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Hidetoshi Inoko - One of the best experts on this subject based on the ideXlab platform.

  • a novel monoclonal antibody mni 58a against the alpha chain of leukocyte function associated antigen 1 lfa 1 blocks the homotypic cell aggregation and actively regulates morphological changes in the phorbol myristate acetate pma activated human monoc
    Tissue Antigens, 1996
    Co-Authors: Nobunao Ikewaki, A Sonoda, Akira Yamada, Hidetoshi Inoko
    Abstract:

    A monoclonal antibody (mAb), designated mNI-58A, was produced by immunizing mice with the lipopolysaccharide (LPS)-stimulated monocyte-like cell line, U937. The antigen defined by mNI-58A was widely expressed on various lymphoid cells and all cell lines examined except the erythroid cell line, K562. When the reactive patterns between mNI-58A and the mAbs to various human differentiation antigens (CD11a, CD11b, CD11c, CD14, CD16, CD18, CD23, CD28, CD29, CD31, CD43, CD44, CD45RA, CD50, CD54, CD58, CD80, CD102, CD106, HLA-class I and-class II antigen) were compared, that of mNI-58A was found to be similar to those of the leukocyte function-associated antigen-1 (LFA-1) mAbs. Using a competitive immunofluorescence binding assay it was found that the preincubation with one of the CD11a mAbs, 2F12 completely blocked the subsequent binding of mNI-58A. mNI-58A prevented the homotypic cell aggregation of the phorbol myristate acetate (PMA)-activated U937 cells (referred to as PMA-U937) and PMA-activated Epstein-Barr virus (EBV)-transformed B cell lines, B-85 and Mann. mNI-58A markedly induced the spread formation of the PMA-U937 cells following this blocking of the homotypic cell aggregation, whereas 2F12 did not under the same condition. The spread formation induced by mNI-58A was completely blocked by cytochalasin B (CyB), cytochalasin D (CyD), cycloheximide (CHX) or protein kinase C inhibitors, sphingosine and H-7. The U937 cells markedly adhered to the tumor necrosis factor-alpha (TNF-alpha)-stimulated human umbilical vein endothelial cells (HUVECs) and also to the extracellular matrix protein, fibronectin, but mNI-58A did not enhance or block these adhesion process. mNI-58A precipitated two glycoproteins with molecular weight 180 kDa and 95 kDa as determined by SDS-PAGE analysis, which were identical to the LFA-alpha (CD11a) and beta (CD18) chains of leukocyte integrin precipitated by the CD11a mAbs, respectively. Sequential immunoprecipitation studies using the CD11a mAb (2F12) also indicate that mNI-58A recognizes an epitope on the alpha-chain of the LFA-1 molecule. The ability of mNI-58A to block the PMA-U937 cells and to induce the spread formation of these cells suggests that mNI-58A is a novel mAb reacting with an epitope on the alpha-chain of LFA-1 different from those recognized with the existing CD11a mAbs.

  • a novel monoclonal antibody mni 58a against the α chain of leukocyte function associated antigen 1 lfa 1 blocks the homotypic cell aggregation and actively regulates morphological changes in the ohorbol myristate acetate pma activated human monocyte
    Tissue Antigens, 1996
    Co-Authors: Nobunao Ikewaki, A Sonoda, Akira Yamada, Hidetoshi Inoko
    Abstract:

    : A monoclonal antibody (mAb), designated mNI-58A, was produced by immunizing mice with the lipopolysaccharide (LPS)-stimulated monocyte-like cell line, U937. The antigen defined by mNI-58A was widely expressed on various lymphoid cells and all cell lines examined except the erythroid cell line, K562. When the reactive patterns between mNI-58A and the mAbs to various human differentiation antigens (CD11a, CD11b, CD11c, CD14, CD16, CD18, CD23, CD28, CD29, CD31, CD43, CD44, CD45RA, CD50, CD54, CD58, CD80, CD102, CD106, HLA-class I and-class II antigen) were compared, that of mNI-58A was found to be similar to those of the leukocyte function-associated antigen-1 (LFA-1) mAbs. Using a competitive immunofluorescence binding assay it was found that the preincubation with one of the CD11a mAbs, 2F12 completely blocked the subsequent binding of mNI-58A. mNI-58A prevented the homotypic cell aggregation of the phorbol myristate acetate (PMA)-activated U937 cells (referred to as PMA-U937) and PMA-activated Epstein-Barr virus (EBV)-transformed B cell lines, B-85 and Mann. mNI-58A markedly induced the spread formation of the PMA-U937 cells following this blocking of the homotypic cell aggregation, whereas 2F12 did not under the same condition. The spread formation induced by mNI-58A was completely blocked by cytochalasin B (CyB), cytochalasin D (CyD), cycloheximide (CHX) or protein kinase C inhibitors, sphingosine and H-7. The U937 cells markedly adhered to the tumor necrosis factor-alpha (TNF-alpha)-stimulated human umbilical vein endothelial cells (HUVECs) and also to the extracellular matrix protein, fibronectin, but mNI-58A did not enhance or block these adhesion process. mNI-58A precipitated two glycoproteins with molecular weight 180 kDa and 95 kDa as determined by SDS-PAGE analysis, which were identical to the LFA-alpha (CD11a) and beta (CD18) chains of leukocyte integrin precipitated by the CD11a mAbs, respectively. Sequential immunoprecipitation studies using the CD11a mAb (2F12) also indicate that mNI-58A recognizes an epitope on the alpha-chain of the LFA-1 molecule. The ability of mNI-58A to block the PMA-U937 cells and to induce the spread formation of these cells suggests that mNI-58A is a novel mAb reacting with an epitope on the alpha-chain of LFA-1 different from those recognized with the existing CD11a mAbs.

