Immunologic potential of donor lymphocytes expressing a suicide gene for early immune reconstitution after hematopoietic T-cell–depleted stem cell transplantation.

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Immunologic potential of donor lymphocytes expressing a suicide gene for early immune reconstitution after hematopoietic T-cell–depleted stem cell transplantation by Sarah Marktel, Zulma Magnani, Fabio Ciceri, Sabrina Cazzaniga, Stanley R. Riddell, Catia Traversari, Claudio Bordignon, and Chiara Bonini Blood Volume 101(4):1290-1298 February 15, 2003 ©2003 by American Society of Hematology

Different activation signals such as PHA, anti-CD3, and anti-CD3 plus anti-CD28 antibodies result in similar transduction efficiency and identical level of transgene expression.(A) Autofluorescence of transduced cells stained with FITC-conjugated goat antim... Different activation signals such as PHA, anti-CD3, and anti-CD3 plus anti-CD28 antibodies result in similar transduction efficiency and identical level of transgene expression.(A) Autofluorescence of transduced cells stained with FITC-conjugated goat antimouse antibody. (B) Transduction efficiency measured by cytofluorometric analysis for ΔLNGFR expression after cell-free, supernatant-mediated transduction. (C) ΔLNGFR expression of the same subpopulation of lymphocytes after immune selection and 14-day culture from initial activation. Sarah Marktel et al. Blood 2003;101:1290-1298 ©2003 by American Society of Hematology

Activation, transduction, and selection procedures result mainly in IL-2 and IFN-γ–producing T cells, documenting a preferential skewing toward CD4+ TH1 and CD8+ TC1 phenotypes.Intracytoplasmic staining of RV cells for IFN-γ (FITC; x axes, all panels), IL-2... Activation, transduction, and selection procedures result mainly in IL-2 and IFN-γ–producing T cells, documenting a preferential skewing toward CD4+ TH1 and CD8+ TC1 phenotypes.Intracytoplasmic staining of RV cells for IFN-γ (FITC; x axes, all panels), IL-2 (PE; y axes, left panels), IL-4 (PE; y axes, central panels), and IL-10 (PE; y axes, right panels) is shown. Results were analyzed gating CD4+ (upper panels) and CD8+ (lower panels). Quadrant markers were positioned to include 95% of stained, unstimulated cells in the lower left square (upper panel of each series). Results from 1 of 3 representative experiments are shown. Sarah Marktel et al. Blood 2003;101:1290-1298 ©2003 by American Society of Hematology

CTLs specific for CMV pp65 are preserved in RV cells CTLs specific for CMV pp65 are preserved in RV cells.T cells specific for the immunodominant HLA-A0201–restricted pp65495-503 peptide derived from the matrix protein pp65 of CMV were detected by staining with a QR-conjugated CD8 and a PE-conjugated pp65 tet... CTLs specific for CMV pp65 are preserved in RV cells.T cells specific for the immunodominant HLA-A0201–restricted pp65495-503 peptide derived from the matrix protein pp65 of CMV were detected by staining with a QR-conjugated CD8 and a PE-conjugated pp65 tetramer followed by cytofluorometric analysis. Upper panels show the expression of ΔLNGFR in PBLs (upper left panel) and RV cells (upper right panel). Middle panels show FL-2 autofluorescence of cells stained with QR-conjugated CD8 antibody and FITC-ΔLNGFR antibody. Lower panels show the percentage of QR-CD8+/PE-pp65-tetramer+ T cells in PBLs. Sarah Marktel et al. Blood 2003;101:1290-1298 ©2003 by American Society of Hematology

RV cells are as efficient as PBLs in generating viral-specific cytotoxic effectors.PBLs (A) and RV cells (B) were stimulated against autologous irradiated EBV-LCL (triangles) or CMV-infected fibroblasts (circles and squares). RV cells are as efficient as PBLs in generating viral-specific cytotoxic effectors.PBLs (A) and RV cells (B) were stimulated against autologous irradiated EBV-LCL (triangles) or CMV-infected fibroblasts (circles and squares). Cytolytic activity was measured in a cold inhibition cytotoxic assay at different effector/target (E/T) ratios against the same targets (closed symbols). As negative control, cytolytic activity against autologous PHA-derived lymphocytes (experiments with EBV-LCL) and autologous noninfected fibroblasts (experiments with CMV) was measured (open symbols). (C) Specific lysis of PBLs (open symbols) and RV cells (closed symbols) stimulated with autologous irradiated CMV-infected fibroblasts against autologous EBV-LCL infected with rVV-pp150 (triangles), rVV-pp65 (squares), or rVV-pp72 (circles) is shown. Sarah Marktel et al. Blood 2003;101:1290-1298 ©2003 by American Society of Hematology

