Bone Marrow Transplantation

Geoff Hill Staff
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Lab Head: Professor Geoff Hill

Allogeneic Bone Marrow Transplantation remains the procedure of choice for the cure of a number of haematologic malignancies (e.g. leukemia and lymphoma) and severe immunodeficiencies. The procedure results in cure rates up to 75% but is limited by its serious complications, particularly graft-versus-host disease (GVHD). This is the process whereby the newly transplanted immune system recognises the transplant recipient as "foreign" and mounts a rejection response. Recently the use of cytokines has allowed the transplantation of blood stem cells (referred to as stem cell transplantation-SCT) that has replaced BMT in clinical practise. Our laboratory has been at the forefront of understanding how these cytokines effect GVHD. We aim to improve transplant outcome by utilising preclinical transplant models where immunological mechanisms of transplant rejection can be dissected so that rational therapeutic strategies can be developed and trialed in clinical practise.

Stem Cell Transplantation Research

Graft-versus-leukemia and graft-versus-host disease
The mobilisation of stem cells by cytokines such as G-CSF has become standard therapy in haematology practise for the purpose of transplantation and has largely replaced bone marrow as a stem cell source. Allogeneic Stem Cell Transplantation (SCT) has improved patient outcome relative to traditional Bone Marrow Transplantation. The major complication of allogeneic SCT remains graft-versus-host disease (GVHD) in which the skin, GI tract, and liver are preferentially damaged by the transplanted donor immune system. The therapeutic potential of SCT relates to the graft-versus-leukemia (GVL) effect, which eradicates host malignancy after SCT and is mediated by donor T and NK cells. Although GVL effects are associated with GVHD, evidence to date suggests that they are separable phenomena.

GVHD occurs in the majority (50-70%) of SCT recipients and is responsible for the transplant-related mortality of up to 50%. Approximately 20% of SCT recipients will develop severe GVHD that is refractory to steroid and cyclosporine-A based therapeutic protocols. These patients have a dismal prognosis and are traditionally treated with preparations of anti-thymocyte globulin or inhibitory antibodies to the IL-2 receptor. Despite initial response rates of up to 50%, the vast majority of patients (80-95%) eventually die from refractory or relapsed GVHD and the infective complications relating to severe and prolonged immunosuppression. Disappointingly, the majority of these patients are cured of their underlying malignancy. Clearly there is a pressing need for new treatment approaches to both prevent and especially, to treat GVHD.

The principal aim of our studies is to determine the potential efficacy of novel new strategies for the induction of antigen-specific tolerance to prevention and treatment of GVHD in well-characterized pre-clinical models. The mechanisms of action of the therapeutic maneuvours are elucidated, which provide important insights into the pathophysiology of the disease as well as the induction of tolerance in established inflammation.

The pathophysiology of acute graft versus-host disease
The pathophysiology of acute GVHD can be viewed as a three-step process and is absolutely dependent on the presence and function of donor T cells in the donor inoculum. In step 1, the conditioning regimen (irradiation and/or chemotherapy) leads to the damage and activation of host tissue by the release of the inflammatory cytokines TNF-a and IL-1. These cytokines can increase the expression of MHC antigens and adhesion molecules on host antigen presenting cells (dendritic cells), enhancing the recognition of host MHC and/or minor histocompatibility antigens by mature donor T cells. Donor T cell activation in step 2 is characterised by proliferation of Th1 T cells and secretion of IL-2 and IFN-y, promoting T cell expansion, CTL and NK cell responses. The effectors of tissue damage in step 3 include the products of mononuclear phagocytes (IL-1 and TNF-a) which are triggered via signals provided by LPS. Damage to the intestinal mucosa in step 1 and by cytolytic effectors activated in step 2 allows translocation of LPS from the intestinal lumen into the circulation. This mechanism may amplify local tissue injury and further promote an inflammatory response which, together with the CTL and NK component, leads to target tissue destruction in the BMT host. The importance of T cells for GVHD and GVL effects is demonstrated by depletion of T cells from the donor graft. This prevents GVHD, but is also associated with increased rates of relapse and infective complications which negate any beneficial effect. However, if inflammatory cytokine dysregulation during GVHD is prevented, while maintaining donor T cell cytotoxicity to host and haematopoetic antigens, leukemia eradication after BMT can be demonstrated in the absence of GVHD. The "Holy Grail" of BMT remains complete separation of GVHD and GVL while preserving cognate T cell responses to non-host (eg. infectious) antigens. The key to this achievement lies in administration of antigen-specific immunotherapy.