  • development and characterization of a novel monoclonal antibody mni 11 that induces cell adhesion of the lps stimulated human monocyte like cell line u937
    Journal of Leukocyte Biology, 1996
    Co-Authors: Nobunao Ikewaki, Hidetoshi Inoko
    Abstract:

    : A monoclonal immunoglobulin G1 (IgG1) antibody (mAb), designated mNI-11, was produced by immunizing mice with the lipopolysaccharide (LPS)-stimulated monocyte-like cell line U937. The reactivity of mNI-11 was tested by the indirect immunofluorescence method. The antigen defined by mNI-11 was found to be expressed on U937 cells, LPS-stimulated U937 cells, normal CD14+ cells (monocytes/macrophages), and human umbilical vein endothelial cells (HUVECs). Expression of the antigen defined by mNI-11 on HUVECs slightly increased in response to exposure to tumor necrosis factor-alpha (TNF-alpha) and phorbol myristate acetate (PMA). When the reactivity of mNI-11 and mAbs binding human differentiation antigens such as CD11a, CD11b, CD11c, CD14, CD16, CD18, CD23, CD28, CD29, CD31, CD43, CD44, CD45RA, CD49d, CD50, CD54, CD58, CD80, CD102, CD106, HLA-class I, or HLA-class II antigen was compared, no mNI-11 reactivity resembling that of these mAbs was found. mNI-11 markedly induced homotypic cell aggregation of U937 cells when they were stimulated with LPS. The mNI-11-induced aggregation of LPS-stimulated U937 cells, referred to as LPS-U937 cells, required neither Fc receptor engagement nor cross-linking of the antigen defined by mNI-11 because aggregation was induced by both F(ab')2 fragments and monovalent F(ab') fragments of mNI-11. The mNI-11-induced aggregation was blocked by the addition of ethylenediaminetetraacetate, and also when incubated at 4 degrees C. mAbs to CD11a/CD18 (lymphocyte-function associated antigen-1; LFA-1) and CD54 (intercellular adhesion molecule-1; ICAM-1) completely blocked the LPS-U937 cell aggregation induced by mNI-11. The LPS-U937 cell aggregation induced by mNI-11 was partially but not completely blocked by the protein kinase C inhibitors sphingosine and H-7, and was completely blocked by the protein-tyrosine kinase inhibitor genistein. Interestingly, mNI-11 markedly promoted LPS-U937 cell adhesion to HUVECs. The mNI-11-induced LPS-U937 cell adhesion to HUVECs was not reduced in the presence of LFA-1 (CD11a/CD18) or ICAM-1 (CD54) mAbs. On the other hand, LPS-U937 cells, whether treated with mNI-11 or not, sufficiently adhered to the extracellular matrix protein fibronectin, but not to laminin or collagen type I. However, mNI-11 did not markedly promote LPS-U937 cell adhesion to fibronectin. Adhesion of LPS-U937 cells treated with mNI-11 to fibronectin was completely blocked by CD29 (beta chain of very late antigens) mAb. The surface antigen recognized by mNI-11 had a molecular size of approximately 97 kDa under non-reducing conditions and approximately 117 kDa under reducing conditions, as determined by immunoblotting analysis. We found that mNI-11 recognizes an adhesion-associated molecule distinct from any previously reported in terms of its pattern of cellular distribution and molecular weight, and also found that mNI-11 has activity which induces cell adhesion/aggregation of U937 cells when stimulated with LPS.

Nobunao Ikewaki - One of the best experts on this subject based on the ideXlab platform.

  • a novel monoclonal antibody mni 58a against the α chain of leukocyte function associated antigen 1 lfa 1 blocks the homotypic cell aggregation and actively regulates morphological changes in the ohorbol myristate acetate pma activated human monocyte
    Tissue Antigens, 1996
    Co-Authors: Nobunao Ikewaki, A Sonoda, Akira Yamada, Hidetoshi Inoko
    Abstract:

    : A monoclonal antibody (mAb), designated mNI-58A, was produced by immunizing mice with the lipopolysaccharide (LPS)-stimulated monocyte-like cell line, U937. The antigen defined by mNI-58A was widely expressed on various lymphoid cells and all cell lines examined except the erythroid cell line, K562. When the reactive patterns between mNI-58A and the mAbs to various human differentiation antigens (CD11a, CD11b, CD11c, CD14, CD16, CD18, CD23, CD28, CD29, CD31, CD43, CD44, CD45RA, CD50, CD54, CD58, CD80, CD102, CD106, HLA-class I and-class II antigen) were compared, that of mNI-58A was found to be similar to those of the leukocyte function-associated antigen-1 (LFA-1) mAbs. Using a competitive immunofluorescence binding assay it was found that the preincubation with one of the CD11a mAbs, 2F12 completely blocked the subsequent binding of mNI-58A. mNI-58A prevented the homotypic cell aggregation of the phorbol myristate acetate (PMA)-activated U937 cells (referred to as PMA-U937) and PMA-activated Epstein-Barr virus (EBV)-transformed B cell lines, B-85 and Mann. mNI-58A markedly induced the spread formation of the PMA-U937 cells following this blocking of the homotypic cell aggregation, whereas 2F12 did not under the same condition. The spread formation induced by mNI-58A was completely blocked by cytochalasin B (CyB), cytochalasin D (CyD), cycloheximide (CHX) or protein kinase C inhibitors, sphingosine and H-7. The U937 cells markedly adhered to the tumor necrosis factor-alpha (TNF-alpha)-stimulated human umbilical vein endothelial cells (HUVECs) and also to the extracellular matrix protein, fibronectin, but mNI-58A did not enhance or block these adhesion process. mNI-58A precipitated two glycoproteins with molecular weight 180 kDa and 95 kDa as determined by SDS-PAGE analysis, which were identical to the LFA-alpha (CD11a) and beta (CD18) chains of leukocyte integrin precipitated by the CD11a mAbs, respectively. Sequential immunoprecipitation studies using the CD11a mAb (2F12) also indicate that mNI-58A recognizes an epitope on the alpha-chain of the LFA-1 molecule. The ability of mNI-58A to block the PMA-U937 cells and to induce the spread formation of these cells suggests that mNI-58A is a novel mAb reacting with an epitope on the alpha-chain of LFA-1 different from those recognized with the existing CD11a mAbs.

