Watt, Eleanor Sinead Igrainne; (2024) Immune Reconstitution in Thymus Transplant Patients. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis investigates the immune reconstitution and repertoire diversity in patients following thymus transplantation, a therapeutic approach for individuals with thymic aplasia or dysfunction. Thymus transplantation holds promise for restoring immune function and improving patient outcomes, yet the process of immune reconstitution is complex, influenced by donor-recipient compatibility, thymic microenvironment, and underlying immune pathology. Initially, assays were developed and optimized to determine the effectiveness of DNA versus RNA sequencing in analysing T-cell receptor (TCR) and B-cell receptor (BCR) diversity. RNA sequencing proved superior, capturing more rare and small clonotypes and providing comprehensive data across most receptor chains. Microchimerism analysis post-transplant revealed the persistence of donor-derived T-cells and B-cells in recipients, with implications for long-term immune monitoring and understanding of autoimmunity and alloreactivity. The presence of donor-derived lymphoid cells suggests potential benefits in immune reconstitution and tolerance. The thesis also assessed TCR and BCR dynamics, observing significant post-transplant increases in TCR diversity and evenness, as indicated by Gini coefficients and Shannon entropy levels. These findings highlight thymus transplantation’s positive impact on immune repertoire diversity, essential for robust immune responses. Patient-specific variations in T-cell clone profiles, including the prevalence of γδ T-cells was also assessed. Furthermore, the impact of human leukocyte antigen (HLA) matching on T-cell diversity was explored, revealing complexities in immune interactions that emphasise the importance of genetic compatibility. BCR sequence analysis showed fluctuations in receptor diversity, particularly in IgH chains, suggesting ongoing immune adaptations post-transplant. During the COVID-19 pandemic, TCR repertoires in paediatric patients with varying disease severities were analysed. Findings indicated distinct TCR features in severely ill children, notably the expansion of TRBV11-2 chains, providing insights into the immunological mechanisms underlying variable clinical outcomes. In conclusion, this research advances the understanding of immune reconstitution dynamics and repertoire diversity post-thymus transplantation, contributing to the development of more effective, personalised transplantation protocols and treatment strategies.

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