ORCID Profile
0000-0001-9567-382X
Current Organisations
Royal Brisbane and Women's Hospital
,
Queensland Institute of Medical Research
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Publisher: Elsevier BV
Date: 12-2014
Publisher: Elsevier BV
Date: 08-2007
Publisher: American Society for Microbiology
Date: 15-03-2013
DOI: 10.1128/JVI.02821-12
Abstract: Calculation of pathogen growth rates is important in understanding the natural history of infection and effects of therapy. However, it is often difficult to estimate pathogen growth because patients are treated immediately upon the detection of infection, leaving only one nonzero untreated reading. Previous approaches have relied on the flawed assumption that pathogen loads just prior to detection are at the assay detection threshold. We have developed a novel method for estimating the pathogen growth rate from a single reading and investigated the initial growth of cytomegalovirus (CMV) in allogeneic hematopoietic stem cell transplant (HSCT) patients. We applied this approach to CMV viral loads measured at least weekly in 122 patients in the 3 months posttransplant. Viral growth rates were estimated by using a modeling approach that accounts for the viral load and the time since the last negative reading. Viral growth rates decreased rapidly within the first week, from 0.72/day (doubling time, 0.96 day) at the point of reactivation to 0.22/day (doubling time, 3.1 days) at 1 week. Results from this method correlated closely with a two-point regression analysis of a subset of 58 patients with detectable subthreshold viral loads immediately prior to overt reactivation. Patients with lymphocyte counts of ≥0.5 × 10 9 /liter had significantly slower viral growth than patients with low lymphocyte counts (0.612/day versus 0.325/day, P 0.0001). Thus, our novel method of estimating pathogen growth rates reveals a rapid slowing of CMV growth during reactivation in HSCT patients and a significant impact of the lymphocyte count on CMV growth.
Publisher: Springer Science and Business Media LLC
Date: 03-08-2023
DOI: 10.1038/S41409-023-02038-9
Abstract: Acute gastrointestinal graft versus host disease (GI-GVHD) is a common complication following allogeneic haematopoietic cell transplantation (HCT), and is characterised by severe morbidity, frequent treatment-refractoriness, and high mortality. Early, accurate identification of GI-GVHD could allow for therapeutic interventions to ameliorate its severity, improve response rates and survival however, standard endoscopic biopsy is inadequately informative in terms of diagnostic sensitivity or outcome prediction. In an era where rapid technological and laboratory advances have dramatically expanded our understanding of GI-GVHD biology and potential therapeutic targets, there is substantial scope for novel investigations that can precisely guide GI-GVHD management. In particular, the combination of tissue-based biomarker assessment (plasma cytokines, faecal microbiome) and molecular imaging by positron emission tomography (PET) offers the potential for non-invasive, real-time in vivo assessment of donor:recipient immune activity within the GI tract for GI-GVHD prediction or diagnosis. In this article, we review the evidence regarding GI-GVHD diagnosis, and examine the potential roles and translational opportunities posed by these novel diagnostic tools, with a focus on the evolving role of PET.
Publisher: American Society of Hematology
Date: 02-08-2012
DOI: 10.1182/BLOOD-2012-01-402404
Abstract: The endogenous presentation of the majority of viral epitopes through MHC class I pathway is strictly dependent on the transporter associated with antigen processing (TAP) complex, which transfers the peptide products of proteasomal degradation into the endoplasmic reticulum. A small number of epitopes can be presented through the TAP-independent pathway, the precise mechanism for which remains largely unresolved. Here we show that TAP-independent presentation can be mediated by autophagy and that this process uses the vacuolar pathway and not the conventional secretory pathway. After macroautophagy, the antigen is processed through a proteasome-independent pathway, and the peptide epitopes are loaded within the autophagolysosomal compartment in a process facilitated by the relative acid stability of the peptide-MHC interaction. Despite bypassing much of the conventional MHC class I pathway, the autophagy-mediated pathway generates the same epitope as that generated through the conventional pathway and thus may have a role in circumventing viral immune evasion strategies that primarily target the conventional pathway.
