Cellular Mechanisms of Adaptive Immune Reconstitution Following Human Bone Marrow Transplantation

Roberto, Alessandra (2015). Cellular Mechanisms of Adaptive Immune Reconstitution Following Human Bone Marrow Transplantation. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000ef73

Abstract

Successful immune reconstitution decreases morbidity and mortality following human bone marrow transplantation (BMT). Unmanipulated haploidentical BMT followed by post-transplant cyclophosphamide (pt-Cy) has recently been introduced not only to provide a donor for nearly all patients lacking an HLA-matched donor, but also to improve immune competence through the transfer of adaptive immune cells with the graft. However, the mechanisms of reconstitution and the Cy-effect on transferred immune cells remain unknown. Here, we investigated the dynamics of B and T cell reconstitution in this setting and provide evidence that they follow two different mechanisms. Adoptively-transferred mature B cells fail to persist in the recipient and the recovering B cells derive from a de novo differentiation process from haematopoietic stem cells or B cell precursors. They display an immature/transitional phenotype in the early weeks post-transplant and then progress through four differentiation stages identified by CD5 and CD21 expression, including a novel CD5^-CD21^- stage of transitional differentiation. Mature, naive B cells later replace transitional cells and predominate in the B cell compartment for 6 months. In contrast, transferred naive T cells (T_N) preferentially survive Cy compared to memory cells. T_N rapidly differentiate into T memory stem cells endowed with superior reconstitution capacity within days post-infusion and later contribute to peripheral reconstitution by differentiating into effectors. Similarly, pathogen-specific memory T cells generated detectable recall responses but only in the presence of the cognate antigen. Therefore, T cell immunity is at least in part preserved following pt-Cy and may act as a first line of defence against reactivating pathogens and residual tumor cells. Differently, B cell immunity is generated de novo and takes at least 6 months to phenotypically resemble that of healthy donors. Overall, these findings define the cellular basis of adaptive immune reconstitution process and shed light on basic aspects of T and B cell differentiation and persistence.