  • a novel monoclonal antibody mni 58a against the alpha chain of leukocyte function associated antigen 1 lfa 1 blocks the homotypic cell aggregation and actively regulates morphological changes in the phorbol myristate acetate pma activated human monoc
    Tissue Antigens, 1996
    Co-Authors: Nobunao Ikewaki, A Sonoda, Akira Yamada, Hidetoshi Inoko
    Abstract:

    A monoclonal antibody (mAb), designated mNI-58A, was produced by immunizing mice with the lipopolysaccharide (LPS)-stimulated monocyte-like cell line, U937. The antigen defined by mNI-58A was widely expressed on various lymphoid cells and all cell lines examined except the erythroid cell line, K562. When the reactive patterns between mNI-58A and the mAbs to various human differentiation antigens (CD11a, CD11b, CD11c, CD14, CD16, CD18, CD23, CD28, CD29, CD31, CD43, CD44, CD45RA, CD50, CD54, CD58, CD80, CD102, CD106, HLA-class I and-class II antigen) were compared, that of mNI-58A was found to be similar to those of the leukocyte function-associated antigen-1 (LFA-1) mAbs. Using a competitive immunofluorescence binding assay it was found that the preincubation with one of the CD11a mAbs, 2F12 completely blocked the subsequent binding of mNI-58A. mNI-58A prevented the homotypic cell aggregation of the phorbol myristate acetate (PMA)-activated U937 cells (referred to as PMA-U937) and PMA-activated Epstein-Barr virus (EBV)-transformed B cell lines, B-85 and Mann. mNI-58A markedly induced the spread formation of the PMA-U937 cells following this blocking of the homotypic cell aggregation, whereas 2F12 did not under the same condition. The spread formation induced by mNI-58A was completely blocked by cytochalasin B (CyB), cytochalasin D (CyD), cycloheximide (CHX) or protein kinase C inhibitors, sphingosine and H-7. The U937 cells markedly adhered to the tumor necrosis factor-alpha (TNF-alpha)-stimulated human umbilical vein endothelial cells (HUVECs) and also to the extracellular matrix protein, fibronectin, but mNI-58A did not enhance or block these adhesion process. mNI-58A precipitated two glycoproteins with molecular weight 180 kDa and 95 kDa as determined by SDS-PAGE analysis, which were identical to the LFA-alpha (CD11a) and beta (CD18) chains of leukocyte integrin precipitated by the CD11a mAbs, respectively. Sequential immunoprecipitation studies using the CD11a mAb (2F12) also indicate that mNI-58A recognizes an epitope on the alpha-chain of the LFA-1 molecule. The ability of mNI-58A to block the PMA-U937 cells and to induce the spread formation of these cells suggests that mNI-58A is a novel mAb reacting with an epitope on the alpha-chain of LFA-1 different from those recognized with the existing CD11a mAbs.

  • development and characterization of a novel monoclonal antibody mni 11 that induces cell adhesion of the lps stimulated human monocyte like cell line u937
    Journal of Leukocyte Biology, 1996
    Co-Authors: Nobunao Ikewaki, Hidetoshi Inoko
    Abstract:

    : A monoclonal immunoglobulin G1 (IgG1) antibody (mAb), designated mNI-11, was produced by immunizing mice with the lipopolysaccharide (LPS)-stimulated monocyte-like cell line U937. The reactivity of mNI-11 was tested by the indirect immunofluorescence method. The antigen defined by mNI-11 was found to be expressed on U937 cells, LPS-stimulated U937 cells, normal CD14+ cells (monocytes/macrophages), and human umbilical vein endothelial cells (HUVECs). Expression of the antigen defined by mNI-11 on HUVECs slightly increased in response to exposure to tumor necrosis factor-alpha (TNF-alpha) and phorbol myristate acetate (PMA). When the reactivity of mNI-11 and mAbs binding human differentiation antigens such as CD11a, CD11b, CD11c, CD14, CD16, CD18, CD23, CD28, CD29, CD31, CD43, CD44, CD45RA, CD49d, CD50, CD54, CD58, CD80, CD102, CD106, HLA-class I, or HLA-class II antigen was compared, no mNI-11 reactivity resembling that of these mAbs was found. mNI-11 markedly induced homotypic cell aggregation of U937 cells when they were stimulated with LPS. The mNI-11-induced aggregation of LPS-stimulated U937 cells, referred to as LPS-U937 cells, required neither Fc receptor engagement nor cross-linking of the antigen defined by mNI-11 because aggregation was induced by both F(ab')2 fragments and monovalent F(ab') fragments of mNI-11. The mNI-11-induced aggregation was blocked by the addition of ethylenediaminetetraacetate, and also when incubated at 4 degrees C. mAbs to CD11a/CD18 (lymphocyte-function associated antigen-1; LFA-1) and CD54 (intercellular adhesion molecule-1; ICAM-1) completely blocked the LPS-U937 cell aggregation induced by mNI-11. The LPS-U937 cell aggregation induced by mNI-11 was partially but not completely blocked by the protein kinase C inhibitors sphingosine and H-7, and was completely blocked by the protein-tyrosine kinase inhibitor genistein. Interestingly, mNI-11 markedly promoted LPS-U937 cell adhesion to HUVECs. The mNI-11-induced LPS-U937 cell adhesion to HUVECs was not reduced in the presence of LFA-1 (CD11a/CD18) or ICAM-1 (CD54) mAbs. On the other hand, LPS-U937 cells, whether treated with mNI-11 or not, sufficiently adhered to the extracellular matrix protein fibronectin, but not to laminin or collagen type I. However, mNI-11 did not markedly promote LPS-U937 cell adhesion to fibronectin. Adhesion of LPS-U937 cells treated with mNI-11 to fibronectin was completely blocked by CD29 (beta chain of very late antigens) mAb. The surface antigen recognized by mNI-11 had a molecular size of approximately 97 kDa under non-reducing conditions and approximately 117 kDa under reducing conditions, as determined by immunoblotting analysis. We found that mNI-11 recognizes an adhesion-associated molecule distinct from any previously reported in terms of its pattern of cellular distribution and molecular weight, and also found that mNI-11 has activity which induces cell adhesion/aggregation of U937 cells when stimulated with LPS.

