Understanding the immunogenetic and clinical factors which influence the outcome of Haematopoietic Stem Cell Transplantation using unrelated donors

Haematopoietic Stem Cell Transplantation (HSCT), using unrelated donors (UD), is now a common modality of treatment for individuals with a variety of different diseases. In spite of years of experience, and obvious improvements in outcome, unresolved issues remain. One of the reasons is the highly complex nature of this treatment modality and the many aspects which affect outcome. These may be patient specific (e.g. age, performance status); donor specific (e.g. genetic disparity, gender) or treatment specific (e. g. conditioning regimen, GvHD prophylaxis). The aim of this study was to analyse the impact of clinical and immunogenetic factors on the complications and outcome in a cohort of UD HSCT pairs. In the analysis of genetic factors, emphasis was placed on the typing of six highly polymorphic transplantation loci (HLA-A, -B, -C, -DRB1, -DQB1, -DPB1) to the allele level. This study includes 423 unrelated UK patient/donor pairs (with a donor provided by the Anthony Nolan Trust). The degree and type of HLA mismatch was found to be a significant factor affecting transplantation outcome. In view of the paucity of information concerning the impact of DPBl on outcome, I focussed on this molecule and was able to report a number of novel findings. In the light of these, I developed a cellular assay, to facilitate better understanding of the function of the DPB1 molecule. I was able to demonstrated a HLA-DPB1 specific response between DPB1 disparate individuals, evidenced by the production of IFNy in an ELISpot assay. In addition to the HLA analysis, I developed an assay for the typing of TNFA promoter polymorphisms (positions -308 and -238). The clinical impact of these was studied in a subset of pairs. Based on the findings of this study, it is possible to offer certain advice concerning the choice of an unrelated donor