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School of Pathology and Laboratory Medicine
Wally Langdon et al
c-Cbl RING finger mutant mice:
A preclinical model for human myeloid leukemias
5% to 20% incidence of c-Cbl RING finger mutations in patients with:
myelodysplastic syndromes (MDS)
chronic myelomonocytic leukemia (CMML)
juvenile myelomonocytic leukemia (JMML)
atypical chronic myeloid leukema (aCML)
secondary acute myeloid leukemia (sAML)
Summary:
• Mice with a c-Cbl RING finger mutation develop a myeloproliferative disease
that progresses to leukemia.
• The c-Cbl RING finger mutation promotes enhances FLT3, c-Kit and
Akt signalling in hematopoietic progenitors.
•Knockout of FLT3 ligand prevents leukemia development in these mice.
[Rathinam, Thien, Flavell and Langdon, Cancer Cell 18, 341-352 (2010)]
Current and future studies:
Treatment of pre-leukemic and leukemic mice with inhibitors of
FLT3, c-Kit, c-Src and PI 3-kinase.
Initial studies with FLT3 inhibitor AC220 are encouraging.
Anatomical Pathology
Royal Perth Hospital
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•
•
Dr Jacqueline Bentel
Dr Marc Thomas
PhD Students
– Jasmine Tay
– Alison Louw
– Ebony Rouse
• Breast cancer
– Effects of androgen receptor and
MAPK signalling on p27 and the
regulation of breast cancer
growth
– Interaction between the
androgen receptor and ETS1 in
breast cancer cells
• Prostate cancer
•
Research performed in Anatomical Pathology,
PathWest Laboratory Medicine, Royal Perth
Hospital in collaboration with Winthrop
Professor Jennet Harvey
– Characterisation of the E3
ubiquitin ligases, RMND5A and
RMND5B
– ETS1 effects on the androgen
responsiveness of prostate
cancer cells
Charles
PaediatricAdrian
pathology
– Adrian Charles
• Wilms tumour
– Identifying chromosome 22 anomalies
– Undersanding genetic progression from precursor lesions
• The role of stroma in acute childhood leukaemia
with Ursula Kees
• Genetic changes in NUT carcinoma, a rare tumour
of children with Ursula Kees
• Stillbirth
– Producing and introducing national guidelines
– Epidemiological research
Using Alloreactive NK cells to treat leukaemia
Campbell Witt, Frank Christiansen, Pathol & Lab Med.
NK cells from allogeneic donors kill leukaemia cells without causing graftversus-host disease.
•Understand immunogenetic genetic difference required between donor
and patient (HLA, KIR genes).
•Find best clinical scenario in which to harness allogeneic NK cell
infusions.
•Developing TGA compliant methods for in vitro expansion of allogeneic
NK cells.
•Currently designing phase I trial.
FOLEY BA, …..CHRISTIANSEN FT, WITT CS. The Reactivity of Bw4-positive HLA-B and HLA-A Alleles with KIR3DL1: Implications
for Patient and Donor Suitability for Haploidentical Stem Cell Transplants. Blood, 2008,112:435-43
DE SANTIS D, FOLEY BA, JOHN E, SENITZER D, CHRISTIANSEN FT, WITT CS. Rapid, flow cytometric assay for NK alloreactivity
reveals exceptions to rules governing alloreactivity. Biol Blood Marrow Transplantation 2010, 16, 179-91.
How does the “9A” Allele of the NK cell receptor KIR2DL4
predispose to asthma?
C Witt, F Christiansen, P Holt. Pathol & Lab Med
Severe RTIs
Serum IgE
100
60 mths
p < 0.01
80
Geometric
Mean IgE 60
(kU/L)
+/-2SEM 40
Asthma
2
30
Incidence
Relative
Risk 1
20
Year 2
Year 5
10
24 mths
20
6 mths
0
0
1
2
p = 0.02
Year 1
p < 0.01
0
0
0
1
2
0
1
Copies of 9A allele
•9A allele encodes non-functional receptor preventing INFg response to ligand HLA-G
•Predisposition to Th2 response?
•IFNg important in defense against viruses in early life?
•IFNg important in generation of Treg cells?
GOODRIDGE, JP, WITT CS, CHRISTIANSEN, FT, WARREN HS. KIR2DL4 (CD158d) genotype influences expression
and function in NK cells. J Immunol (2003) 171: 1768-74.
GOODRIDGE JP …., WlTT CS.. Three Common Alleles of KIR2DL4 (CD158d) Encode Constitutively Expressed,
Inducible and Secreted Receptors in NK Cells. Eur J Immunol 37 (2007), 199-211.
2
The Role of Anti-HLA Antibodies in Renal Allograft Rejection
S Fidler, C Witt, A Irish, F Christiansen. Pathol & Lab Med
High titre, pre-Tx, anti-donor antibodies are
deterimental to graft outcome.
• Role of low titre Abs pre and post Tx unclear.
– Titre, antibody class, complement fixing, locus
(HLA-A,B,C,DR,DQ,DP,MICA,MICB)
– Interaction with transfusions, solCD30
– Predicting permissible HLA mismatches
LANGAN LL, IRISH A, WITT CS, CHRISTIANSEN FT (2007) Post transplant HLA class II antibodies and high soluble
CD30 levels are independently associated with poor kidney graft survival. American Journal of Transplantation. 7,
(2007), 847.