Publisher: The American Association of Immunologists
Date: 15-05-2018
Abstract: IL-6 mediates broad physiological and pathological effects through its receptor signal transducing unit gp130. Due to the reportedly wide cellular expression of gp130, IL-6 is thought to signal ubiquitously via gp130 complex formation with membrane-bound IL-6Rα or soluble IL-6Rα. gp130 signaling primarily induces p-STAT3 and p-STAT1. In contrast to the previous dogma, we show in this article that circulating mouse and human granulocytes are unable to induce p-STAT3 or p-STAT1 after stimulation with IL-6 or an IL-6/soluble IL-6R complex. Furthermore, we demonstrate that this is due to a lack of gp130 expression on mouse and human granulocytes, despite their expression of membrane-bound IL-6R. Importantly, the absence of gp130 is not only a feature of mature granulocytes in healthy in iduals, it is also observed after allogeneic stem cell transplantation. Moreover, granulocyte gp130 expression is lost during maturation, because granulocyte-monocyte progenitor cells express gp130 and respond to IL-6. Given that granulocytes constitute 50–70% of circulating leukocytes, this indicates a significantly smaller scope of IL-6 signaling than previously anticipated and has important implications for therapeutic IL-6 inhibition and the mechanisms of action thereof.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.C.6550138.V1
Abstract: Abstract The adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD) is known to facilitate caspase-1 activation, which is essential for innate host immunity via the formation of the inflammasome complex, a multiprotein structure responsible for processing IL1β and IL18 into their active moieties. Here, we demonstrated that ASC-deficient CD8 sup + /sup T cells failed to induce severe graft-versus-host disease (GVHD) and had impaired capacity for graft rejection and graft-versus-leukemia (GVL) activity. These effects were inflammasome independent because GVHD lethality was not altered in recipients of caspase-1/11–deficient T cells. We also demonstrated that ASC deficiency resulted in a decrease in cytolytic function, with a reduction in granzyme B secretion and CD107a expression by CD8 sup + /sup T cells. Altogether, our findings highlight that ASC represents an attractive therapeutic target for improving outcomes of clinical transplantation. /
Publisher: Springer Science and Business Media LLC
Date: 24-08-2020
Publisher: Elsevier BV
Date: 06-2018
DOI: 10.1016/J.BBMT.2018.01.034
Abstract: Acute gastrointestinal graft-versus-host disease (GI-GVHD) after hematopoietic progenitor cell transplantation (HPCT) is a common and life-threatening complication. Endoscopic biopsy of the GI tract (GIT) is required for diagnosis. However, clear evidence to optimize this diagnostic approach is lacking, leading to variation in diagnostic sensitivity between institutions. We aimed to assess the clinical, endoscopic, and histologic findings of endoscopies performed for suspected acute GI-GVHD at our institution to better define the optimal use of this strategy. We performed a retrospective cohort study of adults who had undergone endoscopy for suspected acute GI-GVHD within 180 days after allogeneic HPCT for hematologic malignancy between 2011 and 2016. Details included symptoms at time of referral for endoscopy, type of procedure performed, macroscopic findings on endoscopy, and histologic findings after gut biopsy. Correlation was made with clinical GVHD severity scores. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated and compared for each procedure. Predictors of histologic GVHD and overall survival were also compared. Of the 123 patients included, acute GI-GVHD occurred in 59 (48%). Lower endoscopy demonstrated greater sensitivity than upper endoscopy (50% versus 39%). Single upper endoscopy for upper symptoms alone had the lowest yield of GI-GVHD (14%). Combination upper and lower endoscopy demonstrated strong histologic concordance between upper and lower procedures. The addition of upper endoscopy to lower endoscopy only identified an extra 2 (4%) cases of GVHD. Advanced age and the presence of lower GIT symptoms were the only pre-endoscopy predictors of histologic GVHD on multivariate analysis. Patients with isolated upper histologic GVHD showed similar survival to patients with negative biopsies. Endoscopy and biopsy only identified 74% of those ultimately requiring treatment for acute GI-GVHD. Acute GI-GVHD remains a clinical diagnosis supported by available histologic evidence. Isolated upper GI-GVHD is rare, and in the absence of lower GIT symptoms, routine upper endoscopy does not significantly improve diagnostic yield for histologic GVHD. Overall, endoscopy and biopsy underdiagnoses 26% of clinical GI-GVHD, highlighting a need for research into novel diagnostic strategies.