Project Highlights

The effect of cytokine therapy on the outcome of bone marrow transplantation.
We are detailing the effects of growth factors on transplant outcome, either when used to mobilize stem cells, to accelerate granulocyte recovery after transplantation, or as cytoprotective agents. These studies have lead to a number of novel discoveries and most recently a Nature Medicine publication on the subject.

The pathways of antigen presentation in graft-versus-host disease and transplant outcome.
In these studies we are dissecting the role of various antigen presenting cell (APC) subsets on the initiation and maintenance of graft versus host disease (GVHD). These studies utilize novel reagents that allow the specific and quantitative determination of antigen presentation in both host and donor subsets, as well as the relative contribution of classical and non-classical APC subsets. It is hoped that this will allow modulation of alloreactive responses at the level of antigen presentation rather than current T cell directed approaches.

The role of TH17 differentiation in graft-versus-host disease and graft-versus-leukemia (GVL) effects.
This new pathway of T cell differentiation may explain some of the immunological complexities in transplantation that fail to fit into previously described TH1 and TH2 paradigms. We are utilizing a number of novel reagents to fully dissect this pathway and its' control of specific GVHD and GVL responses.

Modulation of GVL via NKT activation.
It is now clear that NKT cells can profoundly modulate immune responses, in both directions. In these studies we are focusing on NKT activation with glycolipid variants to improve GVL responses after BMT.

All these studies are based on solid preclinical data and have moved into translation phases at the Bone Marrow Transplant Unit in the Royal Brisbane and Women's Hospital.

Staff

Labhead:	Professor Geoffrey Hill
Senior Research Officer:	Dr Kelli MacDonald
Research Officers:	Dr Motoko Koyama Dr Antiopi Varelias
Research Assistants:	Rachel Kuns Stuart Olver Neil Faffelt Alistair Don Yana Wilson
PhD Scholars:	Kate Markey Renee Rob
Honours Student:	Nurul Osman

To see staff contact details, please type name below and hit Enter

Funding

We gratefully acknowledge support from the following funding bodies:

The Wellcome Trust
The National Health and Medical Research Council of Australia
The Cancer Council Queensland
Atlantic Philanthropies
The Leukaemia Foundation of Queensland

Collaborators

Professor James Ferrara, Director of Bone Marrow Transplantation, Department of Internal Medicine and Pediatrics, University of Michigan, MI, USA
Professor Robert Negrin, Chief, Division of Blood and Marrow Transplantation, Stanford University Medical Center, CA, USA
Professor John Bromberg, Mt Sinai School of Medicine, New York, NY, USA
Professor David Hume, The Roslin Institute and R(D)SVS, University of Edinburgh Roslin, Midlothian, EH25 9PS, Scotland, UK
Professor Ranjeny Thomas, Diamintina Institute, Princess Alexandra Hospital, Brisbane, QLD, Australia
Professor Ian Frazer, Diamintina Institute, Princess Alexandra Hospital, Brisbane, QLD, Australia
Professor Mariapia Degli-Esposti, The University of Western Australia, 35 Stirling Highway, Crawley, WA, Australia
Professor Steven Porcelli, Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA
Professor Mark Smyth, Peter MacCallum Cancer Centre, St Andrews Place, Melbourne, VIC, Australia
Professor Dale Godfrey, Department of Microbiology and Immunology, The University of Melbourne, VIC, Australia
Dr Andrew Clouston, Envoi Pathology, Brisbane, QLD, Australia

Student Projects

Research projects are available within the BMT Laboratory for both BSc Honours and PhD students.
Please contact Prof Geoff Hill or Dr Kelli MacDonald.

