The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Hinrich Abken - One of the best experts on this subject based on the ideXlab platform.
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arming cytokine induced killer cells with chimeric antigen receptors cd28 outperforms combined cd28 ox40 super stimulation
Molecular Therapy, 2013Co-Authors: Andreas Hombach, Gunter Rappl, Hinrich AbkenAbstract:Cytokine-induced killer (CIK) cells raised interest for use in cellular antitumor therapy due to their capability to recognize and destroy autologous tumor cells in a HLA-independent fashion. The antitumor attack of CIK cells, predominantly consisting of terminally differentiated CD8+CD56+ cells, can be improved by redirecting by a chimeric antigen receptor (CAR) that recognizes the tumor cell and triggers CIK cell activation. The requirements for CIK cell activation were, however, so far less explored and are likely to be different from those of “younger” T cells. We revealed that CD28 and OX40 CARs produced higher interferon- secretion as compared with the first-generation ζ-CAR; CD28-ζ and the third-generation CD28-ζ–OX40 CAR, however, performed similar in modulating most CIK cell effector functions. Compared with the CD28-ζ CAR, however, the CD28-ζ–OX40 CAR accelerated terminal maturation of CD56+ CIK cells producing high frequencies in activation-induced cell death (AICD) and reduced antitumor efficiency in vivo. Consequently, CD28-ζ CAR CIK cells of CD56− phenotype were superior in redirected tumor cell elimination. CAR-mediated CIK cell activation also increased antigen-independent target cell lysis; the CD28-ζ CAR was more efficient than the CD28-ζ–OX40 CAR. Translated into therapeutic strategies, CAR-redirected CIK cells benefit from CD28 costimulation; “super-costimulation” by the CD28-ζ–OX40 CAR, however, performed less in antitumor efficacy due to increased AICD.
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tumor specific t cell activation by recombinant immunoreceptors cd3 zeta signaling and cd28 costimulation are simultaneously required for efficient il 2 secretion and can be integrated into one combined cd28 cd3 zeta signaling receptor molecule
Journal of Immunology, 2001Co-Authors: Andreas Hombach, Anja Wieczarkowiecz, Thomas Marquardt, Claudia Heuser, Loretta Usai, C Pohl, Barbara Seliger, Hinrich AbkenAbstract:Recombinant immunoreceptors with specificity for the carcinoembryonic Ag (CEA) can redirect grafted T cells to a MHC/Ag-independent antitumor response. To analyze receptor-mediated cellular activation in the context of CD28 costimulation, we generated: 1) CEA + colorectal tumor cells that express simultaneously B7-1 and B7-2, and 2) CEA-specific immunoreceptors that harbor intracellularly the signaling moities either of CD28 (BW431/26-scFv-Fc-CD28), CD3ζ (BW431/26-scFv-Fc-CD3ζ), or FceRIγ (BW431/26-scFv-Fc-γ). By retroviral gene transfer, we grafted activated T cells from the peripheral blood with these immunoreceptors. T cells that express the FceRIγ or CD3ζ signaling receptor lysed specifically CEA + tumor cells and secreted high amounts of IFN-γ upon receptor cross-linking, whereas anti-CEA-CD28 receptor-grafted T cells did not, indicating that CD28 signaling alone is not sufficient for efficient T cell activation. CD28 costimulation did not affect cytolysis by T cells equipped with γ- or ζ-signaling receptors, but enhanced both IFN-γ secretion and proliferation. CD28 costimulation, however, was required for efficient IL-2 secretion of anti-CEA-γ receptor-grafted T cells. Both purified CD4 + and CD8 + T cells grafted with immunoreceptors required CD28 costimulation for complete T cell activation. We integrated both CD28 and CD3ζ signaling domains into one combined immunoreceptor molecule (BW431/26-scFv-Fc-CD28/CD3ζ) with dual signaling properties. T cells grafted with the combined CD28/CD3ζ signaling receptor secreted high amounts of IL-2 upon Ag binding without exogenous B7/CD28 costimulation, demonstrating that both MHC-independent cellular activation and CD28 costimulation for complete T cell activation can be delivered by one recombinant receptor molecule.