Publisher: Wiley
Date: 2008
DOI: 10.1002/AJH.21062
Abstract: Hepatosplenic T-cell lymphoma (HSTL) is an aggressive lymphoma. In post-transplant immunosuppressed patients, HSTL is usually rapidly fatal. We report successful treatment of post-transplant HSTL in a 50-year-old renal allograft recipient by reducing immunosuppression and using intensive chemotherapy consisting of alternating cycles of HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) and MTX/HiDAC (methotrexate, Ara-C). Remission is ongoing at 8+ years. Literature review identified another 20 cases of HSTL in solid organ transplant recipients: median survival was 4 months no other patients survived beyond 12 months. Bone marrow involvement was universal, but changes were often subtle: 6 of 12 cases had nondiagnostic examinations earlier on. High index of suspicion may lead to more timely diagnosis of this uncommon form of post-transplant lymphoproliferative disorder, and treatment with intensive chemotherapy such as HyperCVAD may be curative.
Publisher: Wiley
Date: 06-2006
DOI: 10.1111/J.1440-1711.2006.01441.X
Abstract: Adoptive T-cell therapy has definite clinical benefit in relapsed leukaemia after allogeneic transplant and in Epstein-Barr virus-associated post-transplant lymphoproliferative disease. However, the majority of tumour targets are weakly immunogenic self-antigens and success has been limited in part by inadequate persistence and expansion of transferred T cells and by tumour-evasion strategies. Adoptive immunotherapy presents the opportunity to activate, expand and genetically modify T cells outside the tolerising environment of the host and a number of strategies to optimize the cellular product, including gene modification and modulation of the host environment, in particular by lymphodepletion, have been developed.
Publisher: BMJ
Date: 06-2020
Abstract: Analysis of vector integration sites in gene-modified cells can provide critical information on clonality and potential biological impact on nearby genes. Current short-read next-generation sequencing methods require specialized instruments and large batch runs. We used nanopore sequencing to analyze the vector integration sites of T cells transduced by the gammaretroviral vector, SFG.iCasp9.2A.ΔCD19. DNA from oligoclonal cell lines and polyclonal clinical s les were restriction enzyme digested with two 6-cutters, NcoI and BspHI and the flanking genomic DNA lified by inverse PCR or cassette ligation PCR. Following nested PCR and barcoding, the licons were sequenced on the Oxford Nanopore platform. Reads were filtered for quality, trimmed, and aligned. Custom tool was developed to cluster reads and merge overlapping clusters. Both inverse PCR and cassette ligation PCR could successfully lify flanking genomic DNA, with cassette ligation PCR showing less bias. The 4.8 million raw reads were grouped into 12,186 clusters and 6410 clones. The 3′long terminal repeat (LTR)-genome junction could be resolved within a 5-nucleotide span for a majority of clusters and within one nucleotide span for clusters with ≥5 reads. The chromosomal distributions of the insertional sites and their predilection for regions proximate to transcription start sites were consistent with previous reports for gammaretroviral vector integrants as analyzed by short-read next-generation sequencing. Our study shows that it is feasible to use nanopore sequencing to map polyclonal vector integration sites. The assay is scalable and requires minimum capital, which together enable cost-effective and timely analysis. Further refinement is required to reduce lification bias and improve single nucleotide resolution.
