Journal articles: 'Murine T Cells'

1

Gaur, Amitabh. "Cloning of Murine T Cells." Methods 9, no. 3 (June 1996): 411–15. http://dx.doi.org/10.1006/meth.1996.0046.

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Sato, Katsuaki, Naohide Yamashita, Masanori Baba, and Takami Matsuyama. "Modified myeloid dendritic cells act as regulatory dendritic cells to induce anergic and regulatory T cells." Blood 101, no. 9 (May 1, 2003): 3581–89. http://dx.doi.org/10.1182/blood-2002-09-2712.

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To exploit a novel strategy to regulate T cell–mediated immunity, we established human and murine modified dendritic cells (DCs) with potent immunoregulatory properties (designed as regulatory DCs), which displayed moderately high expression levels of major histocompatibility complex (MHC) molecules and extremely low levels of costimulatory molecules compared with their normal counterparts. Unlike human normal DCs, which caused the activation of allogeneic CD4+ and CD8+ T cells, human regulatory DCs not only induced their anergic state but also generated CD4+ or CD8+regulatory T (Tr) cells from their respective naive subsets in vitro. Although murine normal DCs activated human xenoreactive T cells in vitro, murine regulatory DCs induced their hyporesponsiveness. Furthermore, transplantation of the primed human T cells with murine normal DCs into severe combined immunodeficient (SCID) mice enhanced the lethality caused by xenogeneic graft-versus-host disease (XGVHD), whereas transplantation of the primed human T cells with murine regulatory DCs impaired their ability to cause XGVHD. In addition, a single injection of murine regulatory DCs following xenogeneic or allogeneic transplantation protected the recipients from the lethality caused by XGVHD as well as allogeneic acute GVHD. Thus, the modulation of T cell–mediated immunity by regulatory DCs provides a novel therapeutic approach for immunopathogenic diseases.

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Craft, Joe, Stanford Peng, Takao Fujii, Masato Okada, and Saeed Fatenejad. "Autoreactive T cells in murine lupus." Immunologic Research 19, no. 2-3 (June 1999): 245–57. http://dx.doi.org/10.1007/bf02786492.

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4

Adkins, Becky, and Mehdi Nassiri. "Apoptosis of Murine Neonatal T Cells." International Reviews of Immunology 18, no. 5-6 (January 1999): 465–84. http://dx.doi.org/10.3109/08830189909088494.

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Mally, Martin I., Marguerite Vogt, Susan E. Swiftt, and Martin Haas. "Oncogene expression in murine splenic T cells and in murine T-Cell neoplasms." Virology 144, no. 1 (July 1985): 115–26. http://dx.doi.org/10.1016/0042-6822(85)90310-1.

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6

Hayakawa, K., and R. R. Hardy. "Murine CD4+ T cell subsets defined." Journal of Experimental Medicine 168, no. 5 (November 1, 1988): 1825–38. http://dx.doi.org/10.1084/jem.168.5.1825.

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We have used two monoclonal anti-murine T cell autoantibodies (SM3G11 and SM6C10) and multi-color immunofluorescence staining to resolve splenic CD4+ cells into four populations. Two of these populations (Fr. I and Fr. III, 35% and 10% of CD4+ cells) show mutually exclusive expression of these determinants and exhibit distinct functions. Fr. III secretes IL-4, but not IL-2 when activated by Con A, and includes memory T cells responsible for secondary antibody formation. In contrast, Fr. I secretes IL-2 but not IL-4 in response to Con A, and does not contribute to the secondary antibody response. Furthermore, these two fractions exhibit differential accessory cell dependence. Whereas Fr. III responds with B cells (and also non-B cells) as accessory cells in Con A-induced activation, Fr. I requires non-B cells. However, we found that many CD4+ cells (Fr. II, 40% of CD4+ cells) express both determinants and are not distinguishable with regard to lymphokine secretion, accessory cell effect, and memory T cell activity. Curiously, the fraction expressing neither determinant (Fr. IV, 10% of CD4+ cells) is unresponsive to experimental conditions used here. We discuss the possible relationships between these T cell subsets and the implications of differential expression of these determinants.

