Mechanisms of Immune Modulation after Stem Cell Transplantation

Renee Robb (2011). Mechanisms of Immune Modulation after Stem Cell Transplantation PhD Thesis, School of Medicine, The University of Queensland.

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Author Renee Robb
Thesis Title Mechanisms of Immune Modulation after Stem Cell Transplantation
School, Centre or Institute School of Medicine
Institution The University of Queensland
Publication date 2011-12
Thesis type PhD Thesis
Supervisor Geoff Hill
Kelli MacDonald
Total pages 130
Total colour pages 15
Total black and white pages 116
Language eng
Subjects 110709 Tumour Immunology
110708 Transplantation Immunology
Abstract/Summary Stem cell transplantation (SCT) is the curative therapy for a majority of haematological malignancies and disorders. Allogeneic SCT allows for reconstitution of the host immune system, with the therapeutic effect being graft versus leukaemia (GVL) responses, which eradicate residual host malignancy. Unfortunately GVL responses are closely intertwined with detrimental graft versus host disease (GVHD), which limits the application of SCT. GVHD is a process where the donor graft recognises the host as foreign and is characterised by immune mediated tissue damage. Current research aims to further dissect the mechanisms involved in both GVHD and GVL and how they can be manipulated to improve patient outcomes. This study investigates the effects of type I-IFN (type I-IFN, IFN-α/β) signalling on GVHD and GVL, IL-17 signalling on GVL and the identification and characterisation of a novel CD8+FoxP3+ regulatory T cell population after SCT. While the effects of type II-interferon (IFN-γ) on graft-versus-host disease (GVHD) and leukaemia relapse are well studied, the effects of type I-interferon (type I-IFN, IFN-α/β) remain unclear. This was investigated utilizing type I-IFN receptor-deficient mice and exogenous interferon-alpha (IFN-α) administration in established models of GVHD and GVL. Type I-IFN signalling in host tissue prevented severe colon-targeted GVHD in CD4-dependent models of GVHD directed towards either major histocompatibility antigens or multiple minor histocompatibility antigens. This protection was the result of suppression of donor CD4+ T cell proliferation and differentiation. Studies in chimeric recipients demonstrated this was due to type I-IFN signalling in hematopoietic tissue. Consistent with this, administration of IFN-α during conditioning inhibited donor CD4+ proliferation and differentiation. In contrast, CD8-dependent GVHD and GVL effects were enhanced when type I-IFN signalling was intact in the host or donor respectively. This reflected the ability of type I-IFN to both sensitize host target tissue/leukaemia to cell mediated cytotoxicity and augment donor cytotoxic lymphocyte function. These data confirm that type I-IFN plays an important role in defining the balance of GVHD and GVL responses and suggests that administration of type I-IFN after SCT could be studied prospectively in patients at high risk of relapse. Multiple groups have investigated the effects of IL-17 on GVHD, however its contribution to GVL responses remain unclear. This study utilised donors for SCT that were either unable to produce IL-17A or respond to IL-17A/E/F. Results indicated that IL-17 signalling and production by the donor graft significantly improved therapeutic GVL responses after transplantation. Importantly, while G-CSF is known to increase IL-17 production, the effects of IL-17 were not restricted to transplants utilising G-CSF mobilised donors. Therefore IL-17 plays an important role in therapeutic GVL responses after transplantation. FoxP3+ confers suppressive properties and is confined to regulatory T cells. It is well established that natural CD4+ regulatory T cells (Treg) are important for controlling GVHD. In contrast, studies investigating Treg that undergo conversion in the periphery are lacking. This has been addressed by utilising recently developed reagents to determine conversion, function and trafficking of FoxP3+ Treg after SCT. Results identified and characterised an important CD8+ population of FoxP3+ regulatory T cells that convert from CD8+ conventional donor T cells after allogeneic but not syngeneic SCT. These CD8+ Treg demonstrate marked tropism for the gastrointestinal tract and associated lymphoid tissue, undergoing conversion at this site under the influence of host dendritic cells and TGFβ. They are more suppressive than natural CD4+ Treg, exerting class-I restricted and antigen-specific suppression. Alleviation of GVHD following adoptive transfer of CD8+FoxP3+ Treg after transplant in preclinical models demonstrates that they are highly suited to manipulation for the control of deleterious allo-immune responses after transplantation. CD8+FoxP3+ Treg are as important for protection from GVHD as the well-studied CD4+FoxP3+ population and represents a potential new regulatory population to preferentially subvert MHC class-I restricted T cell responses following SCT. Overall, the data presented in this thesis identifies multiple novel avenues to manipulate immune responses after SCT to alleviate detrimental GVHD and enhance therapeutic GVL responses.
Keyword stem cell transplantation
graft versus host disease
graft versus leukaemia
regulatory T cell
interferon alpha
Additional Notes Colour pages: 19, 29, 33, 35, 37, 52, 58, 60, 64, 73, 84, 122, 124, 125, 127

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Created: Fri, 25 May 2012, 02:20:41 EST by Renee Robb on behalf of Library - Information Access Service