Publisher: Massachusetts Medical Society
Date: 03-11-2011
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22543108.V1
Abstract: Supplementary Figure S1: GVHD survival of lethally-irradiated (day 0, 1000cGy split dose) B6.WT, B6.ASC-/- or B6.NLRP3-/- recipients transplanted with BALB/c BM (5x106) and T cells (5x106). The non-GVHD control group received TCD BM cells (5x106) only. Results combined from 2 independent experiments (n = 20 per T cell-replete group, n = 8 for TCD BM group). ****P 0.0001 B6.NLRP3-/- vs. B6.WT. Results are presented as means {plus minus} SEM.
Publisher: Wiley
Date: 19-07-2016
DOI: 10.1038/ICB.2016.59
Abstract: Cross-presentation of exogenous protein antigens by B cells through the major histocompatibility complex (MHC) class I pathway in lymphoid malignancies, and transplant setting has been recognised as an important mediator of immune pathogenesis and T cell-mediated immune regulation. However, the precise mechanism of cross-presentation of exogenous antigens in B cells has remained unresolved. Here we have delineated a novel pathway for cross-presentation in B cells, which involves synergistic cooperation of the proteasome and autophagy. After endocytosis, protein antigen is processed through an autophagy- and proteasome-dependent pathway and CD8
Publisher: American Association for the Advancement of Science (AAAS)
Date: 21-04-2017
DOI: 10.1126/SCIIMMUNOL.AAH7152
Abstract: T R 1 cells are the major regulatory population generated after allogeneic bone marrow transplantation.
Publisher: American Society of Hematology
Date: 18-10-2019
DOI: 10.1182/BLOODADVANCES.2019000453
Abstract: Peg-IFNα is tolerated and induces disease response in patients who relapse after allogeneic SCT. Increased pretreatment MAIT and pDC proportions were associated with better progression-free and overall survival after peg-IFNα treatment.
Publisher: Microbiology Society
Date: 08-2010
Abstract: Recent studies have shown that long-term persistence of human cytomegalovirus (HCMV) in mononuclear cells of myeloid lineage is dependent on the UL138 open reading frame, which promotes latent infection. Although T-cell recognition of protein antigens from all stages of lytic HCMV infection is well established, it is not clear whether proteins expressed during latent HCMV infection can also be recognized. This study conducted an analysis of T-cell response towards proteins associated with HCMV latency. Ex vivo analysis of T cells from healthy virus carriers revealed a dominant CD8 + T-cell response to the latency-associated pUL138 protein, which recognized a non-canonical 13 aa epitope in association with HLA-B*3501. These pUL138-specific T cells displayed a range of memory phenotypes that were in general less differentiated than that previously described in T cells specific for HCMV lytic antigens. Antigen-presentation assays revealed that endogenous pUL138 could be presented efficiently by HCMV-infected cells. However, T-cell recognition of pUL138 was dependent on newly synthesized protein, with little presentation from stable, long-lived protein. These data demonstrate that T cells targeting latency-associated protein products exist, although HCMV may limit the presentation of latent proteins, thereby restricting T-cell recognition of latently infected cells.
Publisher: Springer Science and Business Media LLC
Date: 22-01-2022
Publisher: Frontiers Media SA
Date: 06-08-2019
Publisher: American Society of Hematology
Date: 19-06-2014
DOI: 10.1182/BLOOD-2014-01-551671
Abstract: Allodepleted-T-cells containing the iC9 safety gene persist long-term in vivo, promote immune recovery, and protect against infections. GvHD caused by iC9-T cells can be permanently controlled by a single administration of AP1903 without abrogating immune reconstitution.
