Bone Marrow Transplantation

Geoff Hill Staff
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Key Publications
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Lab Head: Dr 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 immunological effects of new growth factors to mobilize stem cells.
We are trialing a number of new cytokines that mobilise stem cells into the blood of transplant donors for their immunomodulatory effects and ability to prevent acute and chronic GVHD. We have demonstrated that at least one of these agents offers considerable advances over currently used cytokines and clinical trials at the Royal Brisbane Hospital are planned to commence in 2004.

The effect of donor APC on GVHD and Transplant Tolerance.
We have previously determined that G-CSF alters the ability of donor T cells to induce GVHD although the mechanisms of this effect remain unclear. We have identified a novel donor antigen presenting cell (APC) that induces tolerance through the induction of regulatory donor T cells. We have also defined the molecular mechanism by which G-CSF and novel new growth factors alter donor T cell function. Current studies aim to elucidate the pathway by which G-CSF and its analogues induce regulatory APC and T cells in the donor.

The effect of Flt-3L containing cytokines on the eradication of leukemia after SCT.
Leukemia relapse after SCT remains a major limitation of the procedure. We are currently studying the ability of Flt-3L containing regimens to improve leukemia eradication after SCT and the mechanisms therein. This work utilises novel leukemia lines that can be tracked by PET scanning using new imaging technology at the QIMR.

The effect of B cells on transplantation tolerance.
Most of the current studies on APC in transplantion biology focus on host professional APC (such as dendritic cells). We are utilising novel B cell deficient mice to study the immunomodulatory effect of B cells on GVHD. This is particularly relevant now that B cell depleting antibodies are widely used in clinical practice prior to allogeneic SCT.

Staff

Labhead:	Dr Geoffrey Hill
Senior Research Officer:	Dr Kelli MacDonald
Research Officers:	Dr Tatjana Banovic Dr Angela Burman
Research Assistants:	Rachel Kuns Vanessa Rowe Helen Bofinger Alistair Don Naomi Odorico
PhD Scholars:	Dr Edward Morris Kate Markey
Gopher:	Patrick Bunn

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Funding

We gratefully acknowledge support from the following funding bodies:

The Wellcome Trust
The National Health and Medical Research Council of Australia
The Queensland Cancer Fund
The Leukemia Foundation of Queensland

Collaborators

Professor James Ferrara, Director of Bone Marrow Transplantation, Department of Internal Medicine and Pediatrics, University of Michigan, USA
A/Prof Ranjeny Thomas, Centre for Immunology and Cancer Research, Princess Alexandra Hospital, Brisbane, Australia

Student Projects

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

Key Publications

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;3093-3103 [pubmed abstract]

Bonovic 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]

Hall P, Kennedy G, Morton J, Hill GR, Durrant S. Twenty-four hour continuous infusion of amphotericin B for the treatment of suspected or proven fungal infection in haematology patients. Intern Med J. (2005) 35:374 [pubmed abstract]

Johnson BJ, Le TT, Dobbin CA, Banovic T, Howard CB, Leon Flores FD, Vanags D, Naylor DJ, Hill GR, Suhrbier A. Heat shock protein 10 Inhibits lipopolysaccharide-induced inflammatory mediator production. J. Biol. Chem. (2005) 280;4037-47 [pubmed abstract]

Kennedy GA, Butler J, Western R, Morton J, Hill G and Durrant S. Predicting survival for myeloid leukaemia after HLA-identical sibling donor allogeneic stem cell transplantation. Leukaemia (2005) 19;317-319

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, Johnson D, Filipich C, Morris ES, Clouston A, Ferrara JLM and Hill GR. Chronic Graft-versus-Host Disease after G-CSF Mobilized Allogeneic Stem Cell Transplantation: The Role of Donor T Cell Dose and Differentiation. Biology of Blood and Bone Marrow Transplantation (2004) 10;373-85 [pubmed abstract]

Koppi T, Munster DJ, Brown L, MacDonald KPA, Hart DN. CMRF-44 antibody-mediated depletion of activated human dendritic cells: a potential means for improving allograft survival. Transplantation (2003) 75:1723-30 [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 KP and Hill GR. Keratinocyte Growth Factor in Hematology and Oncology. Current Pharmaceutical Design (2002) 8:395-403 [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]

Teshima T, Mach N, Hill GR, Brinson YS, Pan L, Gillessen S, Dranoff G and Ferrara JLM. Tumor cell vaccine elicits potent antitumor immunity after allogeneic T-cell-depleted bone marrow transplantation.Cancer Res. (2001) 61:162-71 [pubmed abstract]

