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Title: In Vivo Induction of Regulatory Immune Tolerance
Author: Weng, Ling
ISNI:       0000 0001 3565 9380
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2008
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Low or reduced intensity conditioning (RIC) regimens for allogeneic haematopoietic stem cell transplantation (HSCT) can be very effective at establishing donor haematopoietic engraftment and host-versus-graft (HvG) tolerance. I have investigated the mechanisms of HvG tolerance induction and maintenance in an animal model. Although peripheral clonal deletion and anergy contribute to limit unwanted immune responses, active regulation is the central mechanism of transplantation tolerance. Several T cell subsets have been identified with the ability to suppress immune responses to a variety of self and non-self antigens. Firstly, I studied the role of regulatory T cells. Natural regulatory T (Treg) cells are a subpopulation of thymus-derived CD4+ T cells which constitutively express the interleukin-2 receptor a chain (CD25). I have observed that splenocytes from chimeric mice inhibited donor-specific CD8+ T cell responses both in vitro and in vivo, and their adoptive transfer facilitated donor haematopoietic engraftment. These properties were contained within the CD4+CD25+ population, and the inhibitory effect was antigen-dependent. The administration of anti-CD25 depleting antibodies to conditioned recipients at time of HSCT prevented donor-recipient chimerism, but did not affect engraftment if performed after the establishment of chimerism, thus indicating that recipient Treg cells are required for the generation but not the maintenance of HvG tolerance. Therefore, donor-specific Treg cells of recipient origin are recruited when the donor antigens are present during RIC induced Treg expansion. In the second part of my thesis, I have analysed the effect of natural killer T (NKT) cells on HvG tolerance. NKT cells use an invariant T-cell receptor which interact with synthetic glycolipids such as a-galactosylceramide in the context of the monomorphic CD1 d antigen-presenting molecule. I have found that also NKT cells from the chimeric mice showed inhibitory effects on the anti-donor T cell responses in vivo and in vitro. In the last chapter, I have studied the use of cytotoxic pathways in HvG responses by using FasL deficient (gld) mice and perforin deficient (prf-I-) mice. In prf-I. mice, donor cell engraftment was higher and donor cell rejection was delayed compared with wild type control mice and gld mice, indicating that HvG effect T cells preferentially use perforin-granzyme pathway to reject haematopoietic donor cells. These findings have important implications for the design of tolerogenic regimens in transplantation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available