D J Gottlieb

Westmead Millennium Institute, Paramatta, New South Wales, Australia

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Publications (65)304.09 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Regulation of the lectin, Galectin-9 (Gal-9), was investigated for the first time during Human Cytomegalovirus (HCMV) infection. Gal-9 transcription was significantly upregulated in transplant recipients with reactivated HCMV in vivo. In vitro Gal-9 was potently upregulated by HCMV independently of viral gene expression with interferon-β (IFN-β) identified as the mediator of this effect. This study defines an immunoregulatory protein potently increased by HCMV infection and a novel mechanism to control Gal-9 through IFN-β induction.
    Journal of virology. 07/2014;
  • Seminars in Thrombosis and Hemostasis 02/2014; 40(1):1-4. · 4.22 Impact Factor
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    ABSTRACT: Several human cytomegalovirus (HCMV) genes encode products that modulate cellular functions in a manner likely to enhance viral pathogenesis. This includes UL111A, which encodes homologs of human interleukin-10 (hIL-10). Depending upon signals received, monocytes and macrophages become polarized to either classically activated (M1 pro-inflammatory) or alternatively activated (M2 anti-inflammatory) subsets. Skewing of polarization towards an M2 subset may benefit the virus by limiting the pro-inflammatory responses to infection and so we determined whether HCMV encoded viral IL-10 influenced monocyte polarization. Recombinant viral IL-10 protein polarized CD14(+) monocytes towards an anti-inflammatory M2 subset with an M2c phenotype, as demonstrated by high expression of CD163 and CD14, and suppression of MHC class II. Significantly, in the context of productive HCMV infection, viral IL-10 produced by infected cells polarized uninfected monocytes towards an M2c phenotype. We also assessed the impact of viral IL-10 on heme oxygenase 1 (HO-1), which is an enzyme linked with suppression of inflammatory responses. Polarization of monocytes by viral IL-10 resulted in upregulation of HO-1 and inhibition of HO-1 function resulted in a loss of capacity of viral IL-10 to suppress TNF-α and IL-1β, implicating HO-1 in viral IL-10 induced suppression of pro-inflammatory cytokines by M2c monocytes. In addition, a functional consequence of monocytes polarized with viral IL-10 was a decreased capacity to activate CD4(+) T cells. This study identifies a novel role for viral IL-10 in driving M2c polarization which may limit virus clearance by restricting pro-inflammatory and CD4(+) T cell responses at sites of infection.
    Journal of Virology 07/2013; · 5.08 Impact Factor
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    ABSTRACT: Uncontrolled cytomegalovirus (CMV) reactivation after allogeneic hematopoietic stem cell transplantation causes significant morbidity and mortality. Adoptive transfer of CMV-specific cytotoxic T lymphocytes (CTLs) is a promising therapy to treat reactivation and prevent viral disease. In this article, we describe the generation of clinical-grade CMV-specific CTLs directly from granulocyte colony-stimulating factor–mobilized hemopoietic progenitor cell (G-HPC) products collected for transplantation. This method requires less than 2.5% of a typical G-HPC product to reproducibly expand CMV-specific CTLs ex vivo. Comparison of 11 CMV CTL lines generated from G-HPC products with 52 CMV CTL lines generated from nonmobilized peripheral blood revealed similar expansion kinetics and phenotype. G-HPC–derived CTLs produced IFN-γ after reexposure to CMVpp65 antigen and exhibited CMV-directed cytotoxicity but no alloreactivity against transplantation recipient–derived cells. Seven patients received CMV-specific CTL lines expanded from G-HPC products in a prophylactic adoptive immunotherapy phase I/II clinical trial. Use of G-HPC products will facilitate integration of CTL generation into established quality systems of transplantation centers and more rapid inclusion of T cell therapies into routine clinical care.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 05/2013; 19(5):725–734. · 3.15 Impact Factor
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    ABSTRACT: BACKGROUND: Hematopoietic stem cell (HSC) transplantation using bone marrow and peripheral blood stem cells is a lifesaving treatment for patients with leukemia or other blood disorders. However, donors face the risk of physical and psychosocial complications. We aimed to synthesize qualitative studies on the experiences and perspectives of HSC donors. METHODS: We searched MEDLINE, Embase, PsycINFO, CINAHL, Google Scholar, and reference lists of relevant articles to 13th November 2012. Thematic synthesis was used to analyze the findings. RESULTS: Thirty studies involving 1552 donors were included. The decision to donate included themes of: saving life, family loyalty, building a positive identity, religious conviction, fear of invasive procedures, and social pressure and obligation. Five themes about the donation experience were identified: mental preparedness (pervasive pain, intense disappointment over recipient death, exceeding expectations and valuing positive recipient gains); burden of responsibility (striving to be a quality donor, unresolved guilt, and exacerbated grief); feeling neglected (medical dismissiveness and family inattention); strengthened relationships (stronger family ties, establishing blood bonds); and personal sense of achievement (satisfaction and pride, personal development, hero status and social recognition). CONCLUSIONS: Although HSC donation was appreciated as an opportunity to save life, some donors felt anxious and unduly compelled to donate. HSC donors became emotionally invested and felt responsible for their recipient's outcomes, and were profoundly grieved and disappointed if the transplant was unsuccessful. To maximize donor satisfaction and mitigate the psychosocial risks for HSC donors, strategies to address the emotional challenges of anxiety, sense of coercion, guilt, and grief in donors are warranted.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 04/2013; · 3.15 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We investigated the use of adoptively transferred donor-derived cytomegalovirus (CMV) specific T cells as immune reconstitution post- allogeneic transplant in a phase II study. 50 patients were infused with a single dose of 2x10(7)cells/m(2) after day 28 post-transplant. There were no infusion related adverse events. Twenty-six patients reactivated CMV post-transplant (only 5 post-CTL infusion) and nine required therapy with ganciclovir or foscarnet (only 1 post-CTL infusion). There was one case of fatal CMV disease, attributable to high levels of anti-thymocyte globulin at the time of T-cell infusion. We compared the patients in the phase II study with a group of contemporaneous controls treated at the trial centres. There was no increase in acute or chronic GVHD attributable to CTL infusion; overall and progression free survival were similar in both groups. There was a reduction in percentage of patients who required CMV directed anti-viral therapy (17 v 36%, p=0.01) and in the total number of treatment days per patient in the cohort receiving CTL (3.4 v 8.9 days, p=0.03) without a reduction in CMV reactivation rates. We postulate that adoptively transferred cells are able to expand in response to viral antigen, limit viral replication and prevent progression to tissue infection. The study was registered on the Australian Clinical Trial Registry (ACTRN12605000213640 and ACTRN12607000224426).
    Blood 02/2013; · 9.78 Impact Factor
  • M M Sartor, D J Gottlieb
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    ABSTRACT: Levels of residual disease (RD) are an independent predictor of progression-free survival (PFS) and overall survival (OS) in patients treated for chronic lymphocytic leukemia (CLL). We modified the international standardized approach (ISA) to RD detection using flow cytometry by developing a single tube 10 color antibody assay. METHOD: A single tube incorporated the following monoclonal antibodies: CD81FITC, CD22PE, CD3ECD, CD5PercP5.5, CD20PECY7, CD79bAPC, CD38A700, CD43APC Alexa750, CD19eFluor 450, and CD45KO. A modified ISA gating strategy was developed that removed contaminating events. Sensitivity assays were performed using dilution with normal peripheral blood and bone marrow. Clinical samples were compared using the ISA and the single tube assay. RESULTS: Dilution studies showed that sensitivity of 0.001% was achievable when a minimum of 1.8 × 10(6) total events were acquired. One hundred twenty-nine samples were analyzed and showed RD levels from 0.003 to 22%. In 80 samples analyzed with both assays, there was an excellent correlation between the two methods (slope = 1.0, intercept = 0.07 and R2 = 0.992) and results from Bland-Altman analysis showed a bias of 0.04 ± 0.38 with 95% confidence interval of -0.71 to 0.79. Removal of contaminating events in the single tube assay led to a significant reduction in RD values (P = 0.0014). CONCLUSION: The single tube 10-color assay for the detection of RD in CLL provides equivalent results to the ISA but requires fewer cells, uses fewer reagents, and allows for simpler analysis. By directly removing contaminating events, it improves the accuracy of CLL RD detection and may reclassify the status of some patients following chemotherapy. © 2012 International Clinical Cytometry Society.
    Cytometry Part B Clinical Cytometry 01/2013; · 2.23 Impact Factor
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    ABSTRACT: Abstract Background and aims. Aspergillus fumigatus infections are the leading cause of invasive fungal infection-related deaths in stem cell transplant patients, and may be amenable to correction with adoptive immunotherapy providing T lymphocytes specific for A. fumigatus. However, a clinically usable source of antigen and a reliable procedure for the generation of large numbers of Aspergillus-specific T lymphocytes to clinical-grade standards is not available. Methods. An environmental strain of A. fumigatus (WMAfES) was isolated and cultured using materials and reagents suitable for clinical manufacture. Water-soluble lysate from germinated conidia of WMAfES was used as the antigen source. Peripheral blood mononuclear cells were stimulated with antigen-pulsed autologous dendritic cells on days 0 and 7. Cells were expanded with a cocktail of interleukin (IL)-2, IL-7 and IL-15 from days 7 to 21. Results. We obtained a mean 32.8-fold increase in cell numbers over 21 days of culture (n = 8). Resultant cultures were predominantly effector and central memory CD4(+) T cells, which produced T-helper (h)1 and Th17 cytokines when restimulated with A. fumigatus antigen derived from environmental or clinically isolated A. fumigatus. Cultured cells exhibited a high level of specific expansion and chemokine production when restimulated. Moreover, cultured cells cross-reacted with antigens from other fungi, including Penicillium, Candida albicans and other non-fumigatus Aspergillus species. Conclusions. We describe a simple, robust, reproducible and clinically applicable procedure using a clinically appropriate antigen preparation for the expansion of polyfunctional A. fumigatus-specific T cells from normal donors of varying HLA types.
    Cytotherapy 08/2012; 14(9):1119-30. · 3.06 Impact Factor
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    ABSTRACT: Background:  HLA haploidentical bone marrow transplantation is a treatment option in patients with hematological malignancies who have no available HLA matched donor, but is limited by conditioning regimen toxicity, graft failure, relapse and graft versus host disease. Aims:  To demonstrate safety and efficacy of haploidentical bone marrow transplantation with nonmyeloablative conditioning and high-dose post-transplant cyclophosphamide in adult patients with leukaemia or lymphoma. Methods:  12 patients, median age of 51 years, underwent transplantation with T cell replete bone marrow from a haplotype matched relative. The conditioning regimen consisted of cyclophosphamide, fludarabine, and low-dose TBI. Post-transplant immunosuppression consisted of a single dose of cyclophosphamide 50 mg/kg on day 3, followed by oral tacrolimus and mycophenolatemofetil. Outcomes reported are overall survival, engraftment and chimerism, toxicity, and clinical outcome. Results:  All patients had neutrophil recovery (median 14.5 days), and 11 of 12 had platelet engraftment (median 17 days). Two patients had autologous reconstitution. Seven of 9 assessable patients had complete donor chimerism. Four patients had grade II-III GvHD, and none had grade IV GvHD. Four patientsdeveloped limited stage chronic GvHD. Five patients with AML relapsed. Two patients died of non-relapse causes, both from other malignancies, and 5 patients remain alive and relapse free. Median overall survival was324 days (range 88-1163). Conclusion:  This regimen is feasible and well-tolerated in older patients with high risk leukemia or lymphoma, with minimal short-term toxicity, and low rates of GVHD. The proportion of disease-free survivors indicates a graft versus malignancy effect is present in survivors. © 2012 The Authors. Internal Medicine Journal © 2012 Royal Australasian College of Physicians.
    Internal Medicine Journal 05/2012; · 1.82 Impact Factor
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    ABSTRACT: Varicella zoster virus (VZV) causes life-long latent infection in healthy individuals, which reactivates in 10-68% of stem cell transplant patients. Reconstituting immunity through adoptive transfer of T cells specific for VZV may aid in the prophylaxis and treatment of VZV infections. The potential for generating T cells specific for VZV using a clinically approved VZV vaccine strain was investigated. The Varivax® vaccine was used to stimulate peripheral blood mononuclear cells from healthy donors. Only reagents approved for clinical manufacture were used. Monocyte-derived dendritic cells pulsed with Varivax (R) were used to stimulate autologous mononuclear cells at a responder to stimulator ratio of 10:1. On day 7, a second stimulation was performed; 20 U/mL interleukin (IL)-2 were added from day 7 and 50 U/mL IL-2 from day 14 onwards. Cell phenotype and functionality were assessed after 21 days of culture. A mean increase of 11-fold in cell number was observed (n= 18). Cultures were mainly T cells (mean CD3 (+) 89.7%, CD4 (+) 54.2%, CD8 (+) 28.7%) with effector and central memory phenotypes. Cells produced one or more T helper (Th)1 cytokine (interferon-γ, tumor necrosis factor-α and IL-2), and CD4 (+) (but not CD8 (+) ) cells expressed the cytoxicity marker CD107 when restimulated with VZV antigens. We have demonstrated a clinically applicable method that yields high numbers of highly reactive T cells specific for VZV. We propose that reconstructing host immunity through adoptive transfer of VZV-specific T cells will reduce the frequency of clinical VZV infection in the period of severe immune suppression that follows allogeneic stem cell transplantation.
    Cytotherapy 03/2012; 14(6):724-32. · 3.06 Impact Factor
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    ABSTRACT: This retrospective study was aimed at establishing a clinical score to stratify the risk of cytomegalovirus (CMV) reactivation in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) in order to direct strategies for post-transplant CMV monitoring and therapy. In total, 335 adult patients undergoing HSCT were analyzed and divided into a training set (n = 235) and a validation set (n = 100). Logistic regression analysis on the training set identified recipient and donor CMV seropositivity, acute graft-versus-host disease (GVHD), and use of anti-thymocyte globulin or alemtuzumab as significant risk factors for CMV reactivation. Weighted scores were assigned to each factor. A weighted score (CMV scoring index [CSI]) was calculated for each patient using the scores of all risk factors except for GVHD. The index was collapsed into 3 risk groups - low risk (score of 0-2), intermediate risk (score of 3-5), and high risk (score of 6-7) - and reactivation rates were calculated. In the training set, CMV reactivation occurred in 5.8% in the low-risk group, 44.8% in the intermediate-risk group, and 67.7% in the high-risk group. In patients with an intermediate CSI only, significantly higher reactivation rates were seen in the presence of corticosteroid treatment for GVHD (57.8% vs. 24.5%, P < 0.01). These findings were similar in the validation set with reactivation rates of 0% in the low-risk, 46% in the intermediate-risk, and 68.4% in the high-risk groups. As seen in the training set, the presence of GVHD was associated with higher CMV reactivation rates only in the intermediate-risk group (64% vs. 28% in the absence of GVHD, P = 0.02). Identification of these 3 risk groups in association with the presence or absence of GVHD will help transplant units to make pre-transplant policy decisions about prophylactic, pre-emptive, or experimental CMV prevention strategies in groups of patients undergoing HSCT, as well as in those developing GVHD post transplant.
    Transplant Infectious Disease 01/2012; 14(2):141-8. · 1.98 Impact Factor
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    ABSTRACT: BK virus (BKV) infection causes hemorrhagic cystitis posthemopoietic stem-cell transplant and graft loss in renal transplant recipients. Reactivation occurs in up to 60% of patients in both groups. Treatment-related cellular immunosuppression is a major contributor to the development of BKV-related disease, but the targets of the immune response are not well characterized. Immunotherapy by adoptive transfer of cellular effectors has been shown to be effective in controlling and preventing some virus-related diseases in transplant recipients, particularly Epstein-Barr virus and cytomegalovirus. Infusion of BKV-specific T cells may potentially reconstitute functional BKV immunity and reduce clinical complications of BKV infection. BKV-specific T cells for clinical use in adoptive immunotherapy were generated using monocyte-derived dendritic cells pulsed with overlapping peptide mixes spanning the five BKV proteins VP1, VP2, VP3, large T antigen, and small T antigen. Phenotypic and functional characteristics of the cells were investigated as well as their antigen specificity. Expanded CD4(+) and CD8(+) cells responded to restimulation with BKV peptides principally from VP1, large T, or small T antigens; produced multiple cytokines; and showed cytotoxic activity against antigen-coated targets. Possible clinical uses for BKV-specific T cells generated using this method include immune reconstitution posthemopoietic stem-cell transplantation or prophylaxis and treatment of immune deficiency in renal transplant recipients, fulfilling the need for effective therapy for BKV-related hemorrhagic cystitis and renal dysfunction.
    Transplantation 11/2011; 92(10):1077-84. · 3.78 Impact Factor
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    ABSTRACT: This review evaluates the latest information on the mobilisation of haemopoietic stem cells for transplantation, with the focus on what is the current best practice and how new understanding of the bone marrow stem cell niche provides new insights into optimising mobilisation regimens. The review then looks at the mobilisation of mesenchymal stromal cells, immune cells as well as malignant cells and what clinical implications there are.
    Pathology 10/2011; 43(6):547-65. · 2.66 Impact Factor
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    ABSTRACT: Influenza viruses cause potentially fatal respiratory infections in stem cell transplant patients. Specific T cells provide long-lived host adaptive immunity to influenza viruses, and the potential for generating such cells for clinical use was investigated. The inactivated influenza vaccine (Fluvax) approved for human use was used as the antigen source. Monocyte-derived dendritic cells pulsed with Fluvax were used to stimulate autologous peripheral blood mononuclear cells (PBMC) on days 0 and 7. Cells were expanded with interleukin (IL)-2 from day 7 onwards. Cell numbers and phenotype were assessed on day 21. The presence of influenza virus-specific cells was assessed by cytokine production and proliferative responses following restimulation with influenza antigens. Over 21 days of culture, a mean fold increase of 26.3 in cell number was observed (n = 7). Cultures were predominantly effector and central memory CD4+ cells, and expressed a phenotype characteristic of activated antigen-specific cells capable of B-cell helper function. Cytotoxic CD4+ and CD8+ cells specific for influenza and a high percentage of CD4+ cells specific for each of three influenza viruses targeted by Fluvax (H1N1, H3N2 and Brisbane viruses) were generated. In addition, T cells expanded when restimulated with antigens derived from influenza viruses. We have demonstrated a clinically usable method for producing influenza virus-specific T cells that yield high numbers of highly reactive CD4+ cells suitable for adoptive immunotherapy. We propose that reconstructing host immunity through adoptive transfer of influenza virus-specific T cells will reduce the frequency of influenza-related deaths in the period of severe immune suppression that follows stem cell transplantation.
    Cytotherapy 09/2011; 14(2):182-93. · 3.06 Impact Factor
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    ABSTRACT: The recent Food and Drug Administration (FDA) approval of a cellular therapy to treat castration resistant prostate cancer has reinforced the potential of cellular therapy to consolidate current pharmacological approaches to treating cancer. The emergence of the cell manufacturing facility to facilitate clinical translation of these new methodologies allows greater access to these novel therapies. Here we review different strategies currently being explored to treat haematological malignancies with a focus on adoptive allogeneic or autologous transfer of antigen specific T cells, NK cells or dendritic cells. These approaches all aim to generate immunological responses against overexpressed tissue antigens, mismatched minor histocompatability antigens or tumour associated antigens. Current successes and limitations of these different approaches will be discussed with an emphasis on challenges encountered in generating long term engraftment, antigen selection and implementation as well as therapeutic immune monitoring of clinical responses, with examples from recent clinical trials.
    Pathology 09/2011; 43(6):605-15. · 2.66 Impact Factor
  • Bone marrow transplantation 07/2011; 47(5):737-8. · 3.00 Impact Factor
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    ABSTRACT: There are limited data on the impact of H1N109 infection in patients undergoing hematopoietic stem cell transplantation (HSCT). We reviewed individual medical records of patients who underwent HSCT or were on follow-up post-HSCT between May and September 2009. Thirteen patients with H1N109 infection were identified: 2 <100 days post-HSCT, 7 >100 days post-HSCT, and 4 just prior to HSCT. Five (38.7%) had lower respiratory tract involvement (LRTI), whereas the remainder had upper respiratory tract involvement (URTI). LRTI occurred in patients who were profoundly neutropenic post-HSCT or on potent immunosuppression for chronic graft-versus-host disease (cGVHD). At 100 days post-H1N109 infection, only 1 patient with LRTI survived, whereas all with URTI are alive. Four patients successfully treated for H1N109 infection prior to HSCT underwent the procedure after 4 to 6 weeks without any complications. Another 6 patients received oseltamivir prophylaxis during conditioning and none developed H1N109 infection. In conclusion, H1N109 infection was associated with LRTI in HSCT recipients who were profoundly neutropenic or immunosuppressed. Prior H1N109 infection did not affect the successful outcome of HSCT and oseltamivir prophylaxis in a small group of recipients resulted in no infection. Further studies are required.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 01/2011; 17(1):147-53. · 3.15 Impact Factor
  • Biology of Blood and Marrow Transplantation - BIOL BLOOD MARROW TRANSPLANT. 01/2011; 17(2).
  • E. Blyth, L. E. Clancy, R. Simms, D. J. Gottlieb
    Biology of Blood and Marrow Transplantation - BIOL BLOOD MARROW TRANSPLANT. 01/2011; 17(2).
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    David J Gottlieb
    Blood 11/2010; 116(22):4391-3. · 9.78 Impact Factor

Publication Stats

1k Citations
304.09 Total Impact Points

Institutions

  • 2000–2014
    • Westmead Millennium Institute
      Paramatta, New South Wales, Australia
  • 2007–2013
    • Westmead Millennium Institute
      Sydney, New South Wales, Australia
  • 1997–2013
    • University of Sydney
      Sydney, New South Wales, Australia
  • 1993–2013
    • Westmead Hospital
      • • Institute of Clinical Pathology and Medical Research
      • • Department of Haematology
      • • Department of Medicine
      Sydney, New South Wales, Australia
  • 2009
    • University of Queensland
      Brisbane, Queensland, Australia