The Experts below are selected from a list of 135 Experts worldwide ranked by ideXlab platform
Michael J. Chorney - One of the best experts on this subject based on the ideXlab platform.
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An Increased γδ T Cell Population in the Intestine of Thymus-Leukemia Antigen Transgenic Mice☆
Cellular immunology, 1997Co-Authors: Padmanee Sharma, Michael J. Page, Lisa S. Poritz, Walter A. Koltun, Michael J. ChorneyAbstract:Abstract In an approach to study thymic Leukemia Antigen's (TL's) function, we have developed transgenic mice that express T18 d on virtually all somatic cells; in such mice, we initially observed changes in T cells within the thymus and lymph nodes as well as the ability of TL to undergo recognition by splenic T cells. As phase II of our study, we now present the results on the composition of gut T cell populations which may be a better measure of TL's true function. We have demonstrated an increase in the number of γδ + T cells as well as the increase in γδ + T cells expressing the Vγ2 chain. These cells appear to be both CD4 and CD8 negative. This suggests that TL may select for a subset of γδ T cells within the gut and bolsters earlier reports implicating an H-2T regional gene product as the major histocompatibility complex ligand for γδ + T cells.
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Transgenic Mice Expressing the Thymus Leukemia Antigen Fail to Control Cutaneous Herpes Simplex Virus Infection
Cellular immunology, 1996Co-Authors: Padmanee Sharma, Colena A. Johnson, Robert H. Bonneau, C.max Lang, Michael J. ChorneyAbstract:Abstract TL-transgenic mice expressing the thymus Leukemia Antigen demonstrate a lack of viral clearance following cutaneous HSV infection of the footpad. In this study, both uninfected and HSV-infected TL-trans- genic mice demonstrate increased concentrations of IL-4 as well as decreased concentrations of IFN-γ which may possibly underlie the impairment of viral clearance. Furthermore, lymphocytes from HSV-infected nontransgenic mice, adoptively transferred into HSV-infected TL-transgenic mice, promoted viral clearance and led to an increase in IFN-γ production. Transgenic mice which were subcutaneously injected with IFN-γ in the right footpad were also capable of clearing the viral challenge; however, clearance was restricted solely to the right footpad. These studies support the possibility of perturbations in the immune system of TL-transgenic mice and effectively demonstrate the utility of this model system in the study of HSV clearance, persistence, and potential spontaneous reactivation. Moreover, the TL-transgenic animals may provide a useful model system for additional studies requiring a host system skewed toward a Th2 phenotype.
Richard G Cook - One of the best experts on this subject based on the ideXlab platform.
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surface expression of β2 microglobulin associated thymus Leukemia Antigen is independent of tap2
European Journal of Immunology, 1995Co-Authors: John R Rodgers, Vidya Mehta, Richard G CookAbstract:Mouse thymus-Leukemia Antigen (TL), like other major histocompatibility complex (MHC) class I-b Antigens, displays signs of a specialized function. It is normally expressed at high levels on immature thymocytes and at moderate levels on gut epithelium and activated mature T cells. A promoter/enhancer region unique among class I genes accounts for this narrow range of tissue distribution. Like most other class I molecules, TL is dependent upon endogenous beta 2-microglobulin (beta 2m) for transport to the surface. However, here we show that unlike most other MHC class I molecules, TL is expressed efficiently in the absence of functional transporter associated with Antigen processing subunit 2 (TAP2). A putative fourth TLa gene cloned from A.SL1 cells was expressed in RMA and RMA-S cells. In bulk transformants, TL expression is higher in TAP2-RMA-S cells than in wild-type RMA cells, and is not elevated by incubation at reduced temperatures or exposure to exogenous beta 2m. Analysis of immunoprecipitated molecules by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate indicates that TL is processed normally in RMA-S cells and is associated with beta 2m both intracellularly and at the cell surface. However, TL heavy chains expressed on the cell surface in the absence of TAP2 are cleaved to a predominant 38 kDa fragment, presumably the result of an altered conformation that renders TL more susceptible to proteolysis. These results suggest that while TL may normally acquire TAP2-dependent peptides, this class I-b molecule does not require them for efficient export to, and stable expression at the cell surface.
