McCracken, S, Hadfield, KA, Yenson, VM, Ariyakumar, G, McKelvey, KJ, Woodland, NB, Ashton, AW & Morris, JM 2016, 'NF-κB Regulation in T-cells in Pregnancy is Mediated via Fas/FasL Interactions: The Signal for which is Derived from Exosomes Present in Maternal Plasma', Journal of Reproductive Immunology, vol. 1, no. 2, pp. 1-11.View/Download from: UTS OPUS or Publisher's site
Background: Regulated suppression of maternal Th1 immunity is necessary for normal pregnancy since inappropriate Th1 responses results in increased pregnancy loss and complications including intrauterine growth restriction (IUGR). We have shown that suppression of the p65 subunit of NF-κB in maternal T-cells underlies this change in T-cell responses. This study aimed to determine mechanism(s) that control p65 suppression. Methods and findings: Maternal plasma contained particulate factor’s that suppress p65 and induce T-cell apoptosis in Jurkat T-cells and the factor’s was positive for FasL and TRAIL. Both the Fas activating antibody CH11 and recombinant human TRAIL induced Jurkat apoptosis. Specific Fas activation resulted in p65 suppression which was reversed in the presence of the Fas inactivating antibody ZB4. Despite inducing apoptosis, recombinant TRAIL did not suppress p65 expression. Maternal T-cells expressed increased Fas relative to non-pregnant controls. Fas activation in Jurkats resulted in p65 suppression thus limited IL-2 and IFNï§ transcription in response to PMA/ionomycin stimulation. In contrast, partial knockdown of Fas in Jurkats prevented suppression of p65 in response to CH11, leading to increased IL-2 and IFNï§ production when stimulated with PMA/ionomycin. FasL+ Exosomes isolated from the particulate fraction of maternal plasma specifically induced p65 suppression in Jurkats since suppression was completely reversed with ZB4. In pregnancies complicated with IUGR where Th1 cytokine production is increased, placental expression of FasL was reduced compared to normal controls. Conclusion: Taken together these data suggest that pregnancy derived FasL+ exosomes in maternal plasma regulate p65 levels in circulating T-cells through Fas activation. The expression of Fas on T-cells and FasL on exosomes both dictate the level of p65 suppression and the level of cytokine production in response to stimulation throughout pregnancy. Inappropriate expr...
Suen, H, Brown, R, Yang, S, Weatherburn, C, Ho, PJ, Woodland, N, Nassif, N, Barbaro, P, Bryant, C, Hart, D, Gibson, J & Joshua, D 2016, 'Multiple myeloma causes clonal T-cell immunosenescence: identification of potential novel targets for promoting tumour immunity and implications for checkpoint blockade', LEUKEMIA, vol. 30, no. 8, pp. 1716-1724.View/Download from: UTS OPUS or Publisher's site
McAuliffe, S, Brown, R, Catalano, A, Ho, PJ, Nassif, N, Woodland, N, Hart, D, Weatherburn, C, Yang, S, Suen, H, Paul, C, Joshua, D & Gibson, J 2015, 'Using digital polymerase chain reaction to detect minimal residual disease in myeloma by identifying FGFR3 up-regulation', LEUKEMIA & LYMPHOMA, vol. 56, no. 9, pp. 2714-2716.View/Download from: UTS OPUS or Publisher's site
Favaloro, J, Liyadipitiya, T, Brown, R, Yang, S, Suen, H, Woodland, N, Nassif, N, Hart, D, Fromm, P, Weatherburn, C, Gibson, J, Ho, PJ & Joshua, D 2014, 'Myeloid derived suppressor cells are numerically, functionally and phenotypically different in patients with multiple myeloma', LEUKEMIA & LYMPHOMA, vol. 55, no. 12, pp. 2893-2900.View/Download from: UTS OPUS or Publisher's site
Bryant, C, Suen, H, Brown, R, Yang, S, Favaloro, J, Aklilu, E, Gibson, J, Ho, PJ, Iland, H, Fromm, P, Woodland, N, Nassif, N, Hart, D & Joshua, DE 2013, 'Long-term survival in multiple myeloma is associated with a distinct immunological profile, which includes proliferative cytotoxic T-cell clones and a favourable Treg/Th17 balance', Blood Cancer Journal, vol. 3, pp. 1-7.View/Download from: UTS OPUS or Publisher's site
Despite improved outcomes in multiple myeloma (MM), a cure remains elusive. However, even before the current therapeutic era, 5% of patients survived
for >10 years and we propose that immune factors contribute to this longer survival. We identified patients attending our clinic, who had survived
for >10 years (n=20) and analysed their blood for the presence of T-cell clones, T-regulatory cells (Tregs) and T helper 17 (Th17) cells. These results were compared with MM patients with shorter follow-up and age-matched healthy control donors. The frequency of cytotoxic T-cell clonal expansions in patients with <10 years follow-up (MM patients) was 54% (n=144), whereas it was 100% (n=19/19) in the long-survivors (LTS-MM). T-cell clones from MM patients proliferated poorly in vitro, whereas those from LTS-MM patients proliferated readily (median proliferations 6.1% and 61.5%, respectively (P<0.0001)). In addition, we found significantly higher Th17 cells and lower Tregs in the LTS-MM group when compared with the MM group. These results indicate that long-term survival in MM is associated with a distinct immunological profile, which is consistent with decreased immune suppression.