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t cell activation by recombinant receptors cd28 costimulation is required for interleukin 2 secretion and receptor mediated t cell proliferation but does not affect receptor mediated target cell lysis
Cancer Research, 2001Co-Authors: Andreas Hombach, Claudia Heuser, C Pohl, Barbara Seliger, Dagmar Sent, Claudia Schneider, Dimitra Koch, Hinrich AbkenAbstract:Recombinant T-cell receptors with antibody-like specificity are successfully used to direct CTLs toward a MHC-independent immune response against target cells. Here we monitored the specific activation of receptor grafted CTLs in the context of CD28 costimulation. Peripheral blood T cells were retrovirally engrafted with recombinant anti-CD30 and anti-carcinoembryonic antigen receptors, respectively, that harbor either the FceRI-γ or the CD3-ζ intracellular signaling domain. Cross-linking of recombinant receptors by solid-phase bound ligand, i.e., CD30 and a carcinoembryonic antigen receptor-specific anti-idiotypic antibody, respectively, induces IFN-γ secretion that is further enhanced by CD28 costimulation of grafted T cells. Induction of interleukin (IL)-2 secretion, in contrast, requires CD28 costimulation in addition to receptor cross-linking, irrespective of T-cell preactivation by anti-CD3 monoclonal antibody plus IL-2 or by anti-CD3 monoclonal antibody plus anti-CD28 monoclonal antibody. Accordingly, induction of IL-2 secretion upon receptor cross-linking by membrane-bound antigen requires CD28/B7 costimulation whereas IFN-γ secretion and cell proliferation does not. The efficiency of cytolysis by receptor-grafted CTLs does not depend on and is not affected by CD28 costimulation. The data demonstrate that CTL proliferation, cytokine secretion, and cytolysis upon receptor cross-linking are differentially modulated by CD28 costimulation and that cytolysis does not require B7 expression on target cells.
Masakazu Kobayashi - One of the best experts on this subject based on the ideXlab platform.
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a blocking anti cd28 specific antibody induces long term heart allograft survival by suppression of the pkc theta jnk signal pathway
Transplantation, 2008Co-Authors: Mei Shiang Jang, Laurie Erickson, Ogert Fisniku, Gladys Crews, C Wynn, In Chul Hong, K Tamura, Masakazu KobayashiAbstract:Abstract This study investigated the effects of a blocking anti-CD28 antibody (Anti-CD28-PV1-IgG3) in vitro and in vivo. Anti-CD28-PV1-IgG3, a hamster-mouse chimeric antibody against murine CD28, which does not provide CD28-positive signaling during TCR-driven T cell activation, enabled long-term survival of heart allografts across a complete mismatch of the MHC in rats. Among the T cell signaling proteins tested in the spleens from recipients, we found that recipients treated with anti-CD28-PV1-IgG3 exhibited suppression of alloantigen-initiated proximal TCR signaling events, including Lck, Zap70, Vav, and PI3K expression, and their PKC theta- and JNK-regulated expression/activation. This leads to attenuation of intragraft T cell infiltration and expression of T cell effector molecules. These results indicate that targeting the CD28 receptor with a blocking antibody leads to long-term allograft survival by reducing activation of alloantigen-mediated key signaling events in T cells that might be crucial for full T cell activation.
Carl H. June - One of the best experts on this subject based on the ideXlab platform.