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Surface expression of β2‐microglobulin‐associated thymus‐Leukemia Antigen is independent of TAP2
European journal of immunology, 1995Co-Authors: John R Rodgers, Vidya Mehta, Richard G CookAbstract:Mouse thymus-Leukemia Antigen (TL), like other major histocompatibility complex (MHC) class I-b Antigens, displays signs of a specialized function. It is normally expressed at high levels on immature thymocytes and at moderate levels on gut epithelium and activated mature T cells. A promoter/enhancer region unique among class I genes accounts for this narrow range of tissue distribution. Like most other class I molecules, TL is dependent upon endogenous beta 2-microglobulin (beta 2m) for transport to the surface. However, here we show that unlike most other MHC class I molecules, TL is expressed efficiently in the absence of functional transporter associated with Antigen processing subunit 2 (TAP2). A putative fourth TLa gene cloned from A.SL1 cells was expressed in RMA and RMA-S cells. In bulk transformants, TL expression is higher in TAP2-RMA-S cells than in wild-type RMA cells, and is not elevated by incubation at reduced temperatures or exposure to exogenous beta 2m. Analysis of immunoprecipitated molecules by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate indicates that TL is processed normally in RMA-S cells and is associated with beta 2m both intracellularly and at the cell surface. However, TL heavy chains expressed on the cell surface in the absence of TAP2 are cleaved to a predominant 38 kDa fragment, presumably the result of an altered conformation that renders TL more susceptible to proteolysis. These results suggest that while TL may normally acquire TAP2-dependent peptides, this class I-b molecule does not require them for efficient export to, and stable expression at the cell surface.
Ellis L Reinherz - One of the best experts on this subject based on the ideXlab platform.
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graft versus Leukemia Antigen cml66 elicits coordinated b cell and t cell immunity after donor lymphocyte infusion
Clinical Cancer Research, 2010Co-Authors: Wandi Zhang, Edwin P Alyea, Christine Canning, Jaewon Choi, Wanyong Zeng, Shelby A Rogers, James G Rheinwald, Vladimir Brusic, Tetsuro Sasada, Ellis L ReinherzAbstract:Purpose: The target Antigens of graft-versus-Leukemia that are tumor associated are incompletely characterized. Experimental Design: We examined responses developing against CML66, an immunogenic Antigen preferentially expressed in myeloid progenitor cells identified from a patient with chronic myelogenous Leukemia who attained long-lived remission following CD4+ donor lymphocyte infusion (DLI). Results: From this patient, CML66-reactive CD8+ T-cell clones were detected against an endogenously presented HLA-B*4403–restricted epitope (HDVDALLW). Neither CML66-specific antibody nor T-cell responses were detectable in peripheral blood before DLI. However, by 1 month after DLI, CD8+ T cells were present in peripheral blood and at 10-fold higher frequency in marrow. Subsequently, plasma antibody to CML66 developed in association with disease remission. Donor-derived CML66-reactive T cells were detected at low levels in vivo in marrow before DLI by ELISpot and by a nested PCR-based assay to detect clonotypic T-cell receptor sequences but not in blood of the patient pre-DLI nor of the graft donor. Conclusions: CD4+ DLI results in rapid expansion of preexisting marrow-resident Leukemia-specific donor CD8+ T cells, followed by a cascade of Antigen-specific immune responses detectable in blood. Our single-Antigen analysis thus shows that durable posttransplant tumor immunity is directed in part against nonpolymorphic overexpressed Leukemia Antigens that elicit coordinated cellular and humoral immunity. Clin Cancer Res; 16(10); 2729–39. ©2010 AACR.