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7

Lucas, P. J., C. V. Bare, and R. E. Gress. "The human anti-murine xenogeneic cytotoxic response. II. Activated murine antigen-presenting cells directly stimulate human T helper cells." Journal of Immunology 154, no. 8 (April 15, 1995): 3761–70. http://dx.doi.org/10.4049/jimmunol.154.8.3761.

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Abstract Generation of a human T cell anti-murine xenogeneic response has previously been shown to be dependent on presentation of murine Ag by human APC. We have undertaken a series of experiments to better delineate the cellular defects that prevent effective production of IL-2 by human T cells upon direct exposure to murine stimulator populations. It was found that although resting human T cells cannot respond effectively to resting murine APC, they can respond to activated murine stimulator populations. Such APC activation could be mediated by murine granulocyte-macrophage-CSF or LPS that were associated with increased expression of B7-2 on the xenogeneic stimulating cell populations. Blocking studies with Ab provided further evidence that costimulation through CD28 played a critical role in the stimulation of human T cells by activated murine-stimulator cells in the production of IL-2. These results demonstrate the usefulness of this xenogeneic system in understanding human T cell-APC interactions and defining minimally sufficient T cell activation requirements. They further delineate the cellular level of deficient activation in the xenogeneic stimulation of human T cells by murine cell populations, and identify the potential importance of CD28/CTLA4 and its ligands in xenogeneic responses. These observations and concepts have implications for clinical efforts in xenografting.

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Baars, Paul A, Sophie Sierro, Ramon Arens, Kiki Tesselaar, Berend Hooibrink, Paul Klenerman, and René A W. van Lier. "Properties of murine CD8+CD27- T cells." European Journal of Immunology 35, no. 11 (November 2005): 3131–41. http://dx.doi.org/10.1002/eji.200425770.

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9

Du, Jing, Katelyn Paz, Govindarajan Thangavelu, Dominik Schneidawind, Jeanette Baker, Ryan Flynn, Omar Duramad, et al. "Invariant natural killer T cells ameliorate murine chronic GVHD by expanding donor regulatory T cells." Blood 129, no. 23 (June 8, 2017): 3121–25. http://dx.doi.org/10.1182/blood-2016-11-752444.

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Algood, Holly M. Scott, Victor J. Torres, Derya Unutmaz, and Timothy L. Cover. "Resistance of Primary Murine CD4+ T Cells to Helicobacter pylori Vacuolating Cytotoxin." Infection and Immunity 75, no. 1 (October 30, 2006): 334–41. http://dx.doi.org/10.1128/iai.01063-06.

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ABSTRACT Persistent colonization of the human stomach by Helicobacter pylori is a risk factor for the development of gastric cancer and peptic ulcer disease. H. pylori secretes a toxin, VacA, that targets human gastric epithelial cells and T lymphocytes and enhances the ability of H. pylori to colonize the stomach in a mouse model. To examine how VacA contributes to H. pylori colonization of the mouse stomach, we investigated whether murine T lymphocytes were susceptible to VacA activity. VacA inhibited interleukin-2 (IL-2) production by a murine T-cell line (LBRM-33), similar to its effects on a human T-cell line (Jurkat), but did not inhibit IL-2 production by primary murine splenocytes or CD4+ T cells. VacA inhibited activation-induced proliferation of primary human CD4+ T cells but did not inhibit the proliferation of primary murine CD4+ T cells. Flow cytometry studies indicated that the levels of VacA binding to primary murine CD4+ T cells were significantly lower than levels of VacA binding to human CD4+ T cells. This suggests that the resistance of primary murine CD4+ T cells to VacA is attributable, at least in part, to impaired VacA binding to these cells.

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11

Balasubramaniam, Vivek, and Pierette M. Appasamy. "Development of murine pre-T cells into γδ T-cell receptor bearing cells." Developmental & Comparative Immunology 18, no. 3 (May 1994): 179–91. http://dx.doi.org/10.1016/0145-305x(94)90010-8.

