Immune Repertoire Diversity in Allogeneic Stem Cell Transplantation and Its Implications for Infections and the Graft Versus Leukemia Effect
Year: 2014
Type: dissertation
Study design: Observational Study
Abstract: The beneficial graft versus leukemia effect (GVL) and its detrimental counterparts, graft versus \nhost disease (GVHD) and susceptibility to infections, are all coupled to a multitude of events \nduring the immune reconstitution (IR) after hematopoietic stem cell transplantation (HSCT). \nThe general aim of this thesis has been to learn more about the IR in HSCT with a particular \nfocus on the impact of infections, natural killer (NK) cell mediated GVL effects and the \npossibility to apply GVL effects in adoptive cell therapy. \n \n \n \nIn paper I, we identified factors interfering with the IR, thereby making the patients susceptible \nto late lethal infections. We found that cytomegalovirus (CMV) was an independent risk factor \nfor death in late infections. NK cells are important for controlling CMV infections and patients \nlacking NK cells suffer from cyclic herpes virus reactivations.1-3 NK cells are also known to \nmediate GVL-effects and have been coupled to reduced relapse rates after HSCT. The results of \npaper I thus prompted us to study NK cell-mediated GVL effects and the interaction between \nCMV and NK cell repertoire dynamics. \n \n \n \nIn paper II we examined NK cell-mediated alloreactivityin 105 patients with myeloid malignancies undergoing human leukocyte antigen (HLA )-identicalsibling transplantation. A longitudinal analysis revealed maintained NK cell tolerance at all timepoints \nduring the IR. In agreement with these experimental data, no clinically evident GVL effect \nwas observed based on stratification of missing ligands to killer cell immunoglobulin-like \nreceptors (KIRs ) in the recipients. \n \n \n \nIn paper III we determined the size of the alloreactive subset \nand graded the ability of different donors to deliver GVL effects in HLA -mismatched \ntransplantation. The educated subsets expressing KIRs in presence of a corresponding HLA - \nreceptor ligand varied between 12-68% (mean 33%) resulting in 0-62% (mean 8%) alloreactive \nNK cells depending on recipient HLA -ligands. This algorithm served as a template for studies \nconducted in paper IV, where we further dissected the role of pre-transplant NK cell repertoires \nin the donor and post-transplant repertoires developing after 9-12 months. Unsupervised \nhierarchical clustering was used to group donors and recipients based on their NK cell receptor \nrepertoires. The result showed that donors with naïve receptor repertoires had less relapse and \nrecipients with a tendency to reset their repertoires towards naivety had less relapse and better \noverall survival. \n \n \n \nIn summary this thesis shed new light on the relationships between early and late infections and \nthe recovery of the immune system after HSCT, linking specific NK cell repertoires to \nprotection from relapse and increased overall survival. This knowledge may be useful for the \ndevelopment of new strategies utilizing NK cells in cellular therapies against hematological \nmalignancies.
Source: Figshare
Author: Andreas T. Björklund
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2129372273