A spatially resolved, in depth analysis of tissue signatures of tolerance and rejection in transplantation

Thesis

Vascularised composite allotransplantation (VCA) is an intervention that can offer functional and aesthetic restoration after significant tissue loss, enhancing the quality of life for carefully selected patients. However, the high incidence of acute rejection, which may compromise allograft longevity, and the morbidity associated with chronic immunosuppression remain significant challenges. The immunogenicity of skin, a key component of most VCAs, is theorised to drive this apparent vulnerability to rejection. However, due to small patient cohorts and a paucity of comprehensive analyses, the alloresponse to vascularised skin, and its impact on concurrently transplanted organs, remains incompletely understood.

To address these challenges, exploratory analyses are essential for identifying novel therapeutic targets and potential biomarkers of rejection. Such analyses may also highlight histological features to assist pathologists in diagnosing cases of uncertain or borderline rejection. However, many existing studies within the literature lack the comprehensiveness needed for these insights. Chapters 3 and 6 of this thesis employ high-plex, spatially resolved methods to address this gap.

Immunomodulatory interventions, such asregulatory T cell therapy, represent a promising strategy for minimising the immunosuppressive burden required to maintain VCA survival. Despite the numerous preclinical and clinical trials completed to date, several questions remain unresolved, including optimal dosing and mechanisms of action within the allograft microenvironment. The influence of these interventions on skin rejection and the allograft transcriptome will be addressed using immunehumanised mouse models in Chapter 4. The effect of Treg therapy in clinical transplant recipients will be explored in Chapter 5.

This thesis represents the first whole transcriptome analysis of rejecting allogeneic skin transplants in both mouse and human samples and aims to extend current understanding of VCA specific mechanisms.

Authors: Short, S

• DOI: 10.5287/ora-nrgqzzjd8
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: rejection; regulatory t cells; vascularised composite allotransplantation; transplantation
• Subjects: Transplantation immunology; Immunological tolerance; Graft rejection