Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a standard treatment for hematological disorders like acute leukemia and primary immune deficiencies. Various parameters at the pre, peri and post-transplant stages have been shown to significantly influence clinical outcome and patient’s prognosis. In this thesis submitted to the University of Geneva for the degree of Privat-Docent, several of the latest advances in transplantation immunology, histocompatibility and immunogenetics are examined by integrating five of my recent studies to a review of the scientific literature on this thematic. Two main aspects are discussed more specifically.

At the pre-transplant stage, the importance of optimal genetic compatibility between donor and patient and the development of integrative donor selection algorithms that allow to better predict post-transplant risks are discussed through the lens of the HLA-DPB1 paradigm. Different contributions and models to adjust and fine-tune the degree of HLA matching, such as the concept of permissive mismatches, are presented, including a perspective on the availability of new therapeutic protocols and alloHSCT platforms. Indeed, the increasing choice among different types of donors means that almost every patient can now benefit from a suitable donor. However, several questions remain open and are revisited regularly with the publication of new data and results. For instance, what is the best option to consider when several potential donors are available within and outside the patient’s family? If the current gold standards for matching are not achievable, which mismatch constellation(s) should be favored? Because the therapy is highly personalized, different approaches are not mutually exclusive and can be tailored to the patient’s needs.

At the post-transplant stage, immune recovery of the patient is central to the success of this cellular therapy. Notably, the reconstitution of a broad and tolerant T-cell repertoire is required to alleviate the burden of post-transplant complications such as graft-versus-host disease and infections. The development of high throughput sequencing approaches has enabled the indepth characterization of the repertoire and has uncovered the complexity of the adaptive immune response to foreign (and self) antigens. In this context, the interest of alloHSCT as a unique model in humans to explore the dynamics and architecture of the T-cell receptor (TCR) repertoire is presented. In addition, the hurdles at characterizing and predicting the alloimmune response and the promises of translating these results to an optimized and personalized posttransplant monitoring of patients are discussed.