T-cell immune responses to Wilms tumor 1 protein in myelodysplasia responsive to immunosuppressive therapy

Sloand, Elaine M.; Melenhorst, J. Joseph; Tucker, Zachary; Pfannes, Loretta; Brenchley, Jason M.; Yong, Agnes S. M.; Visconte, Valeria; Wu, Colin O.; Gostick, Emma; Scheinberg, Phillip; Olnes, Matthew J.; Douek, Daniel C.; Price, David A.; Barrett, A. John; Young, Neal S.

doi:10.1182/blood-2010-04-277921

Cited by 77 publications

(47 citation statements)

References 55 publications

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“…KA2 cells and KA2 cells pulsed with the WT1 126-134 peptide were not efficient targets for the expanded T cells. This indicated that the anti-WT1 cytotoxic reactivity seems to be highly dependent on the level of WT1 endogenous presentation by the target cells, which is an important consideration, since hematopoietic stem and progenitor cells express lower levels of WT1 than leukemia cells (Sloand et al, 2011). T-cell expansion and anti-WT1 reactivity were highly correlated for both the analyses performed with samples obtained from the healthy donor and the AML patient.…”

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confidence: 79%

“…Nevertheless, mice did not show any signs of progressive generalized autoimmunity or toxicity. For SmartDC/tWT1, since it was recently shown that patients with trisomy 8 with myelodypsplastic syndrome (MDS) show detectable levels of CD8 + T-cell responses directed against WT1 in hematopoieitic progenitor cells, a hypothetical concern would be that the potent anti-WT1 immune response generated by SmartDC/tWT1 could lead to reactivity against hematopoietic progenitor cells and myelosuppression (Sloand et al, 2011). This biosafety concern remains to be evaluated in immune-competent mouse models or in immune-deficient mice reconstituted with human hematopoietic stem cells.…”

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confidence: 99%

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Lentivirus-Induced Dendritic Cells for Immunization Against High-Risk WT1⁺ Acute Myeloid Leukemia

Sundarasetty

Singh²,

Salguero

et al. 2013

Human Gene Therapy

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Wilms' tumor 1 antigen (WT1) is overexpressed in acute myeloid leukemia (AML), a high-risk neoplasm warranting development of novel immunotherapeutic approaches. Unfortunately, clinical immunotherapeutic use of WT1 peptides against AML has been inconclusive. With the rationale of stimulating multiantigenic responses against WT1, we genetically programmed long-lasting dendritic cells capable of producing and processing endogenous WT1 epitopes. A tricistronic lentiviral vector co-expressing a truncated form of WT1 (lacking the DNA-binding domain

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confidence: 79%

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confidence: 99%

Lentivirus-Induced Dendritic Cells for Immunization Against High-Risk WT1⁺ Acute Myeloid Leukemia

Sundarasetty

Singh²,

Salguero

et al. 2013

Human Gene Therapy

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“…53 In addition, a relationship between T-bet overexpression and BM failure has been demonstrated in patients with aplastic anemia and MDS. 9,[54][55][56][57][58] It is worthwhile mentioning that Sca-1 becomes aberrantly expressed and some of the HSCs in this case are in fact myeloid progenitors, when IFNs are upregulated as in the current transgenic mouse. 59,60 Taking these previous reports into account, there could have been an increase in the frequency of myeloid progenitors in the BM of T-bet tg mice, which is also in line with the result of the CFC assay.…”

Section: Blood 8 January 2015 X Volume 125 Number 2 Aberrant T Cellmentioning

confidence: 99%

T-cell–restricted T-bet overexpression induces aberrant hematopoiesis of myeloid cells and impairs function of macrophages in the lung

Iriguchi

Kikuchi

Kaneko

et al. 2015

Blood

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Key Points• Mice overexpressing T-bet in T cells show aberrant hematopoiesis of myeloid cells and functional conversion of regional macrophages.• The mice developed a severe PAP-like disease with a hematopoietic disorder resembling the human disease.Although overexpression of T-bet, a master transcription factor in type-1 helper T lymphocytes, has been reported in several hematologic and immune diseases, its role in their pathogenesis is not fully understood. In the present study, we used transgenic model mice (T-bet tg/wt and T-bet tg/tg ) to investigate the effects of T-bet overexpression selectively in T lymphocytes on the development of hematologic and immune diseases. The results showed that T-bet overexpression in T cells spontaneously induced maturation arrest in the mononuclear phagocyte lineage, as well as spontaneous dermatitis and pulmonary alveolar proteinosis (PAP)-like disease in T-bet tg/wt and T-bet tg/tg mice, respectively. T-bet tg/tg alveoli with the PAP phenotype showed remarkable reorganization of alveolar mononuclear phagocyte subpopulations and impaired function, in addition to augmented T-cell infiltration. In addition, PAP development in T-bet tg/tg mice was found to be associated with increased migration of myeloid cells from the bone marrow into the peripheral blood. These findings reveal an unexpected link between T-bet overexpression in T lymphocytes and the development of PAP caused by reorganization of mononuclear phagocytes in the lung, and provide new insight into the molecular pathogenesis of secondary PAP accompanied by hematologic disorders. (Blood. 2015;125(2):370-382)

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“…2 Laboratory and clinical findings in studies of myelodysplasia in adults suggest that autoimmunity directed against hematopoietic stem cells contributes to the development of cytopenia in MDS. [3][4][5][6][7] In addition, it is generally believed that there is a pathophysiological overlap between aplastic anemia and hypocellular MDS. 8 These concepts have led to the use of immunosuppressive therapy (IST), which has proven to be effective in some adults with MDS.…”

Section: Introductionmentioning

confidence: 99%

Comparison of horse and rabbit antithymocyte globulin in immunosuppressive therapy for refractory cytopenia of childhood

Yoshimi

Heuvel‐Eibrink

Baumann³

et al. 2013

Haematologica

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Refractory cytopenia of childhood is the most common subtype of myelodysplastic syndrome in children. In this study, we compared the outcome of immunosuppressive therapy using horse antithymocyte globulin (n=46) with that using rabbit antithymocyte globulin (n=49) in 95 patients with refractory cytopenia of childhood and hypocellular bone marrow. The response rate at 6 months was 74% for horse antithymocyte globulin and 53% for rabbit antithymocyte globulin (P=0.04). The inferior response in the rabbit antithymocyte globulin group resulted in lower 4-year transplantation-free (69% versus 46%; P=0.003) and failure-free (58% versus 48%; P=0.04) survival rates in this group compared with those in the horse antithymocyte globulin group. However, because of successful second-line hematopoietic stem cell transplantation, overall survival was comparable between groups (91% versus 85%; P=ns). The cumulative incidence of relapse (15% versus 9%; P=ns) and clonal evolution (12% versus 4%; P=ns) at 4 years was comparable between groups. Our results suggest that the outcome of immunosuppressive therapy with rabbit antithymocyte globulin is inferior to that of horse antithymocyte globulin. Although immunosuppressive therapy is an effective therapy in selected patients with refractory cytopenia of childhood, the long-term risk of relapse or clonal evolution remains. (ClinicalTrial.gov identifiers: NCT00662090) Comparison of horse and rabbit antithymocyte globulin in immunosuppressive therapy for refractory cytopenia of childhood 16 In addition, a number of non-randomized studies showed inferior results for rabbit-ATG in adults and children with aplastic anemia. [17][18][19] No published series of patients with aplastic anemia has shown that rabbit-ATG is superior to horse-ATG in the context of first-line IST. [16][17][18][19][20][21][22] To date, there have only been a few reports on the efficacy of IST with rabbit-ATG in patients with MDS. 10,23,24 In this study, we compared the outcome of IST using horse-ATG with that of IST using rabbit-ATG in a large series of children with RCC. Methods Selection of patients for immunosuppressive therapyBone marrow and peripheral blood smears and bone marrow biopsies were centrally reviewed by reference pathologists in each country and the diagnosis of RCC was made according to the WHO criteria. 1,25 Fanconi anemia was excluded in all patients. Patients with RCC aged ≤18 years were enrolled in the prospective studies EWOG-MDS-98 (05/1998-12/2006) and EWOG-MDS-2006 (01/2007-08/2011. These studies were approved by the institutional review board of each participating institution. Written informed consent was provided by the patients' parents according to the Declaration of Helsinki.Patients with RCC are treated according to a risk-based strategy (Figure 1). Because of a high risk of disease progression, all patients with monosomy 7/7q-or three or more chromosomal aberrations undergo allogeneic hematopoietic stem cell transplantation (HSCT). 26 For patients without these unfavorable karyot...

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T-cell immune responses to Wilms tumor 1 protein in myelodysplasia responsive to immunosuppressive therapy

Cited by 77 publications

References 55 publications

Lentivirus-Induced Dendritic Cells for Immunization Against High-Risk WT1⁺ Acute Myeloid Leukemia

Lentivirus-Induced Dendritic Cells for Immunization Against High-Risk WT1⁺ Acute Myeloid Leukemia

T-cell–restricted T-bet overexpression induces aberrant hematopoiesis of myeloid cells and impairs function of macrophages in the lung

Comparison of horse and rabbit antithymocyte globulin in immunosuppressive therapy for refractory cytopenia of childhood

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T-cell immune responses to Wilms tumor 1 protein in myelodysplasia responsive to immunosuppressive therapy

Cited by 77 publications

References 55 publications

Lentivirus-Induced Dendritic Cells for Immunization Against High-Risk WT1+ Acute Myeloid Leukemia

Lentivirus-Induced Dendritic Cells for Immunization Against High-Risk WT1+ Acute Myeloid Leukemia

T-cell–restricted T-bet overexpression induces aberrant hematopoiesis of myeloid cells and impairs function of macrophages in the lung

Comparison of horse and rabbit antithymocyte globulin in immunosuppressive therapy for refractory cytopenia of childhood

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Lentivirus-Induced Dendritic Cells for Immunization Against High-Risk WT1⁺ Acute Myeloid Leukemia

Lentivirus-Induced Dendritic Cells for Immunization Against High-Risk WT1⁺ Acute Myeloid Leukemia