Publisher: Wiley
Date: 30-10-2002
DOI: 10.1046/J.1365-2141.2002.03843.X
Abstract: Re-treatment with rituximab for B-cell non-Hodgkin's lymphoma (NHL) relapsing after previous rituximab therapy has recently been shown to be clinically efficacious. Although the mechanism of resistance to rituximab re-treatment in non-responding patients is unknown, it is possible that loss of CD20 expression in the relapsed NHL could be important in some patients. We examined the incidence and nature of CD20 negative relapses following rituximab therapy in aggressive B-cell NHL treated at our institution. Of a total of 18 patients who received rituximab, 13 have relapsed, with 10 patients subsequently undergoing repeat tissue biopsy. Six of these 10 patients (60%) were shown to have lost CD20 expression by either immunohistochemistry and/or flow cytometry. Furthermore, three of the six patients who relapsed with CD20-negative NHL also suffered relapses at unusual anatomical sites. We conclude that loss of CD20 expression in aggressive B-cell NHL relapsing post-rituximab therapy is common. As such, repeat tissue biopsy should be undertaken to document CD20 expression by both flow cytometry and immunohistochemistry prior to considering repeated courses of rituximab in relapsed aggressive lymphomas.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.C.6550138
Abstract: Abstract The adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD) is known to facilitate caspase-1 activation, which is essential for innate host immunity via the formation of the inflammasome complex, a multiprotein structure responsible for processing IL1β and IL18 into their active moieties. Here, we demonstrated that ASC-deficient CD8 sup + /sup T cells failed to induce severe graft-versus-host disease (GVHD) and had impaired capacity for graft rejection and graft-versus-leukemia (GVL) activity. These effects were inflammasome independent because GVHD lethality was not altered in recipients of caspase-1/11–deficient T cells. We also demonstrated that ASC deficiency resulted in a decrease in cytolytic function, with a reduction in granzyme B secretion and CD107a expression by CD8 sup + /sup T cells. Altogether, our findings highlight that ASC represents an attractive therapeutic target for improving outcomes of clinical transplantation. /
Publisher: American Association for the Advancement of Science (AAAS)
Date: 18-01-2019
Abstract: Cytomegalovirus (CMV) infection and reactivation are common and potentially fatal complications after bone marrow or hematopoietic stem cell transplantation (BMT). Martins et al. developed faithful preclinical murine models of CMV reactivation following BMT and found that humoral immunity can prevent this process (see the Perspective by Alegre). After BMT, antiviral antibodies that would have kept CMV at bay dwindle because host plasma cells are ablated and the donor B cell pool reconstitutes poorly. CMV reactivation was prevented by transferring antibody-containing immune serum. Such a therapeutic strategy would avoid some limitations of cellular therapies for BMT patients. Science , this issue p. 288 see also p. 232
Publisher: Wiley
Date: 06-2014
DOI: 10.1038/CTI.2014.11
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22543105
Abstract: Supplementary Table S1 (related to Fig. 4A): (A) Ingenuity Pathway Analysis derived from the uncorrected dataset displaying top canonical signaling pathways involving differentially regulated genes in recipients as described in Fig.4A. (B) 10 selected immunologically relevant genes identified as differentially regulated in mice transplanted with B6.WT or B6.ASC-/- grafts.
Publisher: Springer Science and Business Media LLC
Date: 18-11-2023
DOI: 10.1038/S41375-022-01755-2
Abstract: Chemotherapy-resistant acute myeloid leukemia (AML), frequently driven by clonal evolution, has a dismal prognosis. A genome-wide CRISPR knockout screen investigating resistance to doxorubicin and cytarabine (Dox/AraC) in human AML cell lines identified gene knockouts involving AraC metabolism and genes that regulate cell cycle arrest (cyclin dependent kinase inhibitor 2A (CDKN2A), checkpoint kinase 2 (CHEK2) and TP53) as contributing to resistance. In human AML cohorts, reduced expression of CDKN2A conferred inferior overall survival and CDKN2A downregulation occurred at relapse in paired diagnosis-relapse s les, validating its clinical relevance. Therapeutically targeting the G
Publisher: Springer Science and Business Media LLC
Date: 25-03-2011
DOI: 10.1007/S12185-011-0813-Z
Abstract: Primary familial and congenital polycythaemia (PFCP) is a rare form of inherited erythrocytosis caused by heterozygous mutations in the erythropoietin receptor gene (EPOR). We present a novel mutation in the EPOR in a 15-year-old male who was referred to our clinic for investigation of a persistently elevated haemoglobin level. A significant family history of unexplained erythrocytosis spanning four generations of the patient's family was established. The family history was also significant for an apparent increased rate of cerebrovascular disease in in iduals with erythrocytosis. The mutation detected in our patient resides in exon 8 of EPOR, similar to all other EPOR mutations responsible for PFCP. These mutations result in truncation of the cytoplasmic domain of the receptor and impair down-regulation of signalling via the erythropoietin receptor (EPOR). Clinical manifestations in published cases have varied widely and there is a paucity of firm recommendations regarding the management of affected patients. Given the strong family history of complications attributable to erythrocytosis we have recommended venesection with a haematocrit target of ≤0.45 for our patient.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-0027
DOI: 10.1158/2326-6066.22543108
Abstract: Supplementary Figure S1: GVHD survival of lethally-irradiated (day 0, 1000cGy split dose) B6.WT, B6.ASC-/- or B6.NLRP3-/- recipients transplanted with BALB/c BM (5x106) and T cells (5x106). The non-GVHD control group received TCD BM cells (5x106) only. Results combined from 2 independent experiments (n = 20 per T cell-replete group, n = 8 for TCD BM group). ****P 0.0001 B6.NLRP3-/- vs. B6.WT. Results are presented as means {plus minus} SEM.