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critical requirement for the membrane proximal cytosolic tyrosine residue for cd28 mediated costimulation in vivo
Journal of Immunology, 2001Co-Authors: Yohsuke Harada, Miyoko Tokushima, Masataka Otsuka, Bonnie D Weiss, Katsuhiko Hayashi, Yasuyo Matsumoto, Shuhei Ogawa, Carl H. JuneAbstract:The YMNM motif that exists in the CD28 cytoplasmic domain is known as a binding site for phosphatidylinositol 3-kinase and Grb-2 and is considered to be important for CD28-mediated costimulation. To address the role of the YMNM motif in CD28 cosignaling in primary T cells, we generated transgenic mice on a CD28 null background that express a CD28 mutant lacking binding ability to phosphatidylinositol 3-kinase and Grb-2. After anti-CD3 and anti-CD28 Ab stimulation in vitro, the initial proliferative response and IL-2 secretion in CD28 Y189F transgenic T cells were severely compromised, while later responses were intact. In contrast to anti-CD3 and anti-CD28 Ab stimulation, PMA and anti-CD28 Ab stimulation failed to induce IL-2 production from CD28 Y189F transgenic T cells at any time point. Using the graft-vs-host reaction system, we assessed the role of the YMNM motif for CD28-mediated costimulation in vivo and found that CD28 Y189F transgenic spleen cells failed to engraft and could not induce acute graft-vs-host reaction. Together, these results suggest that the membrane-proximal tyrosine of CD28 is required for costimulation in vivo. Furthermore, these results indicate that the results from in vitro assays of CD28-mediated costimulation may not always correlate with T cell activation in vivo.
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cd28 costimulation can promote t cell survival by enhancing the expression of bcl xl
Immunity, 1995Co-Authors: Lawrence H Boise, Andy J Minn, Patricia J Noel, Mary Ann Accavitti, Carl H. June, Tullia Lindsten, Craig B. ThompsonAbstract:Abstract T cell activation through the TCR can result in either cell proliferation or cell death. The role of costimulatory receptors i n regulating T cell survival has not been defined. Here, we present data demonstrating that CD28 costimulation enhances the in vitro survival of activated T cells. One mechanism for this enhancement is the ability of CD28 costimulation to augment the production of IL-2, which acts as an extrinsic survival factor for T cells. In addition, CD28 costimulation augments the intrinsic ability of T cells to resist apoptosis. Although CD28 signal transduction had no effect on Bcl-2 expression, CD28 costimulation was found to augment the expression of BCI-x L substantially. Transfection experiments demonstrated that this level of Bcl-x L could prevent T cell death in response to TCR cross-linking, Fas cross-linking, or IL-2 withdrawal. These data suggest that an important role of CD28 costimulation is to augment T cell survival during antigen activation.
V. Wahn - One of the best experts on this subject based on the ideXlab platform.
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Treatment-Resistant Expansion of CD8+CD28− Cells in Pediatric HIV Infection
Pediatric Research, 2000Co-Authors: T Niehues, Gerd Horneff, Sabine Knipp, Ortwin Adams, V. WahnAbstract:There is a disease stage–dependent loss of CD28 expression on T cells in HIV-infected children. In this study, T cell recovery, in particular CD28 expression on T cells, was analyzed after initiation of highly active antiretroviral therapy in a group of eight mostly treatment-naive HIV-infected children. Plasma HIV-RNA levels were recorded, and numbers of CD4, CD8, CD4+CD28+, and CD8+CD28+ cells were determined by two-color flow cytometry. Values after 12 mo of therapy were compared with age-matched, seronegative control subjects. CD4 recovery to subnormal values was observed in all children. CD8+CD28+ cells recovered and were within the normal range after 12 mo of therapy (patients, 703 ± 250 cells/μL; controls, 789 ± 269 cells/μL), whereas CD8+CD28− cells (546 ± 269 cells/μL) remained significantly expanded compared with age-matched controls (140 ± 35 cells/μL). Expansions of CD8+CD28− cells persisted even in cases with long-term suppression of viral replication. Highly active antiretroviral therapy in HIV-infected children induces substantial but incomplete T cell recovery.