School of Pathology and Laboratory
Medicine – RPH Unit
Patricia Price et al
Sensory neuropathy in HIV patients
Our studies of patients treated in Melbourne, Jakarta, Kuala Lumpur and
Johannesburg show neuropathy is more common in
- taller and older patients
- African patients
- patients carrying the genotype TNF-1031 (and we have characterised the
TNF haplotypes around this)
Current studies address the role of chemokines in the accumulation of
inflammatory cells around the neurons and the experience of pain
Patricia Price (UWA), Kate Cherry (Alfred Hosp), Peter Kamermans (Witts, J’burg)
PhD Students: Constance Chew (UWA), Toni Wadley (Witts)
Specific CMV and HIV proteins may modulate natural killer cell
responses and affect the long-term outcome for HIV patients
Immune determinants of the
outcome of Hepatitis C virus
infection and its treatment with
interferon-a /ribavirin
Cohort studies of patients treated at RPH include……..
•An algorithm (“TIPscore”) based on TGF and IP-10 adjusted for age,
sex and HCV genotype optimally predicted virological response to
therapy.
•Low IFNg responses to HCV antigens IFNa / RBV therapy associated
with impaired cytokine responses to dendritic cells
•Propagation of HCV in culture and assessment of neutralizing antibodies.
Patricia Price, Silvia Lee (UWA)
Jim Flexman (RPH)
UNDERSTANDING IMMUNOLOGICAL SUSCEPTIBILITY TO
NON-TUBERCULOUS MYCOBACTERIAL (NTM) LUNG DISEASE
Dr Andrew Lim | Prof. Patricia Price | Prof. Grant Waterer
Lung disease due to NTM is a growing health problem. It remains unclear why some
individuals are susceptible to NTM infection. Current antibiotic treatment is
problematic, so immune-based therapies may be a better alternative.
Aims: (A) To elucidate whether defects exist in innate and adaptive immune
responses in patients with NTM lung disease; and (B) To determine whether these
immune responses associate with treatment outcome.
Immune cells and pathways we are targeting:
• T cells (Th1, Th2, Th17 and IL-10-producing subsets) – are there deficiencies in the
abilities of T cells to produce IFNγ or other proinflammatory cytokines in response
to mitogenic or antigenic stimulation?
• Macrophages (IFNγR, IL-1R and TLR pathways) – are there abnormalities in the
abilities of host macrophages (blood and airway) to mature/activate, to produce
inflammatory molecules or to phagocytose NTM?
Immune Restoration Disease
Some HIV patients responding to ART become sick
following an excessive immune response to antigens of
persistent 2o infections.
IRD are most common in patients starting ART with
opportunistic infections and low CD4 T-cell counts so we
have set up projects in Asia
Our study of HCV IRD in HCV co-infected patients
showed that IRD was most common in patients with
low antibody levels pre-ART. T-cell studies ongoing
In KL, we characterized T-cell, dendritic cell and
monocyte responses during cryptococcal & TB IRD
We demonstrated the importance of mycobacterial burden
in the development of TB IRD in a TB clinic in Delhi
Patricia Price (UWA), Evy Yunihastuti (UI), Adeeba K (UM)…….
PhD Students: Dino Tan & Ben Oliver (UWA)……..
School of Pathology and Laboratory
Medicine – RPH Unit
Martyn French et al
• NH&MRC Program Grant group - HIV and HCV
immunopathogenesis and vaccines
• National Centre in HIV Epidemiology and Clinical
Research
• International Network for Strategic Initiatives in Global
HIV Trials (INSIGHT)
• HIV Pathogenesis Program of the University of KwaZulu
Natal and the Ragon Institute of MIT, MGH and Harvard
• International Network for the Study of HIV-associated
immune reconstitution inflammatory syndrome (INSHI)
School of Pathology and Laboratory
Medicine – RPH Unit
Martyn French et al
Oliver BG, Elliott JH, Price P, Phillips M, Saphonn V, Vun MC, Kaldor JM, Cooper
DA, French MA. Mediators of Innate and Adaptive Immune Responses
Differentially Affect Immune Restoration Disease Associated with
Mycobacterium tuberculosis in HIV Patients Beginning Antiretroviral Therapy. J
Infect Dis. 2010;202:1728-1737.
Haddow LJ, Colebunders R, Meintjes G, Lawn SD, Elliott JH, Manabe YC, Bohjanen
PR, Sungkanuparph S, Easterbrook PJ, French MA, Boulware DR; International
Network for the Study of HIV-associated IRIS (INSHI). Cryptococcal immune
reconstitution inflammatory syndrome in HIV-1-infected individuals: proposed
clinical case definitions. Lancet Infect Dis. 2010;10:791-802.
French MA, Tanaskovic S, Law MG, Lim A, Fernandez S, Ward LD, Kelleher A,
Emery S. Vaccine-induced IgG2 anti-HIV p24 is associated with control of HIV
in patients with a 'high-affinity' FcgammaRIIa genotype. AIDS. 2010;24:198390.
School of Pathology and Laboratory
Medicine – RPH Unit
Martyn French et al
Cozzi-Lepri A, French MA, Baxter J, Okhuysen P, Plana M, Nehaus J, Landay A for
the INSIGHT SMART study group. Resumption of HIV replication in SMART
Study patients is associated with monocyte/macrophage derived cytokine and
chemokine changes in addition to CD4+ T cell decline. To be submitted
Fernandez S, Tanaskovic S, Helbig K, Beard M, Purcell D, Murray J, Lewin S, Price P,
French MA. Naive CD4+ T cell deficiency in HIV patients responding to longterm ART is associated with increased interferon-stimulated gene expression
in CD4+ T cells. To be submitted
Byakagwa H, French MA, Lewin SR, Kelleher AD, Amin J, Garsia R, Haskelberg H,
Kelly M, Boyd MA, Cooper DA, Purcell DFJ, Emery S on behalf of the CORAL
Study Group. Antiretroviral therapy intensification with raltegravir or antilipopolysaccharide immunoglobulin from hyper-immune bovine colostrum in
antiretroviral-treated patients exhibiting a suboptimal CD4+ T-cell response:
the CORAL study. To be submitted