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12

Baumann, Jörg G., Derya Unutmaz, Michael D. Miller, Sabine K. J. Breun, Stacy M. Grill, Jane Mirro, Dan R. Littman, Alan Rein, and Vineet N. KewalRamani. "Murine T Cells Potently Restrict Human Immunodeficiency Virus Infection." Journal of Virology 78, no. 22 (November 15, 2004): 12537–47. http://dx.doi.org/10.1128/jvi.78.22.12537-12547.2004.

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ABSTRACT Development of a mouse model for human immunodeficiency virus type 1 (HIV-1) infection has advanced through the progressive identification of host cell factors required for HIV-1 replication. Murine cells lack HIV-1 receptor molecules, do not support efficient viral gene expression, and lack factors necessary for the assembly and release of virions. Many of these blocks have been described using mouse fibroblast cell lines. Here we identify a postentry block to HIV-1 infection in mouse T-cell lines that has not been detected in mouse fibroblasts. While murine fibroblastic lines are comparable to human T-cell lines in permissivity to HIV-1 transduction, infection of murine T cells is 100-fold less efficient. Virus entry occurs efficiently in murine T cells. However, reduced efficiency of the completion of reverse transcription and nuclear transfer of the viral preintegration complex are observed. Although this block has similarities to the restriction of murine retroviruses by Fv1, there is no correlation of HIV-1 susceptibility with cellular Fv1 genotypes. In addition, the block to HIV-1 infection in murine T-cell lines cannot be saturated by a high virus dose. Further studies of this newly identified block may lend insight into the early events of retroviral replication and reveal new targets for antiretroviral interventions.

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Hiwarkar, Prashant, Waseem Qasim, Ida Ricciardelli, Kimberly Gilmour, Sergio Quezada, Aurore Saudemont, Persis Amrolia, and Paul Veys. "Cord blood T cells mediate enhanced antitumor effects compared with adult peripheral blood T cells." Blood 126, no. 26 (December 24, 2015): 2882–91. http://dx.doi.org/10.1182/blood-2015-06-654780.

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Key Points CB T cells mediate enhanced antitumor responses compared with PB T cells in a murine model of B-cell lymphoma. The antitumor activity correlates with increased tumor-homing of CCR7high CB CD8+ T cells and rapid gain of cytotoxic and Th1 function.

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14

Lontos, Konstantinos, Yiyang Wang, Andrew Frisch, Mason Colbert, Jason Lohmueller, and Greg M. Delgoffe. "89723 CD105-targeted CAR T cells for the treatment of acute myeloid leukemia." Journal of Clinical and Translational Science 5, s1 (March 2021): 18. http://dx.doi.org/10.1017/cts.2021.450.

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ABSTRACT IMPACT: Our work might lead to a new treatment for patients with acute myeloid leukemia OBJECTIVES/GOALS: Acute myeloid leukemia (AML) is a devastating hematologic malignancy, with dismal 5-year survival. Chimeric antigen receptor (CAR) T cells have been approved for B cell malignancies but not for AML. The goal of this study is to explore the safety and efficacy of CAR T cells targeting CD105 (endoglin) to treat AML. METHODS/STUDY POPULATION: We have constructed human and murine CAR T cells targeting CD105. The CARs were created by sequencing the V(D)J regions of hybridomas and designing single chain variable fragments that target CD105 which were subsequently introduced in a CAR backbone via Gibson assembly. The CAR T cells were produced via transduction using retrovirus or lentivirus. Leukemia cell lines were assessed for CD105 expression with flow cytometry. Killing assays were performed via measurement of luminescence of target cells after co-culture with CAR T cells. Activation assays were performed with co-culture of CAR T cells and target cells and measurement of activation markers with flow cytometry. To assess in vivo efficacy and safety, murine CAR T cells were infused into C57BL/6J mice carrying B16 melanoma after lymphodepletion. RESULTS/ANTICIPATED RESULTS: All human leukemia cell lines assessed (Nalm6, MOLM-14, MV4-11, Kasumi-1, THP-1) expressed some degree of endoglin apart from the T cell leukemia Jurkat. Human CD105 CAR T cells were activated by co-culture with leukemia cell lines and effectively killed leukemia cells in vitro in a CD105-specific manner. Murine CAR T cells killed efficiently both murine solid tumors (B16 melanoma) and murine leukemias (C1498) in vitro. Murine CAR T cells did not exhibit any toxicity when infused after low-dose lymphodepletion (cyclophosphamide 100mg/kg) but caused significant morbidity after higher doses (cyclophosphamide 200mg/kg). Murine CAR T cells delayed the growth of B16 melanoma in immunocompetent mice. DISCUSSION/SIGNIFICANCE OF FINDINGS: We have constructed human and murine CD105 CAR T cells with excellent activity in vitro. The activity of human CD105 CAR T cells in xenografts and the biologic relevance of the toxicity of murine CD105 CAR T cells in humans needs to be further investigated. CD105 CAR T cells might prove an important therapeutic option for patients with AML.