  • antibody mnl 1 1 that induces cell adhesion of the lps stimulated human monocyte like cell line u937
    1996
    Co-Authors: Nobunao Ikewaki
    Abstract:

    A monoclonal immunoglobulin Gi (IgGi) antibody (mAb), designated mNI-1 1, was produced by immunizing mice with the lipopolysac- charide (LPS)-stimulated monocyte-like cell line U937. The reactivity of mNI-1 1 was tested by the indirect immunofluorescence method. The antigen defined by mNI-1 1 was found to be expressed on U937 cells, LPS-stimulated U937 cells, normal CD14' cells (monocytes/macrophages), and human umbilical vein endothelial cells (HUVECs). Expres- sion of the antigen defined by mNI-1 1 on HUVECs slightly increased in response to exposure to tumor necrosis factor-a (TNF-a) and phorbol myristate acetate (PMA). When the reactivity of mNI-1 1 and mAbs binding human differentiation antigens such as CD11a, CD11b, CD11c, CD14, CD16, CD18, CD23, CD28, CD29, CD31, CD43, CD44, CD45RA, CD49d, CD5O, CD54, CD58, CD8O, CD1O2, CD1O6, HLA-class I, or HLA-class II anti- gen was compared, no mNI- 1 1 reactivity resembling that of these mAbs was found. mNI-1 1 markedly other hand, LPS-U937 cells, whether treated with mNI-i 1 or not, sufficiently adhered to the extracel- lular matrix protein fibronectin, but not to laminin or collagen type I. However, mNI- 1 1 did not mark- edly promote LPS-U937 cell adhesion to fibronectin. Adhesion of LPS-U937 cells treated with mNI-i 1 to fibronectin was completely blocked by CD29 (� chain of very late antigens) mAb. The surface antigen recognized by mNI- 1 1 had a molecular size of �-�97 kfla under non-reducing conditions and 1 1 7 kDa under reducing conditions, as determined by im- munoblotting analysis. We found that mNI- 1 1 recog- nizes an adhesion-associated molecule distinct from any previously reported in terms of its pattern of cellular distribution and molecular weight, and also found that mNI- 1 1 has activity which induces cell adhesion/aggregation of U937 cells when stimulated with LPS. J. Leukoc. Biol. 59: 697-708; 1996.

Yuan Kong - One of the best experts on this subject based on the ideXlab platform.

  • cd38 CD58 is an independent adverse prognostic factor in paediatric philadelphia chromosome negative b cell acute lymphoblastic leukaemia patients
    Leukemia Research, 2016
    Co-Authors: Leping Zhang, Yazhe Wang, Yazhen Qin, Honghu Zhu, Yueyun Lai, Yuan Kong, Xiaojun Huang, Yan Chang, Yanrong Liu
    Abstract:

    To explore new risk predictors for a high risk of relapse in Philadelphia chromosome negative (Ph-) B cell acute lymphoblastic leukaemia (B-ALL) patients, 196 paediatric Ph- B-ALL patients (≤ 18 years) were retrospectively analysed. We mainly focus on investigating the prognostic value of CD38 and CD58 expression in leukemic blasts in these patients by four colour flow cytometry. The CD38+ CD58- group (n=16) had a higher relapse rate, a shorter 3-year event-free survival (EFS) and overall survival (OS) than the CD38+ CD58+ group (n=157; 31.3% vs 10.2%, P=0.04; 52.4% vs 92.3%, P<0.01; 32.5% vs 91.0%, P=0.01); CD38+ CD58- was an independent adverse prognostic predictor for relapse (hazard ratio [HR], 0.203; 95%CI, 0.063-0.656; P=0.01), 3-year EFS (HR, 0.091; 95%CI, 0.023-0.355; P<0.01) and OS (HR, 0.102; 95%CI, 0.026-0.3971; P<0.01) in this cohort, as determined by Cox multivariate analysis. We identified, for the first time, a higher risk population of paediatric Ph- B-ALL patients with CD38+ CD58- who had a higher relapse risk and a shorter survival. Our results may allow better risk stratification and individualized treatment.

  • presence of cd34 cd38 CD58 leukemia propagating cells at diagnosis identifies patients at high risk of relapse with ph chromosome positive all after allo hematopoietic sct
    Bone Marrow Transplantation, 2015
    Co-Authors: Yuan Kong, Yingjun Chang, Qian Jiang, Hao Jiang, Yazhen Qin, Yong Liu, Yuanwei Sun, Yangyuan Wang, Huan Chen, Xiaojun Huang
    Abstract:

    Relapse of Ph chromosome-positive ALL (Ph+ALL) results from the persistence of leukemia-propagating cells (LPCs). In Ph+ALL, a xenograft assay recently determined that LPCs are enriched in the CD34+CD38−CD58− fraction. Therefore, the prognostic significance of LPCs in Ph+ALL subjects after allogeneic hematopoietic SCT (allo-HSCT) was investigated. A total of 80 consecutive adults with Ph+ALL who underwent allo-HSCT were eligible. A multi-parameter flow cytometry analysis examining CD58–FITC/CD10–PE/ CD19–APC–Cy7/CD34–PerCP/CD45–Vioblue/ CD38–APC on gated leukemia BM blasts was performed at diagnosis. Based on the original blast phenotypes, subjects were stratified into the CD34+CD38−CD58−group (N=15) and other phenotype group (N=65). During minimal residual disease monitoring, significantly higher levels of BCR/ABL transcripts were detected in subjects in the CD34+CD38−CD58− group than in other phenotype group, especially at 3 months post HSCT. In addition, CD34+CD38−CD58−LPCs are directly correlated with a higher 3-year cumulative incidence of relapse (CIR) and worse leukemia-free survival (LFS) and OS. Multivariate analyses indicated that presence of CD34+CD38−CD58− LPCs at diagnosis, and BCR–ABL reduction at 3 months post HSCT were independent risk factors for relapse, LFS and OS. Our data suggest that presence of CD34+CD38−CD58− LPCs at diagnosis allows rapid identification of high-risk patients for relapse after allo-HSCT.

  • cd34 cd38 CD58 leukemia propagating cells at diagnosis could identify patients at high risk for relapse in philadelphia chromosome positive acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation
    Blood, 2014
    Co-Authors: Yuan Kong, Yingjun Chang, Yanrong Liu, Qian Jiang, Hao Jiang, Yazhen Qin, Huan Chen, Yuqian Sun, Yu Wang, Xiaojun Huang
    Abstract:

    Background: Relapse of Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph + ALL) may result from the persistence of leukemia stem cells sometimes termed leukemia-propagating cells (LPCs). We recently found that Ph + ALL LPCs are enriched in the CD34 + CD38 - CD58 - fraction using anti-CD122-conditioned NOD/SCID xenograft assay by intra-bone marrow injection, which translating to adverse clinical outcomes (Kong Y, et al. Leukemia 2014. accepted). Despite the widespread use of abelson tyrosine kinase inhibitors (TKIs) in Ph + ALL, allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the best curative option. However, whether the prognostic significance of the identified LPCs phenotype to identify patients at high risk for relapse could retain in Ph + ALL after allo-HSCT, if any, is unknown. Aims: To investigate the prognostic significance of the candidate CD34 + CD38 - CD58 - LPCs in Ph + ALL subjects underwent allo-HSCT. Methods: A total of 80 consecutive adults (18-60 years) with Ph + ALL underwent allo-HSCT were eligible for the study at Peking University Institute of Hematology from January 1, 2009 to December 31, 2013. Imatinib was routinely administered in subjects pre- and post-HSCT as previously reported. A multi-parameter flow cytometry analysis of CD58-FITC/CD10-PE/CD19-APC-Cy7/CD34-PerCP/CD45-Vioblue/ CD38-APC on gated leukemia blasts of bone marrow was performed at diagnosis. Furthermore, minimal residual disease (MRD) was monitored by BCR/ABL transcripts in bone marrow samples at diagnosis, directly before transplantation, as well as serially at 1, 2, 3, 6, 9, 12,24,36,60 months post-HSCT and at relapse using real-time quantitative polymerase chain reaction. Cumulative incidences of relapse (CIR) and non-relapse mortality were calculated using the Kalbfleisch and Prentice method. Leukemia-free survival (LFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared using the log-rank test. Factors at a level of P Results: On the basis of blasts phenotypes at diagnosis, subjects were stratified into CD34 + CD38 - CD58 - group (N=15) and other phenotype group (N=65). The demographic and clinical characteristics showed no significant difference between the two phenotype groups. Median follow-up was 25.5 mo (range, 6-65 mo) for all subjects and 33 mo (range, 6-65 mo) for survivors. During the MRD monitoring, significantly higher levels of BCR/ABL transcripts were detected in subjects in CD34 + CD38 - CD58 - group than persons in other phenotype group especially at 3 mo post-HSCT [0.12(0-152.4)% vs. 0(0-100)%, P =0.001]. Additionally, CD34 + CD38 - CD58 - LPCs phenotype directly correlated with higher 3-year CIR (63.2% [58.2-68.1%] vs . 5.3% [5.1-5.5%]; P vs . 78.7% [64.5-87.7%]; P =0.001) and OS (37.7% [12.6-63.2%] vs . 82.3% [68.5-90.4%]; P =0.0004). Multivariate analyses indicated that CD34 + CD38 - CD58 - LPCs phenotype at diagnosis and BCR-ABL reduction at 3 mo post-HSCT were independent risk factors for relapse, LFS and OS in adults with Ph + ALL underwent allo-HSCT. Summary/Conclusion: Our data suggest that a candidate CD34 + CD38 - CD58 - LPCs phenotype at diagnosis allows rapid identification of high-risk patients for relapse even after allo-HSCT. Risk-stratification post-HSCT therapy incorporating analysis of CD34 + CD38 - CD58 - LPCs phenotype at diagnosis promises to benefit the adults with Ph + ALL in the future. Acknowledgement: Supported by the National Natural Science Foundation of China (grant nos. 81370638&81230013), the Beijing Municipal Science and Technology Program (grant no. Z141100000214011), and Peking University People’s Hospital Research and Development Funds (grant no. RDB2012-23). Disclosures No relevant conflicts of interest to declare.

  • cd34 cd38 CD58 cells are leukemia propagating cells in philadelphia chromosome positive acute lymphoblastic leukemia
    Leukemia, 2014
    Co-Authors: Yuan Kong, Yingjun Chang, Yazhe Wang, Qian Jiang, Hao Jiang, Yazhen Qin, Yueyun Lai, Yong Liu, Caiwen Duan, Dengli Hong
    Abstract:

    CD34 + CD38 − CD58 − cells are leukemia-propagating cells in Philadelphia chromosome-positive acute lymphoblastic leukemia

  • CD58 negtive leukemia initiating cells are independently associated with high risk of relapse in b precursor acute lymphoblastic leukemia a comprehensive clinical and biological profiling study
    Blood, 2012
    Co-Authors: Yuan Kong, Yanrong Liu, Qian Jiang, Hao Jiang, Honghu Zhu, Daihong Liu, Guorui Ruan, Bin Jiang, Kaiyan Liu, Xiaojun Huang
    Abstract:

    Abstract 1397 Background: Using neonatal NOD/SCID/IL2rγ null xenotransplantation model, we previously demonstrated that CD34 + CD38 + CD19 + cells as well as CD34 + CD38 − CD19 + cells have the capacities to initiate B-precursor ALL (B-ALL) in vivo and to self-renew, that is, leukemia initiating cells(LICs) are enriched in the CD34 + CD19 + phenotype in human B-ALL (Kong Y et al. Leukemia 2008; 22: 1207–1213). Nevertheless, in order to distinguish B-ALL initiating cells from their normal compartment, further markers have to be identified. CD58 (lymphocyte function–associated antigen 3), a cell surface adhesion molecule binding to CD2, plays a critical role in the attachment of cytotoxic T lymphocytes and non-specific killer cells to their targets. Recent data give evidence that diffuse large B cell lymphoma patients with poor expression of CD58 appear to be more aggressive by escaping from immune-surveillance of the host. However, the prognostic relevance of CD58 expression on B-ALL initiating cells is largely unknown. Objectives: To investigate the expression profile of CD58 on CD34 + CD19 + B-ALL initiating cells. To evaluate the prognostic significance of CD58 expression on LICs in human B-precursor ALL. Materials and methods: Using a cohort of 139 patients (including pediatric and adult patients) with CD34 + B-ALL, the expression profile of CD58 on LICs(CD34 + CD19 + phenotype) were examined by multicolor flow cytometry (FCM) at diagnosis. A total of 1,050,000 events were routinely collected. More than 20% of LICs with CD58 expression were defined as CD58-positive LICs (CD34 + CD19 + CD58 + phenotype, abbreviated by CD58 + LICs), all other cases were defined as CD58-negtive LICs (CD34 + CD19 + CD58 − phenotype, abbreviated by CD58 − LICs). Furthermore, the impact of CD58 − LICs at diagnosis on the clinical outcome was prospectively investigated. The study was approved by the Ethics Committee of Peking University People9s Hospital and written informed consent was obtained from all subjects. Results: Among the newly diagnosed B-ALL patients, 119 cases were detected with CD58 + LICs and the remaining 20 cases with CD58 − LICs. The expression of CD58 on LICs at diagnosis was inversely related to the age, WBC at diagnosis and NCCN risk group of the B-ALL patients ( P =0.002, P =0.015 and P =0.009, respectively). CD58 + LICs group had a higher complete remission(CR) rate after one course induction than CD58 − LICs group (87.39% vs. 65.00%, P =0.019).Cumulative incidence of relapse (CIR) at 2-year in the CD58 + LICs group was significantly lower than that in the CD58 − LICs group (18.20% ± 0.15% vs. 72.00% ± 1.30%, P + LICs group resulted in superior survival compared to CD58 − LICs group (2-year disease-free survival(DFS), 77.95% ± 4.36% vs. 28.00% ± 10.58%, P P = 0.0016). Multivariate analysis revealed CD58 − LICs at diagnosis as independent risk factor affecting relapse (HR=3.413, P =0.001) and DFS (HR=2.857, P =0.004) in B-ALL patients. By summing up the risk factors(RF) defined as CD58 status on LICs (CD58 + LICs=0,CD58 − LICs=1),age( 1)could be discriminated, which differed significantly with regard to 2-year CIR(9.18%±0.14% vs. 49.94%±0.67%, P P P Conclusions: CD58-negtive leukemia initiating cells at diagnosis independently correlate with unfavorable prognosis. Combined analysis of CD58 status on CD34 + CD19 + leukemia initiating cells at diagnosis, age and NCCN risk group may help to optimize currently available prognostic stratification model in B-ALL. Acknowledgments: This work was supported by grants from National Natural Science Foundation of China (30800483) and Beijing Municipal Science and Technology Program (Z111107067311070). Disclosures: No relevant conflicts of interest to declare.