Publisher: Springer Science and Business Media LLC
Date: 07-01-2020
DOI: 10.1007/S12185-019-02813-9
Abstract: We have previously reported that haematopoietic progenitor cell transplantation recipients with biopsy-negative acute Gastrointestinal Graft versus Host Disease (Discordant GVHD) demonstrate superior survival compared to "True Positive" cases. We aimed to elucidate this discrepancy by examining clinical and laboratory predictors of survival among patients treated for True Positive or Discordant GVHD. Data were obtained by retrospective chart review. At diagnosis, the incidence of severe symptoms, hypoalbuminaemia, hyperbilirubinaemia, and poor performance status were recorded. Following treatment, the incidence of non-response to first-line corticosteroids was assessed. Differences between cohorts were compared using Fisher's exact test. 74 patients were identified, comprising 55 (74%) True Positive and 19 (26%) Discordant GVHD cases. True Positive cases were significantly more likely to have baseline severe symptoms (84% vs. 36% p = 0.0002) and hypoalbuminaemia (94% vs. 75% p = 0.023). There was no significant difference between cohorts in terms of hyperbilirubinaemia or performance status. Non-response to corticosteroid therapy was observed significantly more frequently in the True Positive cohort (55% vs. 11% p = 0.001). In summary, the superior survival observed in Discordant GVHD is explained by a less severe GI-GVHD phenotype at diagnosis and a greater likelihood of response to corticosteroids. Further research is warranted to explain biological mechanisms for these findings.
Publisher: American Association for Cancer Research (AACR)
Date: 08-2020
DOI: 10.1158/2326-6066.CIR-19-0653
Abstract: The adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD) is known to facilitate caspase-1 activation, which is essential for innate host immunity via the formation of the inflammasome complex, a multiprotein structure responsible for processing IL1β and IL18 into their active moieties. Here, we demonstrated that ASC-deficient CD8+ T cells failed to induce severe graft-versus-host disease (GVHD) and had impaired capacity for graft rejection and graft-versus-leukemia (GVL) activity. These effects were inflammasome independent because GVHD lethality was not altered in recipients of caspase-1/11–deficient T cells. We also demonstrated that ASC deficiency resulted in a decrease in cytolytic function, with a reduction in granzyme B secretion and CD107a expression by CD8+ T cells. Altogether, our findings highlight that ASC represents an attractive therapeutic target for improving outcomes of clinical transplantation.