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15

Hedrick, J. A., V. Saylor, D. Figueroa, L. Mizoue, Y. Xu, S. Menon, J. Abrams, T. Handel, and A. Zlotnik. "Lymphotactin is produced by NK cells and attracts both NK cells and T cells in vivo." Journal of Immunology 158, no. 4 (February 15, 1997): 1533–40. http://dx.doi.org/10.4049/jimmunol.158.4.1533.

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Abstract Injection of lymphotactin (Lptn) into the peritoneum caused an influx of lymphocytes at 24 h. Phenotypic analysis of the cellular influx showed that a large proportion of these cells were T lymphocytes; however, a large number of NK cells was also present. This effect of murine Lptn (mLptn) was specific since the cellular influx was blocked with a mLptn-specific mAb. Similar results were observed when Lptn was injected s.c. and the tissue was analyzed by immunohistochemistry using an anti-CD3epsilon mAb. Microchemotaxis assays confirmed that murine NK cells respond to mLptn, and also showed human NK clones to be similarly responsive to recombinant human Lptn (rhLptn). Immunohistochemical analysis of IL-2-activated murine NK cells and Northern analysis of human NK clones revealed that these cells also produce Lptn, suggesting that a self-regulatory migration mechanism exists in NK cells. Together these data confirm, in vivo, the lymphocyte specificity of Lptn previously observed in vitro and extend its chemotactic effects to the NK cell lineage. We also investigated the functional consequences of truncating the carboxyl terminus of hLptn. This truncated molecule (which is missing the carboxyl-terminal 22 amino acids of hLptn) had no detectable activity on human PBLs. In addition, while hLptn was found to attract murine splenocytes in vitro, the carboxyl-terminal truncated hLptn was again inactive on murine splenocytes. This observation indicates the presence of structural features in the carboxyl terminus of Lptn that are necessary for its biologic activity.

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16

Behar, Samuel M., T. A. Podrebarac, C. J. Roy, C. R. Wang, and M. B. Brenner. "Diverse TCRs Recognize Murine CD1." Journal of Immunology 162, no. 1 (January 1, 1999): 161–67. http://dx.doi.org/10.4049/jimmunol.162.1.161.

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Abstract Human and murine T cells that specifically recognize CD1d and produce IL-4 and IFN-γ play a role in immunoregulation and tumor rejection. In the mouse, most CD1d1-reactive T cells described express an invariant Vα14-Jα281 TCR associated with TCR β-chains of limited diversity. Similarly, human CD1d-reactive T cells express a highly restricted TCR repertoire. Here we report the unexpected result that in mice immunized with CD1d1-bearing transfectant cells, a diverse repertoire of TCRs was expressed by CD1d1-reactive T cell clones isolated by limiting dilution without preselection for NK1 expression. Only 3 of 10 CD1d1-reactive T cell clones expressed the invariant Vα14-Jα281 TCRα rearrangement. T cells expressing Vα10, -11, -15, and -17, and having non-germline-encoded nucleotides resulting in diverse V-J junctions were identified. Like CD1d1-reactive T cells expressing the invariant Vα14-Jα281 TCR α-chain, CD1d1-reactive clones with diverse TCRs produced both Type 1 (IFN-γ) and Type 2 (IL-4, IL-10) cytokines. This establishes the existence of significant diversity in the TCRs directly reactive to the CD1d1 protein. Our findings reveal that CD1d interacts with a broad array of TCRs, suggesting substantial redundancy and flexibility of the immune system in providing T cells serving the role(s) mediated by CD1d reactivity.

