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Title: Cellular mechanisms of adaptive immune reconstitution following human bone marrow transplantation
Author: Roberto, Alessandra
ISNI:       0000 0004 7965 943X
Awarding Body: Open University
Current Institution: Open University
Date of Award: 2015
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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 (TN) preferentially survive Cy compared to memory cells. TN 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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral