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CD63 e CD123 expressão, autoanticorpos IgG e acurácia do teste do soro autólogo em pacientes com urticária crônica

Calamita, Zamir; Antunes, Roseli Nunes da Silveira; Almeida Filho, Odilon Marques de; Baleotti Júnior, Wilson; Calamita, Andrea Bronhara Pelá; Fukasawa, Josianne Thomazini; Cavaretto, Débora de Aguiar
Fonte: Universidade Estadual Paulista Publicador: Universidade Estadual Paulista
Tipo: Artigo de Revista Científica Formato: 21-28
Português
Relevância na Pesquisa
37.78%
Introduction: The autologous serum skin test (ASST) may suggest an autoimmune etiology in chronic urticaria (CU). A new laboratory technique called basophil activation test (BAT) has been currently employed for its diagnosis. Objective: To analyze ASST in relation to BAT as well as to evaluate interleukin 3 (IL3) receptors (CD123) and non-specific immunoglobulin G (IgG) autoantibodies bound to basophils in patients with chronic urticaria. Methods: We studied 33 adults with CU and mean age of 42.5 + 14 years. After stimulation by serum from patients with CU, CD63 expression on basophils from one atopic donor was analyzed by flow cytometry. Furthermore, we investigated CD123 and IgG autoantibody expressions. Results: The odds ratio (OR) between ASST and BAT was 1.00 (95% confidence interval [CI]: 0.22 to 4.5). The ASST for autoimmune CU diagnosis showed an accuracy of 54.5%, sensitivity of 66%, specificity of 33%, positive predictive value of 63%, and negative predictive value of 36%. There was no statistical difference between the studied groups as to mean non-specific IgG and CD123 expressions (for a p < 0.05). Discussion: This study demonstrated that ASST has low accuracy in the diagnosis of autoimmune CU. Concerning other analyzed aspects...

CD63 e CD123 expressão, autoanticorpos IgG e acurácia do teste do soro autólogo em pacientes com urticária crônica

Calamita,Zamir; Antunes,Roseli Nunes da Silveira; Almeida Filho,Odilon Marques de; Baleotti Júnior,Wilson; Calamita,Andrea Bronhara Pelá; Fukasawa,Josianne Thomazini; Cavaretto,Débora de Aguiar
Fonte: Sociedade Brasileira de Patologia Clínica; Sociedade Brasileira de Patologia; Sociedade Brasileira de Citopatologia Publicador: Sociedade Brasileira de Patologia Clínica; Sociedade Brasileira de Patologia; Sociedade Brasileira de Citopatologia
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/02/2012 Português
Relevância na Pesquisa
37.78%
INTRODUÇÃO: Na urticária crônica (UC), o teste cutâneo do soro autólogo (TCSA) pode sugerir a etiologia autoimune. Recentemente, uma nova técnica laboratorial denominada teste de ativação de basófilos (TAB) vem sendo utilizada para esse diagnóstico. OBJETIVOS: Analisar o TCSA em relação ao TAB, assim como avaliar os receptores da interleucina 3 (IL3) (CD123) e a presença de autoanticorpos da classe de imunoglobulina G (IgG) inespecíficos ligados aos basófilos de pacientes com UC. MÉTODOS: Estudamos 33 adultos com UC espontânea com idade média de 42,5 + 14 anos. Por meio da citometria de fluxo foi feita a análise da expressão das moléculas CD63 em basófilos de um doador atópico após o estímulo pelo soro dos pacientes com UC. Também realizamos a pesquisa da expressão da molécula CD123 e de autoanticorpos IgG inespecíficos. RESULTADOS: O odds ratio (OR) entre o TCSA e o TAB foi de 1 (intervalo de confiança [IC] 95%: 0,22-4,5). O TCSA para o diagnóstico da UC autoimune mostrou acurácia de 54,5%, sensibilidade de 66%, especificidade de 33%, valor preditivo positivo de 63% e valor preditivo negativo de 36%. Não houve diferença estatística entre os grupos estudados quanto à média de expressão dos anticorpos IgG inespecíficos e das moléculas CD123 (para um p < 0...

Overexpression of CD123 correlates with the hyperdiploid genotype in acute lymphoblastic leukemia

Djokic, Miroslav; Björklund, Elisabet; Blennow, Elisabeth; Mazur, Joanna; Söderhäll, Stefan; Porwit, Anna
Fonte: Ferrata Storti Foundation Publicador: Ferrata Storti Foundation
Tipo: Artigo de Revista Científica
Publicado em /07/2009 Português
Relevância na Pesquisa
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This study on patients with acute lymphoblastic leukemia (ALL) shows that overexpression of CD123 is an aberrant phenotype present in a subset of precursor-B ALL with hyperdiploid genotype, and represents an additional marker of good prognosis in pediatric precursor-B ALL.

A plasmacytoid dendritic cell (CD123+/CD11c-) based assay system to predict contact allergenicity of chemicals

Ayehunie, Seyoum; Snell, Maureen; Child, Matthew; Klausner, Mitchell
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
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27.16%
A predictive allergenicity test system for assessing the contact allergenicity of chemicals is needed by the cosmetic and pharmaceutical industry to monitor product safety in the marketplace. Development of such non-animal alternative assay systems for skin sensitization and hazard identification has been pursued by policy makers and regulatory agencies. We investigated whether phenotypic and functional changes to a subset of dendritic cells (DC), plasmacytoid DC (pDC), could be used to identify contact allergens. To achieve this goal, normal human DC were generated from CD34+ progenitor cells and cryopreserved. Frozen DC were thawed and the pDC fraction (CD123+/CD11c-) was harvested using FACS sorting. The pDC were cultured, expanded, and exposed to chemical allergens (N=26) or non-allergens (N=22). Concentrations of each chemical that resulted in >50% viability was determined using FACS analysis of propidium iodide stained cells using pDC from 2-5 donors. Expression of the surface marker, CD86, which has been implicated in dendritic cell maturation, was used as a marker of allergenicity. CD86 expression increased (≥ 1.5 fold) for 25 of 26 allergens (sensitivity = 96%) but did not increase for 19 of 22 non-allergens (specificity = 86%). In a direct comparison to historical data for the regulatory approved...

Expression of the T Cell Receptor αβ on a CD123+ BDCA2+ HLA-DR+ Subpopulation in Head and Neck Squamous Cell Carcinoma

Thiel, Annette; Kesselring, Rebecca; Pries, Ralph; Puzik, Alexander; Wittkopf, Nadine; Wollenberg, Barbara
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 11/01/2011 Português
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27.16%
Human Plasmacytoid Dendritic Cells (PDCs) infiltrating solid tumor tissues and draining lymph nodes of Head and Neck Squamous Cell Carcinoma (HNSCC) show an impaired immune response. In addition to an attenuated secretion of IFN-α little is known about other HNSCC-induced functional alterations in PDCs. Particular objectives in this project were to gain new insights regarding tumor-induced phenotypical and functional alterations in the PDC population. We showed by FACS analysis and RT-PCR that HNSCC orchestrates an as yet unknown subpopulation exhibiting functional autonomy in-vitro and in-vivo besides bearing phenotypical resemblance to PDCs and T cells. A subset, positive for the PDC markers CD123, BDCA-2, HLA-DR and the T cell receptor αβ (TCR-αβ) was significantly induced subsequent to stimulation with HNSCC in-vitro (p = 0.009) and also present in metastatic lymph nodes in-vivo. This subgroup could be functionally distinguished due to an enhanced production of IL-2 (p = 0.02), IL-6 (p = 0.0007) and TGF-β (not significant). Furthermore, after exposure to HNSCC cells, mRNA levels revealed a D-J-beta rearrangement of the TCR-beta chain besides a strong enhancement of the CD3ε chain in the PDC population. Our data indicate an interface between the PDC and T cell lineage. These findings will improve our understanding of phenotypical and functional intricacies concerning the very heterogeneous PDC population in-vivo.

T cells expressing CD123-specific chimeric antigen receptors exhibit specific cytolytic effector functions and antitumor effects against human acute myeloid leukemia

Mardiros, Armen; Dos Santos, Cedric; McDonald, Tinisha; Brown, Christine E.; Wang, Xiuli; Budde, L. Elizabeth; Hoffman, Lauren; Aguilar, Brenda; Chang, Wen-Chung; Bretzlaff, William; Chang, Brenda; Jonnalagadda, Mahesh; Starr, Renate; Ostberg, Julie R.; J
Fonte: American Society of Hematology Publicador: American Society of Hematology
Tipo: Artigo de Revista Científica
Publicado em 31/10/2013 Português
Relevância na Pesquisa
27.46%
CD123 CAR T cells specifically target CD123+ AML cells.AML patient-derived T cells can be genetically modified to lyse autologous tumor cells.

CD123 targeting oncolytic adenoviruses suppress acute myeloid leukemia cell proliferation in vitro and in vivo

Li, G; Li, X; Wu, H; Yang, X; Zhang, Y; Chen, L; Wu, X; Cui, L; Wu, L; Luo, J; Liu, X Y
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
Português
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27.46%
We report here a novel strategy to redirect oncolytic adenoviruses to CD123 by carry a soluble coxsackie-adenovirus receptor (sCAR)-IL3 expression cassette in the viral genome to form Ad.IL3, which sustainably infected acute myeloid leukemia (AML) cells through CD123. Ad.IL3 was further engineered to harbor gene encoding manganese superoxide dismutase (MnSOD) or mannose-binding plant lectin Pinellia pedatisecta agglutinin (PPA), forming Ad.IL3-MnSOD and Ad.IL3-PPA. As compared with Ad.IL3 or Ad.sp-E1A control, Ad.IL3-MnSOD and Ad.IL3-PPA significantly suppressed in vitro proliferation of HL60 and KG-1 cells. Elevated apoptosis was detected in HL60 and KG-1 cells treated with either Ad.IL3-MnSOD or Ad.IL3-PPA. The caspase-9–caspase-7 pathway was determined to be activated by Ad.IL3-MnSOD as well as by Ad.IL3-PPA in HL60 cells. In an HL60/Luc xenograft nonobese diabetic/severe-combined immunodeficiency mice model, Ad.IL3-MnSOD and Ad.IL3-PPA suppressed cancer cell growth as compared with Ad.IL3. A significant difference of cancer cell burden was detected between Ad.IL3 and Ad.IL3-PPA groups at day 9 after treatment. Furthermore, Ad.IL3-MnSOD significantly prolonged mouse survival as compared with Ad.sp-E1A. These findings demonstrated that Ad.IL3-gene could serve as a novel agent for AML therapy. Harboring sCAR-ligand expression cassette in the viral genome may provide a universal method to redirect oncolytic adenoviruses to various membrane receptors on cancer cells resisting serotype 5 adenovirus infection.

Case Report: A case of hypertrophic lupus erythematosus with negative CD123 staining and absence of transepidermal elimination of elastin

Hughes, Matthew; Gardner, Jerad M.; Gao, Ling
Fonte: F1000Research Publicador: F1000Research
Tipo: Artigo de Revista Científica
Publicado em 04/06/2014 Português
Relevância na Pesquisa
27.46%
We report the case of a 49-year-old male with clinical and histological findings consistent with hypertrophic lupus erythematosus (HLE). HLE must be clinically and histologically differentiated from keratoacanthoma, hypertrophic lichen planus, squamous cell carcinoma and plaque type psoriasis. CD123 positivity and transepidermal elimination of elastin have recently been reported as tools to distinguish HLE. Interestingly, in this case, biopsies of two separate lesions failed to reveal these two features. The etiology of this discrepancy is unknown and further studies are needed to clarify the utility of CD123 positivity and transepidermal elimination of elastin in the diagnosis of hypertrophic lupus erythematosus.

Hypertrophic lupus erythematosus: the diagnostic utility of CD123 staining

Ko, Christine J.; Srivastava, Bhaskar; Braverman, Irwin; Antaya, Richard J.; McNiff, Jennifer M.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /11/2011 Português
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CD123-positive plasmacytoid dendrocytes are prominent in the infiltrate of discoid lupus erythematosus (LE). We hypothesized that these cells would also be present in hypertrophic LE and would aid in the histopathologic distinction from squamous cell carcinoma (SCC) and hypertrophic actinic keratosis (AK). Five cases of hypertrophic LE and 10 cases each of SCC and hypertrophic AK were stained with CD123. A heavy band of CD123-positive cells was present at the epidermal–dermal junction in all cases of hypertrophic LE, and only single or rare scattered clusters of CD123-positive cells were seen in SCC and actinic keratoses. The pattern of CD123 staining can be a useful feature to distinguish hypertrophic LE from SCC and hypertrophic AK.

Human BDCA2+CD123+CD56+ dendritic cells (DCs) related to blastic plasmacytoid dendritic cell neoplasm represent a unique myeloid DC subset

Yu, Haisheng; Zhang, Peng; Yin, Xiangyun; Yin, Zhao; Shi, Quanxing; Cui, Ya; Liu, Guanyuan; Wang, Shouli; Piccaluga, Pier Paolo; Jiang, Taijiao; Zhang, Liguo
Fonte: Higher Education Press Publicador: Higher Education Press
Tipo: Artigo de Revista Científica
Português
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Dendritic cells (DCs) comprise two functionally distinct subsets: plasmacytoid DCs (pDCs) and myeloid DCs (mDCs). pDCs are specialized in rapid and massive secretion of type I interferon (IFN-I) in response to nucleic acids through Toll like receptor (TLR)-7 or TLR-9. In this report, we characterized a CD56+ DC population that express typical pDC markers including CD123 and BDCA2 but produce much less IFN-I comparing with pDCs. In addition, CD56+ DCs cluster together with mDCs but not pDCs by genome-wide transcriptional profiling. Accordingly, CD56+ DCs functionally resemble mDCs by producing IL-12 upon TLR4 stimulation and priming naïve T cells without prior activation. These data suggest that the CD56+ DCs represent a novel mDC subset mixed with some pDC features. A CD4+CD56+ hematological malignancy was classified as blastic plasmacytoid dendritic cell neoplasm (BPDCN) due to its expression of characteristic molecules of pDCs. However, we demonstrated that BPDCN is closer to CD56+ DCs than pDCs by global gene-expression profiling. Thus, we propose that the CD4+CD56+ neoplasm may be a tumor counterpart of CD56+ mDCs but not pDCs.

Efficacy of an Fc-modified anti-CD123 antibody (CSL362) combined with chemotherapy in xenograft models of acute myelogenous leukemia in immunodeficient mice

Lee, Erwin M.; Yee, Dean; Busfield, Samantha J.; McManus, Julie F.; Cummings, Nik; Vairo, Gino; Wei, Andrew; Ramshaw, Hayley S.; Powell, Jason A.; Lopez, Angel F.; Lewis, Ian D.; McCall, Martin N.; Lock, Richard B.
Fonte: Ferrata Storti Foundation Publicador: Ferrata Storti Foundation
Tipo: Artigo de Revista Científica
Publicado em /07/2015 Português
Relevância na Pesquisa
27.46%
The prognosis of older patients with acute myelogenous leukemia is generally poor. The interleukin-3 receptor α-chain (CD123) is highly expressed on the surface of acute leukemia cells compared with normal hematopoietic stem cells. CSL362 is a fully humanized, CD123-neutralizing monoclonal antibody containing a modified Fc structure, which enhances human natural killer cell antibody-dependent cell-mediated cytotoxicity. Six continuous acute myelogenous leukemia xenografts established from patient explants and characterized by cell and molecular criteria, produced progressively lethal disease 42-202 days after transplantation. CSL362 alone reduced engraftment of one of four and three of four acute myelogenous leukemia xenografts in the bone marrow and peripheral organs, respectively. A cytarabine and daunorubicin regimen was optimized using this model to identify potentially synergistic interactions with CSL362. Cytarabine/daunorubicin improved the survival of mice engrafted with four of four acute myelogenous leukemia xenografts by 31–41 days. Moreover, CSL362 extended the survival of cytarabine/daunorubicin-treated mice for two of two acute myelogenous leukemia xenografts, while augmentation of natural killer cell-deficient NSG mice with adoptively transferred human natural killer cells improved survival against a single xenograft. Interestingly...

Novel multiparameter flow cytometry techniques for the detection of leukaemia associated phenotypes and minimal residual disease monitoring in acute myeloid leukaemia.

Al-Mawali, Adhra Hilal Nasser
Fonte: Universidade de Adelaide Publicador: Universidade de Adelaide
Tipo: Tese de Doutorado
Publicado em //2008 Português
Relevância na Pesquisa
18.2%
Despite high remission rate in acute myeloid leukaemia (AML) after chemotherapy, relapse of the underlying disease remains a major challenge and one of the most frequent causes of treatment failure. In this study, the presence of leukaemiaassociated phenotypes (LAPs) was first studied retrospectively using our standard diagnostic protocol with 3-colour flow cytometry. LAPs were present in 54 (64%) of 84 AML patients analysed between 2002 to 2004. The presence of LAPs was correlated with failure to respond to induction chemotherapy (p <0.05) in univariate analysis. Presence of LAPs was shown to be an independent predictor for failure to respond to induction chemotherapy with a relative risk ratio of 1.6 (p < 0.05, 95% CI, 1.0-2.6) in multivariate analysis. Subsequently, in a prospective study, we used 5-colour multiparametric flow cytometry (MFC) for detection of LAPs to determine if LAPs could be detected in a greater proportion of leukaemic patients and minimal residual disease (MRD) detection could therefore be applied in more patients. In 54 consecutive, newly diagnosed AML patients from 2005 to 2007, LAPs were identified in 51 (94%). Thus, MRD studies were potentially applicable to virtually all patients. The sensitivity and specificity of MFC technique was improved by analysing 10 normal and 5 regenerating bone marrows (BM) for the presence of these LAPs and by determining maximum log difference (LD). CD7...

Monoclonal antibody-mediated targeting of CD123, IL-3 receptor α chain, eliminates human acute myeloid leukemic stem cells; Monoclonal antibody-mediated targeting of CD123, IL-3 receptor alpha chain, eliminates human acute myeloid leukemic stem cells

Jin, L.; Lee, E.; Ramshaw, H.; Busfield, S.; Peoppl, A.; Wilkinson, L.; Guthridge, M.; Thomas, D.; Barry, E.; Boyd, A.; Gearing, D.; Vairo, G.; Lopez, A.; Dick, J.; Lock, R.
Fonte: Cell Press Publicador: Cell Press
Tipo: Artigo de Revista Científica
Publicado em //2009 Português
Relevância na Pesquisa
27.46%
Leukemia stem cells (LSCs) initiate and sustain the acute myeloid leukemia (AML) clonal hierarchy and possess biological properties rendering them resistant to conventional chemotherapy. The poor survival of AML patients raises expectations that LSC-targeted therapies might achieve durable remissions. We report that an anti-interleukin-3 (IL-3) receptor alpha chain (CD123)-neutralizing antibody (7G3) targeted AML-LSCs, impairing homing to bone marrow (BM) and activating innate immunity of nonobese diabetic/severe-combined immunodeficient (NOD/SCID) mice. 7G3 treatment profoundly reduced AML-LSC engraftment and improved mouse survival. Mice with pre-established disease showed reduced AML burden in the BM and periphery and impaired secondary transplantation upon treatment, establishing that AML-LSCs were directly targeted. 7G3 inhibited IL-3-mediated intracellular signaling of isolated AML CD34(+)CD38(-) cells in vitro and reduced their survival. These results provide clear validation for therapeutic monoclonal antibody (mAb) targeting of AML-LSCs and for translation of in vivo preclinical research findings toward a clinical application.; Liqing Jin, Erwin M. Lee, Hayley S. Ramshaw, Samantha J. Busfield, Armando G. Peoppl, Lucy Wilkinson...

Targeting of acute myeloid leukaemia by cytokine-induced killer cells redirected with a novel CD123-specific chimeric antigen receptor

Tettamanti, S.; Marin, V.; Pizzitola, I.; Magnani, C.; Giordano Attianese, G.; Cribioli, E.; Maltese, F.; Galimberti, S.; Lopez, A.; Biondi, A.; Bonnet, D.; Biagi, E.
Fonte: Blackwell Publishing Ltd Publicador: Blackwell Publishing Ltd
Tipo: Artigo de Revista Científica
Publicado em //2013 Português
Relevância na Pesquisa
38.04%
Current therapeutic regimens for acute myeloid leukaemia (AML) are still associated with high rates of relapse. Immunotherapy with T-cells genetically modified to express chimeric antigen receptors (CARs) represents an innovative approach. Here we investigated the targeting of the interleukin three receptor alpha (IL3RA; CD123) molecule, which is overexpressed on AML bulk population, CD34+ leukaemia progenitors, and leukaemia stem cells (LSC) compared to normal haematopoietic stem/progenitor cells (HSPCs), and whose overexpression is associated with poor prognosis. Cytokine-induced killer (CIK) cells were transduced with SFG-retroviral-vector encoding an anti-CD123 CAR. Transduced cells were able to strongly kill CD123+ cell lines, as well as primary AML blasts. Interestingly, secondary colony experiments demonstrated that anti-CD123.CAR preserved in vitro HSPCs, in contrast to a previously generated anti-CD33.CAR, while keeping an identical cytotoxicity profile towards AML. Furthermore, limited killing of normal monocytes and CD123-low-expressing endothelial cells was noted, thus indicating a low toxicity profile of the anti-CD123.CAR. Taken together, our results indicate that CD123-specific CARs strongly enhance anti-AML CIK functions...

A Phase 1 study of the safety, pharmacokinetics and anti-leukemic activity of the anti-CD123 monoclonal antibody CSL360 in relapsed, refractory or high-risk acute myeloid leukemia

He, S.Z.; Busfield, S.; Ritchie, D.S.; Hertzberg, M.S.; Durrant, S.; Lewis, I.D.; Marlton, P.; McLachlan, A.J.; Kerridge, I.; Bradstock, K.F.; Kennedy, G.; Boyd, A.W.; Yeadon, T.M.; Lopez, A.F.; Ramshaw, H.S.; Iland, H.; Bamford, S.; Barnden, M.; Dewitte,
Fonte: Informa Healthcare Publicador: Informa Healthcare
Tipo: Artigo de Revista Científica
Publicado em //2015 Português
Relevância na Pesquisa
37.95%
Acute myeloid leukemia (AML) blasts express high levels of interlekin-3 (IL-3) receptor-α (CD123). CSL360 is a recombinant, chimeric immunoglobulin G1 (IgG1), anti-CD123 monoclonal antibody (MoAb) that neutralizes IL-3 and demonstrates anti-leukemic activity in vitro. This phase 1 study assessed safety, pharmacokinetics and bioactivity of weekly intravenous CSL360 for 12 weeks in 40 patients with advanced AML across five dose levels (0.1-10.0 mg/kg). Other than mild infusion reactions, CSL360 was well tolerated. The maximal tolerated dose was not reached. The half-life was 4.9 days, and the area under the curve (AUC) and maximum concentration (Cmax) increased proportionally with dose. Doses ≥ 3.0 mg/kg resulted in complete saturation and down-regulation of CD123 and abolition of ex vivo proliferative responsiveness to IL-3, indicating adequate blockade of IL-3 signaling. Two patients responded, with one remaining in complete remission after 17 doses. CSL360 bound CD123 specifically, but did not induce anti-leukemic activity in most patients. While safe, MoAb blockade of CD123 function is insufficient as a therapeutic strategy.; Simon Z. He, Samantha Busfield, David S. Ritchie, Mark S. Hertzberg, Simon Durrant, Ian D. Lewis, Paula Marlton...

Targeting of acute myeloid leukemia in vitro and in vivo with an anti-CD123 mAb engineered for optimal ADCC

Busfield, S.J.; Biondo, M.; Wong, M.; Ramshaw, H.S.; Lee, E.M.; Ghosh, S.; Braley, H.; Panousis, C.; Roberts, A.W.; He, S.Z.; Thomas, D.; Fabri, L.; Vairo, G.; Lock, R.B.; Lopez, A.F.; Nash, A.D.
Fonte: Macmillan Publishers Publicador: Macmillan Publishers
Tipo: Artigo de Revista Científica
Publicado em //2014 Português
Relevância na Pesquisa
27.78%
Acute myeloid leukemia (AML) is a biologically heterogeneous group of related diseases in urgent need of better therapeutic options. Despite this heterogeneity, overexpression of the interleukin (IL)-3 receptor α-chain (IL-3 Rα/CD123) on both the blast and leukemic stem cell (LSC) populations is a common occurrence, a finding that has generated wide interest in devising new therapeutic approaches that target CD123 in AML patients. We report here the development of CSL362, a monoclonal antibody to CD123 that has been humanized, affinity-matured and Fc-engineered for increased affinity for human CD16 (FcγRIIIa). In vitro studies demonstrated that CSL362 potently induces antibody-dependent cell-mediated cytotoxicity of both AML blasts and CD34(+)CD38(-)CD123(+) LSC by NK cells. Importantly, CSL362 was highly effective in vivo reducing leukemic cell growth in AML xenograft mouse models and potently depleting plasmacytoid dendritic cells and basophils in cynomolgus monkeys. Significantly, we demonstrated CSL362-dependent autologous depletion of AML blasts ex vivo, indicating that CSL362 enables the efficient killing of AML cells by the patient's own NK cells. These studies offer a new therapeutic option for AML patients with adequate NK-cell function and warrant the clinical development of CSL362 for the treatment of AML.; S J Busfield...

Distribution and levels of cell surface expression of CD33 and CD123 in acute myeloid leukemia

Ehninger, A; Kramer, M; Röllig, C; Thiede, C; Bornhäuser, M; von Bonin, M; Wermke, M; Feldmann, A; Bachmann, M; Ehninger, G; Oelschlägel, U
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
28%
Owing to the more recent positive results with the anti-CD33 immunotoxin gemtuzumab ozogamicin, therapy against acute myeloid leukemias (AMLs) targeting CD33 holds many promises. Here, CD33 and CD123 expression on AML blasts was studied by flow cytometry in a cohort of 319 patients with detailed information on French–American–British/World Health Organization (FAB/WHO) classification, cytogenetics and molecular aberrations. AMLs of 87.8% express CD33 and would therefore be targetable with anti-CD33 therapies. Additionally, 9.4% of AMLs express CD123 without concomitant CD33 expression. Thus, nearly all AMLs could be either targeted via CD33 or CD123. Simultaneous presence of both antigens was observed in 69.5% of patients. Most importantly, even AMLs with adverse cytogenetics express CD33 and CD123 levels comparable to those with favorable and intermediate subtypes. Some patient groups with unfavorable alterations, such as FMS-related tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations, high FLT3-ITD mutant/wild-type ratios and monosomy 5 are even characterized by high expression of CD33 and CD123. In addition, blasts of patients with mutant nucleophosmin (NPM1) revealed significantly higher CD33 and CD123 expression pointing toward the possibility of minimal residual disease-guided interventions in mutated NPM1-positive AMLs. These results stimulate the development of novel concepts to redirect immune effector cells toward CD33- and CD123-expressing blasts using bi-specific antibodies or engineered T cells expressing chimeric antigen receptors.

CD123 AML targeting by chimeric antigen receptors: A novel magic bullet for AML therapeutics?

