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Title: Induction and maintenance of tolerance generated by temporary blockade of CD4 and CD8 on peripheral T cells in murine allo- and xenografts
Author: Chen, S. K.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 1997
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Herein, I demonstrate that immunological tolerance can be induced in major histocompatibility complex (MHC) mismatched allogeneic heart and skin graft recipients and in concordant xenogeneic heart and skin graft recipients. Tolerance induction was achieved via temporary blockade of CD4 and CD8 co-signalling pathways mediated by non-depleting monoclonal antibodies. Basically, tolerance was demonstrated with four experimental models: 1) mouse heart allograft; 2) mouse skin allograft; 3) rat-to-mouse heart xenograft; and 4) rat-to-mouse skin xenograft. The tolerance induced to heart allograft was further investigated and was found to be specific, stable and transferable. The induced donor specific suppressive regulatory cells were CD4+: these could drive naive alloreactive cells to become new tolerant cells. Thus the population of tolerant cells can be numerically amplified via serial adoptive transfers. Tolerance may spread to linked antigens co-expressed with the original tolerogen. Tolerance, once established, was self perpetuating. To induce peripheral T cell tolerance, direct control of the pathway of T cell activation itself is more effective than control of the pathway of antigen presentation from antigen presentation from antigen presenting cells (APCs). Inhibition of direct antigen presentation via class II MHC had no effect on prolongation of allograft survival. Inhibition of indirect antigen presentation via class II MHC prolonged allograft survival, but did not lead to tolerance. AT cell may be activated to be aggressive, or suppressive, presumably depending upon their signal transduction at the time of antigen stimulation. Evidence provided here showed that the mature immune system can be reprogrammed to accept non-self organ graft as "self". Importantly the induced tolerance was an actively operational state. This is a demonstration that in principle, natural immune regulatory mechanisms may be exploited to induce permanent tolerance and may be developed for clinical use to avoid the need for prolonged immunosuppressive drug therapy.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available