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graft versus Leukemia Antigen cml66 elicits coordinated b and t cell immunity after donor lymphocyte infusion
Blood, 2009Co-Authors: Wandi Zhang, Edwin P Alyea, Christine Canning, Jaewon Choi, Wanyong Zeng, Tetsuro Sasada, Ellis L Reinherz, Robert J Soiffer, Jerome RitzAbstract:Abstract 2449 Poster Board II-426 Donor lymphocyte infusion (DLI) is a highly effective treatment for relapsed chronic myeloid Leukemia (CML) after allogeneic hematopoietic stem cell transplantation (HSCT), in which 70-80% patients achieve curative responses. Despite its efficacy and established clinical use, the mechanism by which DLI achieves anti-tumor immunity remains incompletely understood. CML66 was discovered as an overexpressed nonpolymorphic CML-associated Antigen that elicited a high-titer (>1:50,000) antibody response in a patient who received CD4+ DLI for relapsed CML. CML66 is preferentially expressed on myeloid Leukemia progenitor cells and the development of CML66 antibodies temporally correlated with attainment of molecular remission. Since CD4+ T cell responses are involved in generating both Antigen-specific B cell and CD8+T cell responses, we queried whether development of potent B cell immunity was also associated with the development of cytolytic T cell immunity against CML66. To detect specific T cell responses, post-DLI PBMC from this patient were screened for reactivity against pools of overlapping 15- to 18-mer peptides encoding the entire protein sequence of CML66. Patient CD8+ T cells were found to be reactive against a single CML66-derived peptide pool, and specifically an 8 amino acid peptide (HDVDALLW), beginning at residue 459. This T cell epitope is positioned in a different region of the protein compared to the B cell epitope (at residues 198-217: GFYVSLEWVTISKKNQDNK). A peptide-specific T cell clone was isolated, whose MHC class I molecule binding was restricted to HLA B*4403. The CML66-reactive T cell clone recognized the HLA-B4403-expressing CD34+ AML cell line MUTZ-3, providing evidence that this epitope is naturally processed and presented by myeloid Leukemia cells. Functional cytotoxic T cell responses to CML66 appeared to precede the appearance of Antigen-specific antibody responses. While CML66-specific plasma antibody was only detectable starting 2-3 months after DLI, reactivity to the HLA-B4403-restricted epitope by peripheral blood-derived CD8+ T cells was detected by IFNγ ELISpot as early as one month following DLI. To sensitively detect CD8+ CML66-specific T cells in vivo, we sequenced the CDR3 region specific to the CML66-specific clone, and designed clone-specific quantitative PCR primers. Nested PCR of RNA directly extracted from patient PBMC revealed only minimal detection of the CML66-specific T cell clone prior to DLI, but then expansion between 1 to 6 months after DLI. Similar analysis of marrow-derived RNA also revealed the presence of CML66-specific T cell clone in patient marrow following DLI. Moreover, this clone was already detected in patient marrow prior to DLI, suggesting that marrow is a reservoir of Leukemia-specific T cells following hematopoietic stem cell transplantation. Our studies provide the first description of coordinated adaptive immunity developing against a nonpolymorphic Leukemia-associated Antigen, in close temporal correlation with the attainment of long-lasting immune-mediated clinical remission after allogeneic HSCT. The detected cytolytic T cell response was associated with the secretion of high-titer IgG antibody specific for a distinct epitope in the same target protein. In this setting, our results indicate that infusion of CD4+ donor cells resulted in the rapid activation and expansion of pre-existing marrow-resident Leukemia-specific CD8+ T cells, followed by a cascade of Antigen-specific immune responses detectable in the periphery. Disclosures: No relevant conflicts of interest to declare.
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CD10/neutral endopeptidase 24.11 hydrolyzes bombesin-like peptides and regulates the growth of small cell carcinomas of the lung
Proceedings of the National Academy of Sciences of the United States of America, 1991Co-Authors: Margaret A. Shipp, George E. Tarr, Chang-yan Chen, Stephanie N. Switzer, Louis B. Hersh, Harald Stein, Mary E. Sunday, Ellis L ReinherzAbstract:Bombesin-like peptides are essential autocrine growth factors for many small cell carcinomas (SCCas) of the lung. Herein, we demonstrate that these malignant pulmonary neuroendocrine cells express low levels of the cell surface metalloendopeptidase CD10/neutral endopeptidase 24.11 (CD10/NEP, common acute lymphoblastic Leukemia Antigen) and that this enzyme hydrolyzes bombesin-like peptides. The growth of bombesin-like peptide-dependent SCC as is inhibited by CD10/NEP and potentiated by CD10/NEP inhibition. The results provide evidence that CD10/NEP is involved in the regulation of tumor cell proliferation. Since SCCa of the lung occurs almost exclusively in cigarette smokers and cigarette smoke inactivates CD10/NEP, decreased cell surface CD10/NEP enzymatic activity may be causally related to the development of SCCa of the lung.