Publisher: American Society of Hematology
Date: 08-03-2022
Publisher: American Society of Hematology
Date: 18-10-2012
DOI: 10.1182/BLOOD-2012-03-420182
Abstract: T-box transcription factors T-bet (Tbx21) and Eomesodermin (Eomes) are critical players in CD8+ cytotoxic T lymphocyte effector function and differentiation, but how the expression of these transcription factors is regulated remains poorly defined. Here we show that dominant T cells directed toward human CMV, expressing significantly higher levels of T-bet with graded loss of Eomes expression (T-bethiEomeshi/lo), are more efficient in recognizing endogenously processed peptide-major histocompatibility complexes (pMHC) compared with subdominant virus-specific T cells expressing lower levels of T-bet and high levels of Eomes (T-betintEomeshi). Paradoxically, the T-bethiEomeshi/lo dominant populations that efficiently recognized endogenous antigen demonstrated lower intrinsic avidity for pMHC, whereas T-betintEomeshi subdominant populations were characterized by higher pMHC avidity and less efficient recognition of virus-infected cells. Importantly, differential endogenous viral antigen recognition by CMV-specific CD8+ T cells also correlated with the differentiation status and expression of perforin, granzyme B and K. Furthermore, we demonstrate that the expression of T-bet correlates with clonal expansion, differentiation status, and expression of perforin, granzyme B and K in antigen-specific T cells. These findings illustrate how endogenous viral antigen presentation during persistent viral infection may influence the transcriptional program of virus-specific T cells and their functional profile in the peripheral blood of humans.
Publisher: Cold Spring Harbor Laboratory
Date: 07-11-2019
DOI: 10.1101/833897
Abstract: Vector integration site analysis can be important in the follow-up of patients who received gene-modified cells, but current platforms based on next-generation sequencing are expensive and relatively inaccessible. We analyzed polyclonal T cells transduced by a gammaretroviral vector, SFG.iCasp9.2A.ΔCD19, from a clinical trial. Following restriction enzyme digestion, the unknown flanking genomic sequences were lified by inverse polymerase chain reaction (PCR) or cassette ligation PCR. Nanopore sequencing could identify thousands of unique integration sites within polyclonal s les, with cassette ligation PCR showing less bias. The assay is scalable and requires minimum capital, which together enable cost-effective and timely analysis.
Publisher: Wiley
Date: 04-2004
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22543105.V1
Abstract: Supplementary Table S1 (related to Fig. 4A): (A) Ingenuity Pathway Analysis derived from the uncorrected dataset displaying top canonical signaling pathways involving differentially regulated genes in recipients as described in Fig.4A. (B) 10 selected immunologically relevant genes identified as differentially regulated in mice transplanted with B6.WT or B6.ASC-/- grafts.
Publisher: Oxford University Press (OUP)
Date: 15-03-2010
DOI: 10.1086/650007
Abstract: We describe a unique case of fulminant infectious mononucleosis and recurrent Epstein-Barr virus reactivation presenting in an adolescent. Detailed assays of Epstein-Barr virus-specific T cell immunity revealed defects in the patient's T cell receptor signalling pathway characterized by a lack of interleukin-2 and CD25 expression, which may have contributed to her clinical course. Allogeneic stem cell transplantation reversed the clinical and laboratory phenotype.
Publisher: Springer Science and Business Media LLC
Date: 15-08-2022
Publisher: Informa UK Limited
Date: 12-2012
DOI: 10.4161/AUTO.21860
Publisher: Springer Science and Business Media LLC
Date: 27-10-2023
Publisher: Elsevier BV
Date: 04-2007
Abstract: Gene-marking studies were the first gene-transfer protocols approved for human use. Their intent was not directly therapeutic but rather to track the behavior and fate of cells in vivo, and to use this information to improve treatment protocols. For more than fifteen years, gene-marking studies using retroviral vectors have provided invaluable information about the biology of human hematopoietic cells and T lymphocytes, and have helped guide cell therapies intended to treat malignant disease. Although the safety record of marking studies has been impeccable, the development of leukemia by immunodeficient children treated with retroviral vectors cast a pall over the entire field and essentially brought the era of pure gene-marking studies to an abrupt end. Paradoxically, the impetus these events gave to studying retroviral integration sites in host cell DNA emphasized the additional information that marker studies could provide about the behavior of cells at the clonal level. As confidence has slowly returned, marker studies have reappeared, usually as components of gene therapy protocols in which a marker gene or sequence is incorporated to allow the modified cells to be tracked or imaged in vivo. Hence, gene marking continues to have much to offer in terms of our understanding of the behavior, fate, and safety of gene-modified cells in vivo.