Key Publications

Hill GR, Tey S, Beagley L, Crough T, Morton J, Clouston AD, Whiting P, Khanna R. Successful immunotherapy of HCMV disease using virus-specific T-cells expanded from allogeneic stem cell transplant recipient. Am. J. Transplant. (2009) In Press

Markey KA, Burman A, Banovic T, Kuns RD, Raffelt NC, Rowe V, Olver S, Don AL, Morris ES, Pettit AR, Wilson YA, Robb RJ, Randall LM, Korner H, Engwerda CR, Clouston AD, MacDonald KP and Hill GR. Soluble lymphotoxin is an important effector molecule in GVHD and GVL. Blood. (2009) In Press

Markey K, MacDonald KP and Hill GR. Recipient plasmacytoid DC are not required to prime allogeneic T cell responses after BMT (Letter). Blood. (2009) 113:6038-9. [pubmed abstract]

Kuns R, Morris ES, MacDonald KP, Markey KA, Morris H, Raffelt N, Banovic T, Olver S, Don A, Rowe V, Burman AC, Clouston AD, Farah C, Besra GS, Illarionov PA, Smyth MJ, Porcelli SA, Hill GR. Invariant NKT - NK cell interactions dictate transplant outcome following -galactosylceramide administration. Blood. (2009) 113:5999-6010. [pubmed abstract]

Markey KA, Banovic T, Kuns R, Olver S, Don A, Raffelt N, Wilson Y, Raggatt LZ, Pettit A, Bromberg J, Hill GR, MacDonald KP. Conventional dendritic cells are the critical donor APC presenting alloantigen after experimental BMT. Blood. (2009) 113:5644-9. [pubmed abstract]

Morris ES, MacDonald KP, Kuns K, Morris H, Banovic T, Don LJ, Rowe V, Wilson YA, Raffelt NC, Engwerda CR, Burman AC, Markey KA, Godfrey DI, Smyth MJ, Hill GR. Induction of NKT Cell-Dependent Alloreactivity by Administration of G-CSF after Bone Marrow Transplantation. Nature Medicine. (2009) 15:436-41. [pubmed abstract]

Banovic T, MacDonald KP, Markey K, Morris E, Kuns RD, Varelias A, Hill GR. Donor pretreatment with a multi-pegylated-G-CSF maximizes graft-versus-leukemia effects. Biology of Blood and Marrow Transplantation. (2009) 15:126-30. [pubmed abstract]

Banovic T, Markey K, Kuns RD, Olver S, Rafellt N, Don A, Degli-Esposti M, Engwerda C, MacDonald KP, Hill GR. Graft versus host disease prevents the maturation of plasmacytoid dendritic cells. J Immunol. (2009) 182:912-920. [pubmed abstract]

Burman A, Banovic T, Kuns RD, Rowe V, Clouston A, Morris, ES, Stanley A, Bofinger H, Fahey, O, McColl S, Engwerda C, MacDonald KP and Hill GR. IFNgamma differentially controls the development of idiopathic pneumonia syndrome and GVHD of the gastrointestinal tract. Blood. (2007) 110:1064-72. [pubmed abstract]

MacDonald KP, Kuns RD, Rowe V, Morris ES, Bonovic T, Bofinger H, O'Sullivan B, Markey K, Don A, Thomas R and Hill GR. Effector and regulatory T cell function is differentially regulated by RelB within antigen presenting cells during GVHD. Blood. (2007) 109:5049-57. [pubmed abstract]

Rowe V, Bonovic T, MacDonald KP, Kuns R, Don A, Morris ES, Burman AC, Clouston A and Hill GR. Host B cells produce IL-10 following TBI and attenuate acute GVHD after allogeneic bone marrow transplantation. Blood. (2006) 108:2485-92. [pubmed abstract]