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CD28 Expression in Pediatric Human Immunodeficiency Virus Infection
Pediatric Research, 1998Co-Authors: T Niehues, Jennifer Ndagijimana, Gerd Horneff, V. WahnAbstract:Increased apoptosis of lymphocytes represents a key event of immune destruction in HIV infection. In this study it was investigated at which stage of the disease and in which T lymphocyte subpopulation (CD4^+ or CD8^+) protection against apoptosis may be lost as measured by decreased CD28 expression. In 26 HIV-infected and 20 healthy children, as well as 10 infants exposed to HIV, expression of CD28 and the apoptosis-related marker CD95 was studied by fluorescence-activated cell sorting analysis. According to established Centers for Disease Control and Prevention definitions, children were divided into three immunologic categories. In the CD8 population, patients in category 1 already showed a markedly decreased mean CD28 (36.2% ± 16.1 SD) and increased CD95 expression (48.8 ± 24.1%), compared with the age-matched control group(67.7 ± 14.4%, 15.8 ± 8.9%). In the CD4 population, mean CD28 and CD95 expression was not altered in category 1 patients. Of the exposed children, the child with the lowest CD28 expression on CD8 cells was determined later to be infected with HIV. Significant immunophenotypical alterations are observed in early stage pediatric HIV infection, which may indicate an early loss of protection against apoptosis in the CD8^+ T cell population.
Graham Pawelec - One of the best experts on this subject based on the ideXlab platform.
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infection with cytomegalovirus but not herpes simplex virus induces the accumulation of late differentiated cd4 and cd8 t cells in humans
Journal of General Virology, 2011Co-Authors: Evelyna Derhovanessian, Andrea B Maier, Karin Hahnel, Robert Beck, Anton J M De Craen, Eline Slagboom, Rudi G J Westendorp, Graham PawelecAbstract:Human cytomegalovirus (CMV) establishes persistent, usually asymptomatic, infection in healthy people. Because CMV infection is associated with the presence of lower proportions of peripheral naive CD8+ T-cells and a higher fraction of late-differentiated CD8+ cells, commonly taken as biomarkers of age-associated compromised adaptive immunity (‘immunosenescence’), we asked whether chronic exposure to any persistent virus mediates these effects. Herpes simplex virus (HSV) is also a widespread herpesvirus that establishes lifelong persistence, but, unlike CMV, its impact on the distribution of T-cell subsets has not been established. Here, we analysed T-cell subsets in 93 healthy people aged 42–81 years infected or not infected with CMV and/or HSV. Individuals harbouring CMV were confirmed to possess lower frequencies of naive CD8+ T-cells (defined as CD45RA+CCR7+CD27+CD28+) and greater proportions of late-differentiated effector memory (CD45RA−CCR7−CD27−CD28−) and so-called TEMRA (CD45RA+CCR7−CD27−CD28−) CD4 and CD8 subsets, independent of HSV seropositivity. In CMV-seronegative donors, HSV did not affect T-cell subset distribution significantly. We conclude that these hallmarks of age-associated alterations to immune signatures are indeed observed in the general population in people infected with CMV and not those infected with a different persistent herpesvirus.
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Multiparameter flow cytometric analysis of CD4 and CD8 T cell subsets in young and old people.
Immunity & ageing : I & A, 2008Co-Authors: Sven Koch, Dennis Ozcelik, Elena Naumova, Anis Larbi, Evelyna Derhovanessian, Graham PawelecAbstract:BACKGROUND T cell-mediated immunity in elderly people is compromised in ways reflected in the composition of the peripheral T cell pool. The advent of polychromatic flow cytometry has made analysis of cell subsets feasible in unprecedented detail. RESULTS Here we document shifts in subset distribution within naïve (N), central memory (CM) and effector memory (EM) cells defined by CD45RA and CCR7 expression in the elderly, additionally using the costimulatory receptors CD27 and CD28, as well as the coinhibitory receptors CD57 and KLRG-1, to further dissect these. Although differences between young and old were more marked in CD8 than in CD4 cells, a similar overall pattern prevailed in both. Thus, the use of all these markers together, and inclusion of assays of proliferation and cytokine secretion, may enable the construction of a differentiation scheme applicable to CD4 as well as CD8 cells, with the model (based on Romero et al.) suggesting the progression N-->CM-->EM1-->EM2-->pE1-->pE2-->EM4-->EM3-->E end-stage non-proliferative effector cells. CONCLUSION Overall, the results suggest that both differences in subset distribution and differences between subsets are responsible for age-related changes in CD8 cells but that differences within rather than between subsets are more prominent for CD4 cells.