Publisher: American Society of Hematology
Date: 08-04-2021
Abstract: We determined the efficacy of tocilizumab (TCZ) in preventing grade 2-4 acute graft-versus-host disease (aGVHD) in patients with acute leukemia or myelodysplasia undergoing matched sibling donor (MSD) or volunteer unrelated donor (VUD) allogeneic stem cell transplantation after myeloablative or reduced-intensity conditioning across 5 Australian centers. A total of 145 patients (50 MSD, 95 VUD) were randomly assigned to placebo or TCZ on day −1. All patients received T-cell–replete peripheral blood stem cell grafts and graft-versus-host disease (GVHD) prophylaxis with cyclosporin/methotrexate. A planned substudy analyzed the VUD cohort. With a median follow-up of 746 days, the incidence of grade 2-4 aGVHD at day 100 for the entire cohort was 36% for placebo vs 27% for TCZ (hazard ratio [HR], 0.69 95% confidence interval [CI], 0.38-1.26 P = .23) and 45% vs 32% (HR, 0.61 95% CI, 0.31-1.22 P = .16) for the VUD subgroup. The incidence of grade 2-4 aGVHD at day 180 for the entire cohort was 40% for placebo vs 29% for TCZ (HR, 0.68 95% CI, 0.38-1.22 P = .19) and 48% vs 32% (HR, 0.59 95% CI, 0.30-1.16 P = .13) for the VUD subgroup. Reductions in aGVHD were predominantly in grade 2 disease. For the entire cohort, transplant-related mortality occurred in 8% vs 11% of placebo-treated vs TCZ-treated patients, respectively (P = .56), and overall survival was 79% vs 71% (P = .27). Median day to neutrophil and platelet engraftment was delayed by 2 to 3 days in TCZ-treated patients, whereas liver toxicity and infectious complications were similar between groups. In this phase 3 randomized double-blind trial, TCZ showed nonsignificant trends toward reduced incidence of grade 2-4 aGVHD in recipients from HLA-matched VUDs but no improvements in long term-survival.
Publisher: American Association for Cancer Research (AACR)
Date: 14-12-2014
DOI: 10.1158/0008-5472.CAN-14-1339
Abstract: BRAF V600E is a major oncogenic mutation found in approximately 50% of human melanoma that confers constitutive activation of the MAPK pathway and increased melanoma growth. Inhibition of BRAFV600E by oncogene targeting therapy increases overall survival of patients with melanoma, but is unable to produce many durable responses. Adaptive drug resistance remains the main limitation to BRAFV600E inhibitor clinical efficacy and immune-based strategies could be useful to overcome disease relapse. Tumor microenvironment greatly differs between visceral metastasis and primary cutaneous melanoma, and the mechanisms involved in the antimetastatic efficacy of BRAFV600E inhibitors remain to be determined. To address this question, we developed a metastatic BRAFV600E-mutant melanoma cell line and demonstrated that the antimetastatic properties of BRAF inhibitor PLX4720 (a research analogue of vemurafenib) require host natural killer (NK) cells and perforin. Indeed, PLX4720 not only directly limited BRAFV600E-induced tumor cell proliferation, but also affected NK cell functions. We showed that PLX4720 increases the phosphorylation of ERK1/2, CD69 expression, and proliferation of mouse NK cells in vitro. NK cell frequencies were significantly enhanced by PLX4720 specifically in the lungs of mice with BRAFV600E lung metastases. Furthermore, PLX4720 also increased human NK cell pERK1/2, CD69 expression, and IFNγ release in the context of anti-NKp30 and IL2 stimulation. Overall, this study supports the idea that additional NK cell-based immunotherapy (by checkpoint blockade or agonists or cytokines) may combine well with BRAFV600E inhibitor therapy to promote more durable responses in melanoma. Cancer Res 74(24) 7298–308. ©2014 AACR.
No related grants have been discovered for Siok-Keen Tey.