Morris ES, Macdonald KP, Rowe V, Banovic T, Kuns RD, Don AL, Bofinger HM,Burman AC, Olver SD, Kienzle N, Porcelli SA, Pellicci DG, Godfrey DI, Smyth MJ,Hill GR. NKT cell-dependent leukemia eradication following stem cell mobilization with potent G-CSF analogs. J Clin Invest. (2005) 115;3093-310. [pubmed abstract]

Banovic T, MacDonald KP, Morris ES, Rowe V, Kuns R, Don A, Kelly J, Ledbetter S, Clouston A and Hill GR. TGFbeta in allogeneic stem cell transplantation: Friend or Foe? Blood. (2005) 106;2206-2214. [pubmed abstract]

MacDonald KP, Rowe V, Bofinger HM, Thomas R, Sasmono T, Hume D and Hill GR. The CSF-1 receptor is epressed on dendritic cells during differentiation and regulates their expansion. J. Immunol. (2005) 175;1399-1405. [pubmed abstract]

Morris ES, MacDonald KP and Hill GR. Stem cell mobilization with G-CSF analogs: a rational approach to separate GVHD and GVL? Blood. 2006;107:3430-3435. [pubmed abstract]

Morris ES and Hill GR. Advances in the understanding of acute graft-versus-host disease. Br J Haematol. 2007;137:3-19. [pubmed abstract]

MacDonald KP, Rowe V, Clouston A, Welply JK, Kuns RD, Ferrara JLM, Thomas R and Hill GR. Cytokine expanded myeloid precursors function as regulatory antigen presenting cells and promote tolerance through IL-10 producing regulatory T cells. J. Immunol. (2005) 174;1841-1850 [pubmed abstract]

Morris ES, MacDonald KP, Rowe V, Clouston A, and Hill GR. Donor treatment with pegylated G-CSF induces the generation of IL-10 producing regulatory T cells and promotes transplant tolerance. Blood. (2004) 103;3573-81 [pubmed abstract]

MacDonald KP, Rowe V, Filipich C, Clouston A, Thomas R, Welply J, Hart DN, Ferrara, JLM, and Hill GR. Donor pretreatment with Progenipoietin-1 is superior to G-CSF for the prevention of GVHD following allogeneic SCT. Blood (2003) 101;2033 [pubmed abstract]

MacDonald KPA, Munster DJ, Clark GJ, Dzionek A, Schmitz J, Hart DN. Characterization of human blood dendritic cell subsets. Blood (2002) 100:4512-20 [pubmed abstract]

Hill GR, Ferrara JLM. The primacy of the gastrointestinal tract as a target organ of graft versus host disease: Rationale for the use of cytokine shields in allogeneic bone marrow transplantation. Blood (2000) 95:2754-2759 [pubmed abstract]

Hill GR, Teshima T, Gerbitz A, Pan L, Cooke KR, Brinson YS , Crawford JM and Ferrara JLM. Differential roles of IL-1 and TNF-a on graft-versus-host disease and graft-versus-leukemia. J. Clin. Invest. (1999) 104:459-467 [pubmed abstract]

Hill GR, Cooke KR, Teshima T, Crawford JM, Keith J Jr, Brinson YS, Bungard D, Ferrara JLM. IL-11 promotes T cell polarization and prevents acute graft-versus-host disease following allogeneic BMT. J. Clin. Invest. (1998) 102:115-123 [pubmed abstract]

Hill GR, Crawford JM, Cooke KR, Brinson YS, Pan L, Ferrara JLM. Total body irradiation and acute graft-versus-host disease. The role of gastrointestinal damage and inflammatory cytokines. Blood (1997) 90:3204-3213 [pubmed abstract]

MacDonald KPA, Nishioka Y, Lipsky PE, Thomas R. Functional CD40 ligand is expressed by T cells in rheumatoid arthritis. J Clin Invest. (1997) 100:2404 [pubmed abstract]