Fallen, Paul Raymond; (2002) Reconstitution of the T-cell compartment post-allogeneic haematopoietic stem cell transplantation. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The effective reconstitution of the T-cell compartment post-haematopoietic cell transplantation (HCT) is essential for the re-establishment of immunity to infectious pathogens. The primary aim of this thesis is to analyse the kinetics and quality of T-cell reconstitution in HCT recipients. This has been achieved using T-cell phenotyping to enable identification of naive, memory and effector T-cells and by measuring the number of circulating thymic emigrants using the TREC assay. We know that there are at least two pathways by which T-cell regeneration can occur after HCT, thymic-dependent and thymic-independent. The results presented in this thesis demonstrate that thymic-independent pathways rapidly regenerate the memory and effector T-cell pool within 6 months post-HCT. Thymic-dependent T-cell regeneration was detected by 3 months post-HCT in some patients but generally, detection of circulating thymic emigrants was delayed until 6-9 months post-HCT. In addition, the number of circulating thymic emigrants was highly variable between different individuals. In an analysis of the factors affecting thymic-dependent T-cell regeneration, increasing patient age and the presence of clinical graft-versus-host disease (GVHD; either acute or chronic) were the two most important factors predicting low or absent thymic output. Cord blood transplant recipients also had reduced levels of thymic emigrants compared with age-matched recipients of peripheral blood or bone marrow transplants raising concerns over the reconstitution potential of cord blood cell grafts. Further results from a cohort of severe combined immunodeficiency (SCID) patients suggest that the administration of some fonn of pre-transplant conditioning is essential for the engraftment of donor stem cells and long tenn maintenance of thymic output. Taken together, these results suggest that the thymus is capable of repopulating the T-cell compartment post-HCT in a diverse group of patients. Furthennore, these results suggest that strategies aimed at reactivating the thymus may be beneficial for older HCT recipients and patients who have experienced episodes of GVHD. Larger studies are essential to analyse the effect of post-transplant immunosuppression, individual conditioning regimens and the clinical correlation between level of thymic emigrants and susceptibility to infection.

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