-HLA genetic factors on the clinical outcome, that could explain at least in part the occurrence of unexpected complications in HLA- matched transplants (or their absence in HLA-mismatched ones), is still debated. Due to the extensive polymorphism, the HLA system displays considerable population diversity. Linkage disequilibrium, that is the existence of non-random allele combinations that tend to be inherited together as genes blocks (haplotypes), leads to patterns of HLA genetic variation worldwide that could be informative in regard to human geographic expansions, demographic history and cultural diversification. Along with the improvements in molecular-based typing technologies, it has been recently reasserted that, besides mitochondrial DNA and Y-chromosome (uniparental markers), the immunogenetic polymorphisms still may represent an important and complementary tool for population studies. In this scenario, cord blood banks may play an important role by making available their DNA samples archive and their donors‟ data collections, which include ethnic and geographical origin extended back to grandparents for both the maternal and paternal lineages. Furthermore, the organization of cord blood banks in networks that comprise the national registries may amplify the contribution in this setting. During the three years of my doctoral studies, I mainly focused my research activity on three projects aimed to investigate the genetics of cord blood transplantation, from classical and non-classical HLA towards non-HLA genetics, including population genetics. The first project 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, high definition of both class I and II HLA loci at time of listing is a way to improve the attractiveness of our Cord Blood Bank inventory in Pavia, reducing the time for donor search and procurement and simplifying donor choice, in particular for patients of non-European heritage. The second research project aimed at evaluating the impact of non-HLA genetics on clinical outcome after cord blood transplantation. In fact with the development of human genomics, many studies using single nucleotide polymorphisms of immune response and drug metabolism have shown their influence on post-transplant outcomes. However, in the setting of cord blood transplantation only one study including a small and heterogeneous group of recipients has been described, with no significant association between any of the polymorphisms studied and transplant outcomes. In a multicentric retrospective analysis promoted by Eurocord, including a dataset of 851 cord blood units (including 85 units coming from Pavia) and 173 patients, several candidate genes related to immune response were analysed. We demonstrated the association of cord CTLA-4 GG with lower survival and higher non–relapse mortality, suggesting that this polymorphism might be considered for cord blood donor selection, when more than one unit meeting the current criteria of cell dose and HLA matching is available for a patient. The third study was carried out on 48 cord blood donors with maternal or paternal geographical origins 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 analyses. The high resolution definition of class II HLA alleles, proved 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 were included in a larger dataset and contributed to a study on mitogenome variation aimed to shed light on the Paleo-Indian entry into South America. In the course of my Ph.D. studies I also contributed to two additional projects. In the first we investigated the polymorphisms of HLA-G gene, a non- classical HLA class I locus, in 85 cord blood units aiming to assess the potential role in tolerance mechanisms and related implications for donor selection, while in the second one we analysed the immunogenetic data of 42 families from Venezuela assigning mitochondrial DNA and Y-chromosome haplogroups to acquire new insights on the genetic characteristics of the population of this country. Taken together, the data reported in this thesis remark that the genetics of cord blood transplantation is still an evolving field of endeavour, providing an arena where multidisciplinary approaches may contribute to the progresses achieved in many areas of investigation, ranging from the clinics of hematopoietic stem cell transplantation to the sustainability of cord blood banking programs, involving also apparently not related spheres of interest such as the study of human origins and migrations. Abbreviations 3'UTR, 3' untranslated region 5‟URR, 5' upstream regulatory region AF, allele frequency allo-HSCT, allogeneic hematopoietic stem cell transplantation BM, bone marrow BMDW, Bone Marrow Donors Worldwide BMT, bone marrow transplantation CB, umbilical cord blood CBBs, cord blood banks CBT, cord blood transplant CBUs, cord blood units CCR5, C-C chemokine receptor type 5 CFU-GM, colony forming unit-granulocyte monocyte CIBMTR, Center for International Blood and Marrow Transplant Research CMV, cytomegalovirus CTLA-4, cytotoxic T-lymphocyte antigen 4 DFS, disease free survival EBMT, European Group for Blood and Marrow Transplantation EMDIS, European Marrow Donor Information System G-CSF, granulocyte colony stimulating factor GvHD, Graft versus Host Disease GvL, graft versus leukaemia GWAS, genome-wide association studies HLA, Human Leukocyte Antigen HSCs, hematopoietic stem cells HSCT, hematopoietic stem cell transplantation IL, interleukin KIR, killer immunoglobulin-like receptor LD, linkage disequilibrium LFS, leukaemia-free survival MHC, Major Histocompatibility Complex MUD, matched unrelated donor NIMA, non-inherited maternal antigens MSY, male specific region of the Y chromosome mtDNA, mitochondrial DNA NK, natural killer NMDP, National Marrow Donor Program NRM, non-relapse mortality OS, overall survival PBG, peptide binding groove PBSC, peripheral blood stem cell PCR-SSP, Polymerase Chain Reaction-Sequence-specific primed revPCR-SSO, Reverse Polymerase Chain Reaction - Sequence Specific Oligonucleotide Probe RFS, relapse-free survival SNPs, single nucleotide polymorphisms TC, transplant center TNC, total nucleated cell TNF, tumour necrosis factor TRM, transplant related mortality sHLA-G, soluble HLA-G molecules WMDA, World
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