Tettamanti, Sarah; Biondi, Andrea; Biagi, Ettore; Bonnet, Dominique
Fonte: Landes Bioscience Publicador: Landes Bioscience
Tipo: Artigo de Revista Científica
Publicado em 14/05/2014 Português
Relevância na Pesquisa
27.16%
Chimeric antigen receptor (CAR) modified T cells have emerged as powerful tools for controlling leukemias. We recently showed that anti-CD123 CAR-expressing cytokine-induced killer T cell treatment is an effective immunotherapeutic approach to eradicate Acute Myeloid Leukemia (AML) cells. Here, we discuss how this genetically modified cell-based strategy could be relevant to the field of AML therapeutics.

CD4-/CD56+/CD123+ Hematodermic Neoplasm Showing Early Liver Metastasis

Choi, Kyu-Won; Lee, Ki-Yeol; Lee, Yeong-Kyu; Ku, Bon-Seok; Kim, Hong-Seok; Kim, Young-Hun; Kim, Ki-Ho
Fonte: Korean Dermatological Association; The Korean Society for Investigative Dermatology Publicador: Korean Dermatological Association; The Korean Society for Investigative Dermatology
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
27.16%
Hematodermic neoplasm (HN) is a clinically aggressive neoplasm with a high incidence of cutaneous involvement and a risk of leukemic dissemination. In the recent WHO-EORTC classification, the term blastic natural killer cell lymphoma has been replaced with CD4+/CD56+ HN because of its derivation from a plasmacytoid dendritic cell precursor. Cases of HN that completely lack CD4 or CD56 expression, therefore represents a diagnostic problem. A 68-year-old Korean male was diagnosed with CD4-/CD56+ HN and treated with hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) at initial treatment, and then switched to high dose methotrexate/cytarabine. His disease relapsed and resulted in death from bone and brain disease 6 months after complete clinical remission, despite diagnostic workups, including a radioisotope liver scan and ultrasound-guided fine needle aspiration biopsy. Further cytogenetic studies such as comparative genomic hybridization could elucidate the genetic mechanisms in the development and progression of lymphomas. We report an unusual case of 'CD4-/CD56+/CD123+ HN' showing early liver metastasis.

The intracellular granzyme B inhibitor, proteinase inhibitor 9, is up-regulated during accessory cell maturation and effector cell degranulation, and its overexpression enhances CTL potency

Hirst, C E; Buzza, Marguerite; Bird, Catherina; Warren, Hilary; Cameron, P B; Zhang, Manling; Ashton-Rickardt, Philip G; Bird, Phillip I
Fonte: American Association of Immunologists Publicador: American Association of Immunologists
Tipo: Artigo de Revista Científica
Português
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27.16%
Granzyme B (grB) is a serine proteinase released by cytotoxic lymphocytes (CLs) to kill abnormal cells. GrB-mediated apoptotic pathways are conserved in nucleated cells; hence, CLs require mechanisms to protect against ectopic or misdirected grB. The nucleocytoplasmic serpin, proteinase inhibitor 9 (PI-9), is a potent inhibitor of grB that protects cells from grB-mediated apoptosis in model systems. Here we show that PI-9 is present in CD4+ cells, CD8+ T cells, NK cells, and at lower levels in B cells and myeloid cells. PI-9 is up-regulated in response to grB production and degranulation, and associates with grB-containing granules in activated CTLs and NK cells. Intracellular complexes of PI-9 and grB are evident in NK cells, and overexpression of PI-9 enhances CTL potency, suggesting that cytoplasmic grB, which may threaten CL viability, is rapidly inactivated by PI-9. Because dendritic cells (DCs) acquire characteristics similar to those of target cells to activate naive CD8+T cells and therefore may also require protection against grB, we investigated the expression of PI-9 in DCs. PI-9 is evident in thymic DCs (CD3-, CD4+, CD8-, CD45+), tonsillar DCs, and DC subsets purified from peripheral blood (CD16+ monocytes and CD123+ plasmacytoid DCs). Furthermore...