Cooke KR, Gerbitz A, Crawford JM, Teshima T, Hill GR, Tesolin A, Rossignol DP and Ferrara JLM. LPS antagonism reduces graft-versus-host disease and preserves graft-versus-leukemia activity after experimental bone marrow transplantation. J. Clin. Invest. (2001) 107:1581-9 [pubmed abstract]

Hill GR, Rebel V, Teshima T, Krijanovski OI, Cooke KR, Brinson YS and Ferrara JLM. The p55 TNF-a receptor plays a critical role in T cell alloreactivity. J. Immunol. (2000) 164: 656-663 [pubmed abstract]

Cooke KR, Hill GR, Gerbitz A, Kobzik L, Martin TR, Crawford JM, Brewer J and Ferrara JLM . TNF-a neutralization reduces lung injury after experimental allogeneic bone marrow transplantation. Transplantation (2000) 70:272-9 [pubmed abstract]

Snowden JA, Hill GR, Hunt P, Carnoutsos S, Spearing RL, Espiner E and Hart DNJ. Assessment of cardiotoxicity during haemopoetic stem cell transplantation with plasma brain natriuretic peptide. Bone Marrow Transplant. (2000) 26:309 [pubmed abstract]

Cooke KR, Hill GR, Gerbitz A, Kobzik L, Martin TR, Crawford JM, Brewer J and Ferrara JLM. Hyporesponsiveness of donor cells to LPS stimulation reduces the severity of experimental idiopathic pneumonia syndrome: Potential role for a gut-liver axis of inflammation. J. Immunol.(2000) 165:6612-6619 [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, Cooke KR, Brinson YS and Ferrara JLM. Pretransplant chemotherapy reduces inflammatory cytokine production and graft-versus-host disease after allogeneic bone marrow transplantation. Transplantation (1999) 67:1478-5 [pubmed abstract]

Pan L, Teshima T, Hill GR, Brinson YS, Bungard D, Reddy V, Cooke KR and Ferrara JLM. G-CSF mobilized allogeneic stem cell transplantation maintains graft-versus-leukemia effects through a perforin dependent pathway while preventing graft-versus-host disease. Blood (1999) 90:4071-4078 [pubmed abstract]

Hill GR, Krijanovski OI, Cooke, KR, Teshima T, Brinson YS and Ferrara JLM. Keratinocyte growth factor (KGF) separates graft-versus-leukemia effects from graft-versus-host disease. Blood (1999) 94:825-831 [pubmed abstract]

Teshima T, Hill GR, Pan L, Brinson YS and Ferrara JLM. IL-11 separates graft-versus-leukemia effects from graft-versus-host disease after bone marrow transplantation.J.Clin. Invest. (1999) 104:317-325 [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]

Rebel VI, Hartnett S, Hill GR, Lazo-Kallanian SB, Ferrara JLM, Sieff CA. Essential role for the p55 TNF-a receptor in regulating hematopoesis at a stem cell level. J. Exp. Med. (1999) 190:1493-1504 [pubmed abstract]

Reddy V, Hill GR, Teshima T, Pan L, Gerbitz A, Brinson YS and Ferrara JLM. G-CSF modulates acute GVHD through effects on the donor but not the recipient after allogeneic stem cell transplantation. Transplantation (1999) 69: 691-3 [pubmed abstract]

MacDonald KPA, Pettit AR, Quinn C, Thomas GJ, Thomas R. Resistance of rheumatoid synovial dendritic cells to the immunosuppressive effects of IL-10. J Immunol. (1999) 163:5599 [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]

Cooke KR, Krenger W, Hill GR, Martin TR, Kobzik L, Brewer J, Simmons R, Crawford JM, Van den Brink M, Ferrara JLM. Host reactive donor T cells are associated with lung injury after experimental allogeneic GVHD. Blood (1998) 92:2571-2580

Cooke KR, Hill GR, Crawford JM, Bungard D, Brinson YS, Delmonte Jr J and Ferrara JLM. Tumor necrosis factor- alpha production to lipopolysaccharide stimulation by donor cells predicts the severity of experimental acute graft-versus-host disease. J. Clin. Invest. (1998) 102:1882-1891 [pubmed abstract]

Wichramasinghe SN, Spearing RL and Hill GR. Congenital dyserythropoesis with intraerythroblastic chromatin bridges and ultrasonically-normal erythroblast heterochromatin: a new disorder. Br. J. Haem. (1998)103:831-4 [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]