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Freeman, G. J., G. S. Gray, C. D. Gimmi, D. B. Lombard, L. J. Zhou, M. White, J. D. Fingeroth, J. G. Gribben, and L. M. Nadler. "Structure, expression, and T cell costimulatory activity of the murine homologue of the human B lymphocyte activation antigen B7." Journal of Experimental Medicine 174, no. 3 (September 1, 1991): 625–31. http://dx.doi.org/10.1084/jem.174.3.625.

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Following occupancy of the T cell receptor by antigen, T cell proliferation and lymphokine production are determined by a second costimulatory signal delivered by a ligand expressed on antigen presenting cells. The human B cell activation antigen B7, which is expressed on antigen presenting cells including activated B cells and gamma interferon treated monocytes, has been shown to deliver such a costimulatory signal upon attachment to its ligand on T cells, CD28. We have cloned and sequenced the murine homologue of the human B7 gene. The predicted murine protein has 44% amino acid identity with human B7. The greatest similarity is in the Ig-V and Ig-C like domains. Murine B7 mRNA was detected in murine hematopoietic cells of B cell but not T cell origin. Cells transfected with murine B7 provided a costimulatory signal to human CD28+ T lymphocytes. These results demonstrate the costimulatory activity of murine B7 and provide evidence that the ligand attachment site is conserved between the two species.

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Kochenderfer, James N., Zhiya Yu, Dorina Frasheri, Nicholas P. Restifo, and Steven A. Rosenberg. "Adoptive transfer of syngeneic T cells transduced with a chimeric antigen receptor that recognizes murine CD19 can eradicate lymphoma and normal B cells." Blood 116, no. 19 (November 11, 2010): 3875–86. http://dx.doi.org/10.1182/blood-2010-01-265041.

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Abstract Adoptive T-cell therapy with anti-CD19 chimeric antigen receptor (CAR)–expressing T cells is a new approach for treating advanced B-cell malignancies. To evaluate anti-CD19–CAR-transduced T cells in a murine model of adoptive T-cell therapy, we developed a CAR that specifically recognized murine CD19. We used T cells that were retrovirally transduced with this CAR to treat mice bearing a syngeneic lymphoma that naturally expressed the self-antigen murine CD19. One infusion of anti-CD19–CAR-transduced T cells completely eliminated normal B cells from mice for at least 143 days. Anti-CD19–CAR-transduced T cells eradicated intraperitoneally injected lymphoma cells and large subcutaneous lymphoma masses. The antilymphoma efficacy of anti-CD19–CAR-transduced T cells was critically dependent on irradiation of mice before anti-CD19–CAR-transduced T-cell infusion. Anti-CD19–CAR-transduced T cells had superior antilymphoma efficacy compared with the anti-CD19 monoclonal antibody from which the anti-CD19 CAR was derived. Our results demonstrated impressive antilymphoma activity and profound destruction of normal B cells caused by anti-CD19–CAR-transduced T cells in a clinically relevant murine model.

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SHI, Hui, Kai Hu, Xiaoyan Ke, and Tong Wu. "Secondary Humanized CAR T Cells Salvage Therapy Improves Survival of R/R DLBCL Patients Failed to Murine CD19-CAR T Cells Therapy." Blood 138, Supplement 1 (November 5, 2021): 4836. http://dx.doi.org/10.1182/blood-2021-150108.

