Flynn, T.H.; (2011) Clinical and experimental studies on the cellular mediators of corneal allograft rejection. Doctoral thesis , UCL (University College London).

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Abstract

Despite significant advances in our knowledge of the cellular and molecular elements of transplant immunology the 10 year survival probability for all human corneal grafts is 0.73. In some "high-risk" recipients it is as low as 0.37. To date almost all our knowledge about the cellular events during acute corneal graft rejection comes from animal models. In mice, the presence of pre-existing host corneal vascularisation confers "high-risk" status on a graft and has been shown to accelerate rejection. In the first part of this thesis the effect on survival of grafting to an inflamed conjunctival bed was investigated. Using a mouse model of allergic conjunctivitis significantly reduced survival was seen in graft recipients with perioperative conjunctival inflammation. This appeared to be due to the local effects of conjunctivitis rather than systemic effects of allergy/ atopy. Subsequent experiments investigated the effect of perioperative allergic conjunctivitis on the cellular components of both early (surgical trauma-induced, alloantigen-independent) and late (alloantigen-dependent; rejection) post-keratoplasty anterior segment inflammation and demonstrated significant effects on both. Grafts recipients with allergic conjunctivitis had significantly greater early post-operative corneal inflammation and associated corneal and conjunctival lymphangiogenesis. Analysis of graft infiltrating cells during rejection in mice confirmed that large numbers of CD4+ cells, CD8+ cells and macrophages were recruited. Flow cytometric analysis of human aqueous during acute endothelial rejection demonstrated for the first time the presence of CD4+ cells, CD8+ cells and a surprisingly high proportion of macrophages therein. In mouse recipients with allergic conjunctivitis eosinophils were found in both the graft itself and the ciliary body during rejection although the role of these cells during rejection is uncertain. Chemokine analysis during both murine and human corneal graft rejection demonstrated increased expression of the chemokine IP-10 (CXCL-10) suggesting a potentially important role for this protein in the rejection process.

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