Padmanee Sharma - One of the best experts on this subject based on the ideXlab platform.
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An Increased γδ T Cell Population in the Intestine of Thymus-Leukemia Antigen Transgenic Mice☆
Cellular immunology, 1997Co-Authors: Padmanee Sharma, Michael J. Page, Lisa S. Poritz, Walter A. Koltun, Michael J. ChorneyAbstract:Abstract In an approach to study thymic Leukemia Antigen's (TL's) function, we have developed transgenic mice that express T18 d on virtually all somatic cells; in such mice, we initially observed changes in T cells within the thymus and lymph nodes as well as the ability of TL to undergo recognition by splenic T cells. As phase II of our study, we now present the results on the composition of gut T cell populations which may be a better measure of TL's true function. We have demonstrated an increase in the number of γδ + T cells as well as the increase in γδ + T cells expressing the Vγ2 chain. These cells appear to be both CD4 and CD8 negative. This suggests that TL may select for a subset of γδ T cells within the gut and bolsters earlier reports implicating an H-2T regional gene product as the major histocompatibility complex ligand for γδ + T cells.
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Transgenic Mice Expressing the Thymus Leukemia Antigen Fail to Control Cutaneous Herpes Simplex Virus Infection
Cellular immunology, 1996Co-Authors: Padmanee Sharma, Colena A. Johnson, Robert H. Bonneau, C.max Lang, Michael J. ChorneyAbstract:Abstract TL-transgenic mice expressing the thymus Leukemia Antigen demonstrate a lack of viral clearance following cutaneous HSV infection of the footpad. In this study, both uninfected and HSV-infected TL-trans- genic mice demonstrate increased concentrations of IL-4 as well as decreased concentrations of IFN-γ which may possibly underlie the impairment of viral clearance. Furthermore, lymphocytes from HSV-infected nontransgenic mice, adoptively transferred into HSV-infected TL-transgenic mice, promoted viral clearance and led to an increase in IFN-γ production. Transgenic mice which were subcutaneously injected with IFN-γ in the right footpad were also capable of clearing the viral challenge; however, clearance was restricted solely to the right footpad. These studies support the possibility of perturbations in the immune system of TL-transgenic mice and effectively demonstrate the utility of this model system in the study of HSV clearance, persistence, and potential spontaneous reactivation. Moreover, the TL-transgenic animals may provide a useful model system for additional studies requiring a host system skewed toward a Th2 phenotype.
Cherie H Dunphy - One of the best experts on this subject based on the ideXlab platform.
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immunoreactivity of mic2 cd99 and terminal deoxynucleotidyl transferase in bone marrow clot and core specimens of acute myeloid Leukemias and myelodysplastic syndromes
Archives of Pathology & Laboratory Medicine, 2006Co-Authors: Loveleen C Kang, Cherie H DunphyAbstract:Abstract Context.—MIC2 (“thymus Leukemia”) Antigen has been shown to be expressed by T cells and monocytes, as well as B cells and granulocyte-lineage cells. It is most intensely expressed by the most immature thymus T-lineage cells and is more intensely expressed by CD34-positive/CD33-positive myeloid cells (compared to more mature myeloid cells) and the earliest CD34-positive/CD10-positive B-cell precursor cells (compared to cells of later B-cell precursor stages). CD99 (MIC2) is characteristically expressed in precursor B- and T-cell lymphoblastic lymphomas/Leukemias, as well as in Ewing sarcoma/primitive neuroectodermal tumors (ES/PNET). It has also been shown to be expressed in a few terminal deoxynucleotidyl transferase (TdT)–positive myeloid processes, but has been uniformly negative in TdT-negative myeloid processes. A more recent study showed that 43% of acute myeloid Leukemias (AMLs) and 55% of chloromas express CD99, concluding that CD99 is commonly expressed in AML and rarely seen in myeloprol...