Saleem, Moin A.; (1997) Antigen processing pathways in transplantation. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Antigen presentation and its regulation has been studied, with particular emphasis on the control and function of the MHC class II molecule, and on how this may affect allograft rejection. CIITA is a specific controller of class II expression, and has recently been cloned in the human, using cell lines derived from MHC class II deficient patients. We have started to clone the gene for rat CIITA, using PCR techniques, and have isolated a 433 base pair fragment. The full length CIITA sequence would be used to manipulate class II expression in experimental models, using, initially, antisense oligonucleotides. In the interim, we have gained experience with antisense technology by targeting the IL-2 molecule. This cytokine is integral to the interaction between an APC presenting peptide on its surface, and the T-cell. We have attenuated T-cell proliferation in in vitro assays, and show evidence that this is due to specific down-regulation of IL-2 production. In examining the intermediate steps between CIITA and class II expression, we have focused on the invariant chain. The invariant chain defines the ability of the class II molecule to present exogenous peptide. Its distribution in normal rat organs and transplanted kidneys is described. The results are unexpected, and the possible significance of the invariant chain in influencing self and non-self peptide recognition is discussed. Additionally, we report a new group of patients with MHC class II deficiency, from ethnic groups not previously seen to be affected, and immunohistology studies on fibroblast cell lines from these patients show a complete lack of invariant chain expression. Finally, we have looked for the presence of indirect allorecognition in the clinical situation of graft rejection. We have recruited patients undergoing follow-up for chronic rejection, and performed an in vitro assay to detect a T-cell response indicating the presence of indirect recognition. For reasons that are discussed, the results are negative.

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