RV cells specific for a viral-derived peptide are as efficient as PBLs in proliferating and lysing cells pulsed with the peptide.(A) PBL CD8+ (open symbols) and RV CD8+ cells (closed symbols) were stimulated with the M58-66 Flu peptide and tested in a cold ... RV cells specific for a viral-derived peptide are as efficient as PBLs in proliferating and lysing cells pulsed with the peptide.(A) PBL CD8+ (open symbols) and RV CD8+ cells (closed symbols) were stimulated with the M58-66 Flu peptide and tested in a cold inhibition cytotoxic assay against T2 cells pulsed (triangle) or not (circle) with the same M58-66 peptide. The proportion of Vβ17 TCR on PBLs or RV CD8+ cells stimulated with autologous cells in the absence (C) or in the presence (D) of the M58-66 peptide is measured by cytofluorometric analysis. (B) Autofluorescence of PBLs and RV cells stained with FITC-conjugated goat antimouse antibody is shown. Results from 1 of 3 representative experiments are shown. Horizontal bars indicate % of Vβ17 in panels C and D and % GAM-FITC in panel B. Sarah Marktel et al. Blood 2003;101:1290-1298 ©2003 by American Society of Hematology

RV cells are as efficient as PBLs in generating antiallogeneic-specific cytotoxic effectors.PBLs (A) and RV cells (B) were stimulated against fully mismatched irradiated PBMCs. Cytolytic activity was measured in a cold inhibition cytotoxic assay at differen... RV cells are as efficient as PBLs in generating antiallogeneic-specific cytotoxic effectors.PBLs (A) and RV cells (B) were stimulated against fully mismatched irradiated PBMCs. Cytolytic activity was measured in a cold inhibition cytotoxic assay at different E/T ratios against PHA-derived lymphocytes from the same targets (closed symbols). As negative control, cytolytic activity against autologous PHA-derived lymphocytes (open symbols) was measured. Results from 3 experiments are shown. Sarah Marktel et al. Blood 2003;101:1290-1298 ©2003 by American Society of Hematology

Frequency of allospecific CTL precursors is affected by the culture time-span.(A) MLR of PBLs (squares), standard 14-day cultured RV cells (triangles), and 28-day cultured RV cells (circles; RV 28) against fully mismatched PBMCs was performed. Frequency of allospecific CTL precursors is affected by the culture time-span.(A) MLR of PBLs (squares), standard 14-day cultured RV cells (triangles), and 28-day cultured RV cells (circles; RV 28) against fully mismatched PBMCs was performed. After 1 round of in vitro stimulation, effector cells were tested against the same allogeneic target (closed symbols) and autologous PHA-derived lymphocytes (open symbols) in a standard cytotoxicity assay, performed in cold inhibition. The frequency of CD8+ T-cell precursors elicited in PBLs (B), RV cells (C), and RV 28 cells (D) with 1 round of stimulation with fully mismatched PBMCs was measured by stimulating the effectors in limiting dilution numbers and by performing a cytotoxic assay. Regression curves were interpolated, and precursor frequencies were determined according to Poisson statistics. Precursor frequencies are shown. Sarah Marktel et al. Blood 2003;101:1290-1298 ©2003 by American Society of Hematology

Ex vivo detection of circulating CD45RA+/ΔLNGFR+ T cells long term after infusion of genetically modified donor cells.Cytofluorometric analysis of PBLs derived from patient UPN-87 28 months after the last infusion of genetically modified donor lymphocytes. Ex vivo detection of circulating CD45RA+/ΔLNGFR+ T cells long term after infusion of genetically modified donor cells.Cytofluorometric analysis of PBLs derived from patient UPN-87 28 months after the last infusion of genetically modified donor lymphocytes. Cells were tested for the coexpression of CD45RA+-FITC /ΔLNGFR+-TC (A, right panel) and CD45RO+-PE/ΔLNGFR+-TC (B, right panel). Appropriate isotypic controls are shown in the left panels. Sarah Marktel et al. Blood 2003;101:1290-1298 ©2003 by American Society of Hematology