Yazhen Qin - One of the best experts on this subject based on the ideXlab platform.

  • cd38 CD58 is an independent adverse prognostic factor in paediatric philadelphia chromosome negative b cell acute lymphoblastic leukaemia patients
    Leukemia Research, 2016
    Co-Authors: Leping Zhang, Yazhe Wang, Yazhen Qin, Honghu Zhu, Yueyun Lai, Yuan Kong, Xiaojun Huang, Yan Chang, Yanrong Liu
    Abstract:

    To explore new risk predictors for a high risk of relapse in Philadelphia chromosome negative (Ph-) B cell acute lymphoblastic leukaemia (B-ALL) patients, 196 paediatric Ph- B-ALL patients (≤ 18 years) were retrospectively analysed. We mainly focus on investigating the prognostic value of CD38 and CD58 expression in leukemic blasts in these patients by four colour flow cytometry. The CD38+ CD58- group (n=16) had a higher relapse rate, a shorter 3-year event-free survival (EFS) and overall survival (OS) than the CD38+ CD58+ group (n=157; 31.3% vs 10.2%, P=0.04; 52.4% vs 92.3%, P<0.01; 32.5% vs 91.0%, P=0.01); CD38+ CD58- was an independent adverse prognostic predictor for relapse (hazard ratio [HR], 0.203; 95%CI, 0.063-0.656; P=0.01), 3-year EFS (HR, 0.091; 95%CI, 0.023-0.355; P<0.01) and OS (HR, 0.102; 95%CI, 0.026-0.3971; P<0.01) in this cohort, as determined by Cox multivariate analysis. We identified, for the first time, a higher risk population of paediatric Ph- B-ALL patients with CD38+ CD58- who had a higher relapse risk and a shorter survival. Our results may allow better risk stratification and individualized treatment.

  • presence of cd34 cd38 CD58 leukemia propagating cells at diagnosis identifies patients at high risk of relapse with ph chromosome positive all after allo hematopoietic sct
    Bone Marrow Transplantation, 2015
    Co-Authors: Yuan Kong, Yingjun Chang, Qian Jiang, Hao Jiang, Yazhen Qin, Yong Liu, Yuanwei Sun, Yangyuan Wang, Huan Chen, Xiaojun Huang
    Abstract:

    Relapse of Ph chromosome-positive ALL (Ph+ALL) results from the persistence of leukemia-propagating cells (LPCs). In Ph+ALL, a xenograft assay recently determined that LPCs are enriched in the CD34+CD38−CD58− fraction. Therefore, the prognostic significance of LPCs in Ph+ALL subjects after allogeneic hematopoietic SCT (allo-HSCT) was investigated. A total of 80 consecutive adults with Ph+ALL who underwent allo-HSCT were eligible. A multi-parameter flow cytometry analysis examining CD58–FITC/CD10–PE/ CD19–APC–Cy7/CD34–PerCP/CD45–Vioblue/ CD38–APC on gated leukemia BM blasts was performed at diagnosis. Based on the original blast phenotypes, subjects were stratified into the CD34+CD38−CD58−group (N=15) and other phenotype group (N=65). During minimal residual disease monitoring, significantly higher levels of BCR/ABL transcripts were detected in subjects in the CD34+CD38−CD58− group than in other phenotype group, especially at 3 months post HSCT. In addition, CD34+CD38−CD58−LPCs are directly correlated with a higher 3-year cumulative incidence of relapse (CIR) and worse leukemia-free survival (LFS) and OS. Multivariate analyses indicated that presence of CD34+CD38−CD58− LPCs at diagnosis, and BCR–ABL reduction at 3 months post HSCT were independent risk factors for relapse, LFS and OS. Our data suggest that presence of CD34+CD38−CD58− LPCs at diagnosis allows rapid identification of high-risk patients for relapse after allo-HSCT.

