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Title: The role of donor CD4 T lymphocyte chimerism in lung transplant recipients
Author: Gjorgjimajkoska, Olivera
ISNI:       0000 0004 8507 6636
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2020
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Long-term outcomes for lung transplantation remain disappointing; as many as 50% of lung transplant recipients develop progressive Bronchiolitis Obliterans Syndrome (BOS) by 5 years after transplant. In the last decade, several experimental and clinical studies have demonstrated that cellular and humoral autoimmune responses to ‘self’ antigens may play a causative role in the onset of BOS. Work from our research group has highlighted a novel mechanism for triggering autoimmunity following transplantation. In a murine model of chronic heart rejection, transplant-induced autoimmunity - characterised by production of class-switched anti-nuclear effector autoantibody responses was dependent upon provision of help from donor CD4 T cells that were passengers within the graft. However, the fate of the donor passenger CD4 T cells in clinical organ transplantation is unclear. To assess whether a similar mechanism may occur in human transplant recipients, I have studied the presence and the impact of passenger donor CD4 T cells on the development of humoral auto- and alloimmune responses in a prospective cohort of primary lung transplant recipients (n=21). The development of autoantibody and, in particular, the specificity of target autoantigens was also evaluated in a lung transplant patients with either established grade 2-3 BOS (n=10), or without BOS (n=10). My work suggests that the presence of donor CD4 T cell chimerism in the peripheral blood of lung transplant recipients is a uniform phenomenon. Donor CD4 T lymphocytes were consistently detected in the recipients’ peripheral blood during the first post-operative month; however, the number of detectable donor CD4 T cells fluctuated over time, and varied between individual lung transplant recipients. In a follow-up period of one year after transplantation, three distinct patterns of donor CD4 T cell chimerism were observed: short (donor CD4 T cells detectable for up to six weeks after transplantation, n=13), intermediate (donor CD4 T cells detectable between three to six months after transplantation, n=3) and long-lasting chimerism (donor CD4 T cells detectable for more than six months after transplantation, n=5). Surprisingly, the degree of HLA mismatching and the predicted NK cell alloreactivity did not correlate with the longevity of donor CD4 T cell chimerism, and did not influence the development of BOS. Furthermore, transcriptomic analysis of the donor CD4 T cell population consisted of a heterogenous mixture of different CD4 T cell sub-types, with no consistent pattern evident in patients with short and long lasting donor CD4 T cell chimerism. The assessment of the humoral autoimmune responses revealed unexpected findings. Anti-nuclear IgG autoantibody levels were greater in the recipients’ sera before the transplant, when compared to sera sampled at one and 12 months after transplantation, but the titre of pre-transplant anti-nuclear autoantibody did not correlate with the subsequent development of BOS. Similar findings were observed in the retrospective cohort of 24 lung and 18 heart and lung transplant recipients. Assessment of the repertoire of pretransplant autoantibody did however suggest that a unique set of autoantigens were targeted in those patients that subsequently developed BOS. The involvement of donor CD4 T cell in the development of transplant-induced autoimmunity and augmentation of humoral alloimmunity was not confirmed in human lung transplant recipients and the role of donor CD4 T chimerism remains unclear. However, solid organ transplant recipients are subjected to highly potent T-cell depleting immunosuppressive drugs that can alter the number and function of T cells. This may obviate the impact of donor CD4 T cell chimerism in the development of transplant-induced autoimmunity. Understanding the clinical relevance of the autoantibody repertoire present at the time of transplant may, however, hold potential in identifying recipients with predisposition to develop BOS, and may therefore possibly provide a window of opportunity for targeted immunosuppression.
Supervisor: Pettigrew, Gavin John Sponsor: British Heart Foundation ; Papworth Hospital ; Addenbrooke's Charitable Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: Transplant Immunology ; CD4 T lymphocytes ; Lung transplantation ; Chimerism ; HLA ; Auto-antibody ; Allo-antibody