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Abstract Background: The Chimeric antigen receptor (CAR) T-cell therapy has shown very promising future in relapsed/refractory diffused large B cell lymphoma (R/R DLBCL) patients resisted to second-line chemotherapy and failed to auto hematopoietic cell transplantation. Trials with murine CD19-CAR T-cell therapy have shown only 40%-54% complete remission (CR) rate in patients with R/R DLBCL. However, 30%-60% of patients with previous CR relapse within 1 year. It is critical to develop new strategies to improve survival of R/R DLBCL patients failed to murine CD19-CAR T cells therapy. Forty-two R/R DLBCL patients failed to murine CD19-CAR T cells therapy who accepted secondary humanized CAR T cells salvage therapy in our center were recruited to this study Aim: 1. Investigate the effect and safety of Secondary humanized CAR T cells salvage therapy in R/R DLBCL patients failed to murine CD19-CAR T cells therapy. 2. Analyze the influence factor of curative effect of secondary humanized CAR T cells, to predict the outcome of treatment. Method: We retrospectively analyzed 42 cases treated with secondary humanized CAR T cells salvage therapy after failing to murine CD19-CAR T cells therapy in our center, enrolled from 05/01/2018 to 05/01/2020. According to the new result of tumor immunohistochemical analysis, five patients still chose to target CD19, twenty-one targeted CD20, and sixteen targeted CD22. Pretreatment regimen before infusion of CAR T cells were chemotherapy comprising fludarabine (three doses of 30 mg/m2 daily) and cyclophosphamide (three doses of 300mg/m2 daily). The T-cells with specific CAR expression in peripheral blood were dynamically detected by flow cytometry. After CAR T-cells infusion, PET-CT were performed every 3 months to evaluate the state of disease. Patients were followed up till 06/15/2021 Results: The incidence of cytokine release syndrome (CRS) was 84%, of which 22% was severe CRS (≥grade 3), as the incidence of immune effector cells associated neurologic toxicity (ICANS) was 7.14%, of which 2.83% was severe ICANS. The incidence of target organ damage was 12%. The rate of treatment-related mortality was 7%. In 3 months, complete remission rate was 26.2%, partial remission rate (PR) was 33.3% and the overall response rate (ORR) was 59.5%. Ten patients (26.2%) remained in complete remission at the cutoff date. The median of progression-free survival (PFS) length was 4.42 months (95%CI: 1.87-6.02). The median of overall survival (OS) length was 9.24 months (95%CI: 4.44-~). The 1-year overall survival rate was 38.1%. We also found high level of LDH, heavy tumor burden, no less than 4 IPI score, and double expression of MYC and BCL2 were risk factors of OS, PFS and CR. The patients who had achieved CR or PR after murine CD19-CAR T cells therapy had a favorable OS and PFS. The longer the patients had PFS during murine CD19-CAR T cells therapy, the longer PFS and OS during humanized CAR T cells therapy. Conclusion: 1. Secondary humanized CAR T cells salvage therapy improves survival of R/R DLBCL patients failed to murine CD19-CAR T cells therapy. 2. The incidence of severe CRS and treatment-related causality were relatively low. 3. The patients who got better curative effect during murine CAR T cells therapy prone to a longer survival time. Keywords: Secondary humanized CAR T cells therapy, murine CAR T cells therapy, R/R DLBCL, CRS, ICANS. Disclosures No relevant conflicts of interest to declare.

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Nagasawa, R. "Role of T cells in murine IgA nephropathy." Nephrology Dialysis Transplantation 14, no. 90001 (January 1, 1999): 12–13. http://dx.doi.org/10.1093/ndt/14.suppl_1.12.

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21

Battaglia, Manuela, Bruce R. Blazar, and Maria-Grazia Roncarolo. "The puzzling world of murine T regulatory cells." Microbes and Infection 4, no. 5 (April 2002): 559–66. http://dx.doi.org/10.1016/s1286-4579(02)01573-3.

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22

Chien, Y. H., and J. Hampl. "Antigen-recognition properties of murine γδ T cells." Springer Seminars in Immunopathology 22, no. 3 (September 2000): 239–50. http://dx.doi.org/10.1007/pl00006752.