  • cd34 cd38 CD58 leukemia propagating cells at diagnosis could identify patients at high risk for relapse in philadelphia chromosome positive acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation
    Blood, 2014
    Co-Authors: Yuan Kong, Yingjun Chang, Yanrong Liu, Qian Jiang, Hao Jiang, Yazhen Qin, Huan Chen, Yuqian Sun, Yu Wang, Xiaojun Huang
    Abstract:

    Background: Relapse of Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph + ALL) may result from the persistence of leukemia stem cells sometimes termed leukemia-propagating cells (LPCs). We recently found that Ph + ALL LPCs are enriched in the CD34 + CD38 - CD58 - fraction using anti-CD122-conditioned NOD/SCID xenograft assay by intra-bone marrow injection, which translating to adverse clinical outcomes (Kong Y, et al. Leukemia 2014. accepted). Despite the widespread use of abelson tyrosine kinase inhibitors (TKIs) in Ph + ALL, allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the best curative option. However, whether the prognostic significance of the identified LPCs phenotype to identify patients at high risk for relapse could retain in Ph + ALL after allo-HSCT, if any, is unknown. Aims: To investigate the prognostic significance of the candidate CD34 + CD38 - CD58 - LPCs in Ph + ALL subjects underwent allo-HSCT. Methods: A total of 80 consecutive adults (18-60 years) with Ph + ALL underwent allo-HSCT were eligible for the study at Peking University Institute of Hematology from January 1, 2009 to December 31, 2013. Imatinib was routinely administered in subjects pre- and post-HSCT as previously reported. A multi-parameter flow cytometry analysis of CD58-FITC/CD10-PE/CD19-APC-Cy7/CD34-PerCP/CD45-Vioblue/ CD38-APC on gated leukemia blasts of bone marrow was performed at diagnosis. Furthermore, minimal residual disease (MRD) was monitored by BCR/ABL transcripts in bone marrow samples at diagnosis, directly before transplantation, as well as serially at 1, 2, 3, 6, 9, 12,24,36,60 months post-HSCT and at relapse using real-time quantitative polymerase chain reaction. Cumulative incidences of relapse (CIR) and non-relapse mortality were calculated using the Kalbfleisch and Prentice method. Leukemia-free survival (LFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared using the log-rank test. Factors at a level of P Results: On the basis of blasts phenotypes at diagnosis, subjects were stratified into CD34 + CD38 - CD58 - group (N=15) and other phenotype group (N=65). The demographic and clinical characteristics showed no significant difference between the two phenotype groups. Median follow-up was 25.5 mo (range, 6-65 mo) for all subjects and 33 mo (range, 6-65 mo) for survivors. During the MRD monitoring, significantly higher levels of BCR/ABL transcripts were detected in subjects in CD34 + CD38 - CD58 - group than persons in other phenotype group especially at 3 mo post-HSCT [0.12(0-152.4)% vs. 0(0-100)%, P =0.001]. Additionally, CD34 + CD38 - CD58 - LPCs phenotype directly correlated with higher 3-year CIR (63.2% [58.2-68.1%] vs . 5.3% [5.1-5.5%]; P vs . 78.7% [64.5-87.7%]; P =0.001) and OS (37.7% [12.6-63.2%] vs . 82.3% [68.5-90.4%]; P =0.0004). Multivariate analyses indicated that CD34 + CD38 - CD58 - LPCs phenotype at diagnosis and BCR-ABL reduction at 3 mo post-HSCT were independent risk factors for relapse, LFS and OS in adults with Ph + ALL underwent allo-HSCT. Summary/Conclusion: Our data suggest that a candidate CD34 + CD38 - CD58 - LPCs phenotype at diagnosis allows rapid identification of high-risk patients for relapse even after allo-HSCT. Risk-stratification post-HSCT therapy incorporating analysis of CD34 + CD38 - CD58 - LPCs phenotype at diagnosis promises to benefit the adults with Ph + ALL in the future. Acknowledgement: Supported by the National Natural Science Foundation of China (grant nos. 81370638&81230013), the Beijing Municipal Science and Technology Program (grant no. Z141100000214011), and Peking University People’s Hospital Research and Development Funds (grant no. RDB2012-23). Disclosures No relevant conflicts of interest to declare.

  • cd34 cd38 CD58 cells are leukemia propagating cells in philadelphia chromosome positive acute lymphoblastic leukemia
    Leukemia, 2014
    Co-Authors: Yuan Kong, Yingjun Chang, Yazhe Wang, Qian Jiang, Hao Jiang, Yazhen Qin, Yueyun Lai, Yong Liu, Caiwen Duan, Dengli Hong
    Abstract:

    CD34 + CD38 − CD58 − cells are leukemia-propagating cells in Philadelphia chromosome-positive acute lymphoblastic leukemia

  • cd34 cd38 CD58 candidate leukemia initiating cells are clinically relevant with the unfavorable prognosis in philadelphia chromosome positive acute lymphoblastic leukemia
    Blood, 2013
    Co-Authors: Yingjun Chang, Yanrong Liu, Yazhe Wang, Qian Jiang, Hao Jiang, Yazhen Qin, Jing Wang, Honghu Zhu, Yueyun Lai, Daihong Liu
    Abstract:

    ![Graphic][1] Background The prognosis of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) has been greatly improved in the modern era of imatinib. Nevertheless, relapse is still a major cause of treatment failure in human Ph+ALL. Leukemia-initiating cells (LICs) are presumed to be responsible for relapse in leukemia. Therefore, we conducted a study to identify the candidate LICs that are responsible for disease progression and its clinical significance in patients with Ph+ALL. Aims To investigate the leukemia-initiating and self-renewal capacities of CD34+CD38-CD58- cells and determine the prognostic significance of CD34+CD38-CD58- phenotype in patients with Ph+ALL treated in Peking University Institute of Hematology. Methods The leukemia-initiating potential and self-renewal capacity of the sorted CD34+CD38-CD58-, CD34+CD38-CD58+,CD34+CD38+CD58- and CD34+CD38+CD58+ compartments were investigated in vivo using sublethally irradiated and anti-mouse CD122 monoclonal antibody conditioned NOD/SCID mice by intra-bone marrow–injection. Furthermore, we prospectively analyzed whether the identified CD34+CD38-CD58- compartment at diagnosis correlates with minimal residual disease (MRD) after therapy and clinical outcomes in 63 adult patients (18-60 years) with de novo Ph+ALL. Results Xenotransplantation of the sorted CD34+CD38-CD58- cells led to a repopulation of human B-ALL in primary and secondary recipient mice, which were phenotypically and clonally derived from the original Ph+ALL patients analyzed by flow cytometry, as well as quantitative real-time RT-PCR and fluorescence in situ hybridization for leukemia-specific cytogenetic abnormalities. Furthermore, the candidate CD34+CD38-CD58- LICs phenotype at diagnosis (n=16) significantly correlated with a lower complete remission rate and higher MRD frequency monitored by BCR-ABL mRNA levels in BM of Ph+ALL patients. Additionally, it directly correlated with higher cumulative incidence of relapse (CIR, 60% ± 1.97% vs. 15.51% ± 0.30%, P =0.002) and unfavorable disease-free survival (DFS, 33.75%±12.64% vs. 71.31%±7.17%, P =0.009) at 3-year. The CD34+CD38-CD58- group exhibited a higher rate of BCR-ABL mutations conferring higher level imatinib resistance than the other group (43.75% vs. 17.02%, P =0.04). Multivariate analyses revealed that CD34+CD38-CD58- phenotype at diagnosis was an independent risk factor for relapse (HR=4.35, P =0.009) and DFS (HR=3.38, P =0.008) in adult Ph+ALL. Summary/Conclusion Both the xenotransplantation data as well as the clinical correlation studies show that CD34+CD38-CD58- compartment enrich for leukemia-initiating cells in adult Ph+ALL. CD34+CD38-CD58- phenotype at diagnosis independently correlates with an adverse prognosis, which promises to be an efficient tool for relapse prediction and risk-stratification treatment in adult Ph+ALL patients. Acknowledgments This work was supported by grants from National Natural Science Foundation of China (grants no. 30800483&81230013) and Beijing Municipal Science and Technology Program (grant no.Z111107067311070). Disclosures: No relevant conflicts of interest to declare. [1]: /embed/inline-graphic-2.gif

