Characterising the immune response to combined skin and solid organ transplants

Transplantation offers a life-saving solution for patients with end-stage organ failure. Despite advances in recent years, managing acute rejection episodes remains challenging. This is partly due to difficulties in recognising when acute rejection is taking place. The concept of a sentinel skin flap for monitoring of organ transplantation has recently been introduced as a potential solution for this. The advent of abdominal wall transplants for the reconstruction of large defects in patients undergoing small bowel transplantation has further highlighted the usefulness of skin for monitoring, particularly in differentiating organ rejection from infections. Sentinel skin flaps also provide a site that is easy to biopsy, and which patients can be trained to review. There are limited data in the literature on the alloresponse to a combined skin and solid organ transplant. The aim of this thesis is to characterise in depth this immune response. In chapter 3 the systemic immune response is examined using a combination of flow cytometry and gene expression analysis to analyse blood samples. Chapters 4 and 5 investigate the local immune response in small bowel and skin samples respectively, using the multiplexed gene expression and spatial proteomic techniques. Finally in Chapter 6 a human transgenic mouse model is used to explore the role of Langerhans cell related pathways in skin transplant rejection. This is the first study to characterise both the systemic and local immune response in a combined skin and solid organ transplant, offering unique insights into the dynamic changes in immune phenotype post-transplantation and during rejection. The data provide support for the use of a sentinel skin flap for immune monitoring in solid organ transplantation and will be used to guide future clinical trials.