Brown, R, Kabani, K, Favaloro, J, Yang, S, Ho, PJ, Gibson, J, Fromm, P, Suen, H, Woodland, NB, Nassif, N, Hart, D & Joshua, D 2012, 'CD86+ or HLA-G+ can be transferred via trogocytosis from myeloma cells to T cells and are associated with poor prognosis', Blood, vol. 120, pp. 2055-2063.View/Download from: UTS OPUS or Publisher's site
The transfer of membrane proteins between cells during contact, known as trogocytosis, can create novel cells with a unique phenotype and altered function. We demonstrate that trogocytosis is more common in multiple myeloma (MM) than chronic lymphocytic leukemia and Waldenstrom macroglobulinaemia; that T cells are more probable to be recipients than B or natural killer cells; that trogocytosis occurs independently of either the T-cell receptor or HLA compatibility; and that after trogocytosis, T cells with acquired antigens can become novel regulators of T-cell proliferation. We screened 168 patients with MM and found that CD86 and human leukocyte antigen G (HLA-G) were antigens commonly acquired by T cells from malignant plasma cells. CD3+ CD86acq+ and CD3+ HLA-Gacq+ cells were more prevalent in bone marrow than peripheral blood samples. The presence of either CD86 or HLA-G on malignant plasma cells was associated with a poor prognosis. CD38++ side population cells expressed HLA-G, suggesting that these putative myeloma stem cells could generate immune tolerance. HLA-G+ T cells had a regulatory potency similar to natural Tregs, thus providing another novel mechanism for MM to avoid effective immune surveillance
Reid, S, Johnson, LN, Woodland, NB & Marks, D 2012, 'Pathogen reduction treatment of buffy coat platelet concentrates in additive solution induces proapoptotic signaling', Transfusion, vol. 52, no. 10, pp. 2094-2103.View/Download from: UTS OPUS or Publisher's site
BACKGROUND: Pathogen reduction technology (PRT) can potentially reduce the risk of transfusion-transmitted infections. However, PRT treatment of platelet (PLT) concentrates also results in reduced PLT quality and increased markers of apoptosis during storage. The aim of this study was to investigate changes to the expression and activation of proteins involved in apoptosis signaling. STUDY DESIGN AND METHODS: Samples from riboflavin and ultraviolet light PRT-treated and untreated (control) buffy coatderived PCs in 70% SSP+ and 30% plasma were taken on Days 1, 5, and 7 of storage. Phosphatidylserine (PS) exposure, expression of Bcl-2 family proteins, cytochrome c release, and cleavage of caspase-3 and caspase-3 substrates were analyzed using flow cytometry and Western blotting. RESULTS: Compared to untreated controls, markers of apoptosis signaling were increased after PRT and subsequent storage. PS exposure on the PLT outer membrane was significantly higher after PRT on Days 5 and 7 of storage (p < 0.05). Expression of proapoptotic Bak and Bax was higher after PRT and subsequent storage. Cytochrome c release and caspase-3 cleavage were also greater and occurred earlier in the PRT-treated PLTs. The cleavage of caspase-3 substrates gelsolin and ROCK I were also increased after PRT, compared to untreated controls. CONCLUSIONS: This study demonstrated an increase in proapoptotic signaling during PLT storage, which was exacerbated by PRT. Many of these differences emerged outside the current 5-day storage period. These changes may not currently influence PLT transfusion quality, but will need to be carefully evaluated when considering extending PLT storage beyond 5 days
Reid, S, Yang, S, Brown, R, Kabani, K, Aklilu, E, Ho, PJ, Woodland, N & Joshua, D 2010, 'Characterisation and relevance of CD138-negative plasma cells in plasma cell myeloma', INTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY, vol. 32, no. 6, pp. E190-E196.View/Download from: Publisher's site
Johnson, L, McCracken, SA, Morris, JM, Woodland, NB & Flower, RL 2003, 'Variation in the reliability of RHD antenatal genotyping using the polymerase chain reaction and targeting multiple exons of the RHD gene', Vox Sanguinis, vol. 85, pp. 222-223.
Holley, L, Woodland, N, Hung, WT, Cordatos, K & Reuben, A 1999, 'Influence of fibrinogen and haematocrit on erythrocyte sedimentation kinetics', BIORHEOLOGY, vol. 36, no. 4, pp. 287-297.
Woodland, NB, Flower, RL & Winkler, IG 1999, 'Detection of gene conversion associated with Miltenberger blood group polymorphisms', TRANSFUSION, vol. 39, no. 10, pp. 47S-47S.
McAuliffe, S, Joshua, D, Brown, R, Catalano, A, Ho, PJ, Nassif, N, Woodland, N, Hart, D, Weatherburn, C, Yang, S, Suen, H, Paul, C & Gibson, J 2015, 'Digital PCR for MRD detection of myeloma', Clinical Lymphoma, Myeloma & Leukemia, 15th International Myeloma Workshop, Elsevier, Rome, Italy, pp. E95-E95.View/Download from: UTS OPUS or Publisher's site
A pilot study was performed to investigate the use of digital PCR (dPCR) to detect minimal residual disease (MRD) in patients with multiple myeloma. dPCR allows greater quantitative specificity in PCR reactions by performing multiple, minute PCR reactions on individual DNA templates.
Bryant, CE, Brown, R, Yang, S, Suen, H, Aklilu, E, Favaloro, J, Hart, D, Fromm, P, Woodland, NB, Nassif, N, Iland, H, Gibson, J, Ho, PJ & Joshua, D 2011, 'Ten Year Survivors of Multiple Myeloma Demonstrate a Differential Expression of Immunological Biomarkers Including a High Incidence of Cytotoxic T-Cell Clones Which Have Not Acquired Myeloma-Associated Anergy', 53rd Annual Meeting and Exposition of the American Society of Hematology (ASH), 53rd Annual Meeting and Exposition of the American Society of Hematology (ASH)., The American Society of Hematology, San Diego, California, pp. 1678-1678.