Ellis L. Reinherz - One of the best experts on this subject based on the ideXlab platform.

  • molecular interaction between CD58 and cd2 counter receptors mediates the ability of monocytes to augment t cell activation by il 12
    Journal of Immunology, 1996
    Co-Authors: Jared A Gollob, Ellis L. Reinherz, H Kawasaki, Jennifer Daley, Christopher Groves, Jerome Ritz
    Abstract:

    IL-12 stimulates both T and NK cells and is pivotal in the development of the Th1 immune response. In this work, we show that an interaction between CD2 and CD58 on activated T cells and monocytes, respectively, regulates the T cell response to IL-12. B cells provide little IL-12-specific costimulation, and this correlates with the low level of CD58 on B cells relative to monocytes and the lack of significant up-regulation in response to IFN-gamma or PHA activation. CHO cell transfectants expressing CD58 at a level comparable with that found on monocytes restore IL-12 responsiveness to APC-depleted T cells. This effect is not observed with CHO cells expressing CD48, a second CD2 ligand with a low avidity for CD2 relative to CD58. Thus, in addition to augmenting adhesion between T cells and their cognate APCs and facilitating TCR-triggered activation, the CD2-CD58 interaction uniquely optimizes the T cell response to IL-12.

  • interaction between human cd2 and CD58 involves the major beta sheet surface of each of their respective adhesion domains
    Journal of Experimental Medicine, 1994
    Co-Authors: Antonio R. N. Arulanandam, Alexander E Kister, M J Mcgregor, Daniel F Wyss, Gerhard Wagner, Ellis L. Reinherz
    Abstract:

    The CD58 binding site on human CD2 was recently shown by nuclear magnetic resonance structural data in conjunction with site-directed mutagenesis to be a highly charged surface area covering approximately 770A2 on the major AGFCC'C" face of the CD2 immunoglobulin-like (Ig-like) NH2-terminal domain. Here we have identified the other binding surface of the CD2-CD58 adhesion pair by mutating charged residues shared among CD2 ligands (human CD58, sheep CD58, and human CD48) that are predicted to be solvent exposed on a molecular model of the Ig-like adhesion domain of human CD58. This site includes beta strand residues along the C strand (E25, K29, and K30), in the middle of the C' strand (E37) and in the G strand (K87). In addition, several residues on the CC' loop (K32, D33, and K34) form this site. Thus, the interaction between CD2 and CD58 involves the major beta sheet surface of each adhesion domain. Possible docking orientations for the CD2-CD58 molecular complex are offered. Strict conservation of human and sheep CD58 residues within the involved C and C' strands and CC' loop suggests that this region is particularly important for stable formation of the CD2-CD58 complex. The analysis of this complex offers molecular insight into the nature of a receptor-ligand pair involving two Ig family members.

  • A soluble multimeric recombinant CD2 protein identifies CD48 as a low affinity ligand for human CD2: divergence of CD2 ligands during the evolution of humans and mice.
    The Journal of experimental medicine, 1993
    Co-Authors: Antonio R. N. Arulanandam, Philippe Moingeon, M. F. Concino, Michael A. Recny, K. Kato, H. Yagita, Shigeo Koyasu, Ellis L. Reinherz
    Abstract:

    To search for possible ligands of CD2 distinct from CD58 (lymphocyte function-associated antigen 3), we have produced a soluble pentameric CD2-immunoglobulin (Ig) fusion protein (spCD2) linking the 182-amino acid human CD2 extracellular segment with CH2-CH3-CH4 domains of human IgM heavy chain, thus enhancing the micromolar affinity of the CD2 monomer through multimeric interaction. Using quantitative immunofluorescence and standard stringency wash conditions, we observed that the binding of spCD2 to human B lymphoblastoid JY cells and red blood cells is virtually inhibited by anti-CD58 TS2/9 monoclonal antibody, even though these cells express levels of CD48 and CD59 comparable to CD58. Consistent with these results, spCD2 did not show any binding to Chinese hamster ovary (CHO) cells transfected with human CD48 or CD59. However, binding studies on CD48-, CD58-, or CD59-transfected CHO cells with spCD2 under low stringency wash conditions revealed that human CD48 is a low affinity ligand of human CD2 compared with CD58 (Kd approximately 10(-4) vs. approximately 10(-6) M, respectively). The findings are noteworthy given that in the murine system CD48 is the major ligand for CD2. No detectable binding was observed to CD59-transfected CHO cells despite a report suggesting that CD59 may bind to the human CD2 adhesion domain. Importantly, in cell-cell adhesion assays between CD2+ Jurkat T cells and CD48- or CD59-transfected CHO cells, there was no conjugate formation, whereas binding of Jurkat T cells to CD58-transfected CHO cells was readily detected. Collectively, our findings provide evidence for a conservation of the CD2-CD48 interaction in the human species that may be of limited, if any, functional significance. Given the importance of the CD2-CD48 interaction in the murine system and CD2-CD58 interaction in humans, it would appear that there has been a divergence of functional CD2 ligands during the evolution of humans and mice.