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23

Renno, Toufic, Rana Zeine, Marc Girard, and Trevor Owens. "CD4+ T cells and cytokines in murine EAE." Journal of Neuroimmunology 43, no. 1-2 (March 1993): 210–11. http://dx.doi.org/10.1016/0165-5728(93)90122-f.

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24

Zenclussen, Ana Claudia. "CD4+CD25+ T regulatory cells in murine pregnancy." Journal of Reproductive Immunology 65, no. 2 (April 2005): 101–10. http://dx.doi.org/10.1016/j.jri.2005.01.003.

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Thuere, Catharina, Maria Laura Zenclussen, Anne Schumacher, Stefanie Langwisch, Ursula Schulte-Wrede, Ana Teles, Steffen Paeschke, Hans-Dieter Volk, and Ana Claudia Zenclussen. "Kinetics of Regulatory T Cells During Murine Pregnancy." American Journal of Reproductive Immunology 58, no. 6 (December 2007): 514–23. http://dx.doi.org/10.1111/j.1600-0897.2007.00538.x.

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Ogoshi, M., A. Takashima, and R. S. Taylor. "Mechanisms regulating telomerase activity in murine T cells." Journal of Immunology 158, no. 2 (January 15, 1997): 622–28. http://dx.doi.org/10.4049/jimmunol.158.2.622.

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Abstract Telomeres shorten with successive cell divisions in normal somatic cells, while telomerase plays an important role in maintaining their lengths. Although telomerase activity was originally described as being expressed exclusively by immortal cells and germline cells, a recently developed PCR-based technique (telomeric repeat amplification protocol (TRAP)) has revealed that normal peripheral blood leukocytes also exhibit this activity following mitogenic stimulation. In this study, we examined mechanisms by which mitogenic stimuli up-regulated telomerase activity in T cells. Splenic T cells freshly isolated from BALB/c mice exhibited only negligible telomerase activity. When stimulated with Con A or immobilized anti-CD3 mAb at 10 microg/ml, they acquired an increased telomerase activity and maximal proliferation. By contrast, T cells treated with a much lower concentration (0.03 microg/ml) of anti-CD3 mAb required exogenous IL-2 for telomerase activation and proliferation. Likewise, adult thymocytes treated with anti-CD3 mAb exhibited telomerase activation and proliferation only in the presence of exogenous IL-2, IL-4, IL-7, or IL-15. Furthermore, IL-2 alone was sufficient for telomerase activation in Con A blasts. These results illustrate a pathway through which cytokine receptors transduce telomerase activation signals in T cells. Although telomerase activation was concomitant with cell growth in normal T cells, we have identified T cell lines that showed discrepancies; the CTLL-2 line showed constitutive telomerase activity regardless of cell proliferative state, whereas the 7-17 line proliferated vigorously in response to IL-2, IL-7, or IL-15, without detectable telomerase activity. Thus, telomerase activity, which is ordinarily associated with proliferation in normal T cells, is not necessarily required or sufficient for cell growth.

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Cronin, David C., David W. Lancki, and Frank W. Fitch. "Requirements for activation of CD8+Murine T cells." Immunologic Research 13, no. 4 (December 1994): 215–33. http://dx.doi.org/10.1007/bf02935614.

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28

Herzenberg, Leonor A. "Murine suppressor T cells: mirage or cloudy reality?" Research in Immunology 140, no. 3 (January 1989): 337–38. http://dx.doi.org/10.1016/0923-2494(89)90074-6.

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Will, Antje, Martin Röllinghoff, and André Gessner. "Stable transfection of cloned murine T helper cells." Journal of Immunological Methods 188, no. 1 (December 1995): 139–46. http://dx.doi.org/10.1016/0022-1759(95)00212-x.

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30

Seo, N., Y. Tokura, F. Furukawa, and M. Takigawa. "Predominant activation of ????T cells but not ????T cells in murine B16 melanoma lesions." Melanoma Research 7, Supplement 1 (June 1997): S144. http://dx.doi.org/10.1097/00008390-199706001-00500.

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31

Li, Jau-Yi, Jonathan Adams, Laura M. Calvi, Timothy F. Lane, Richard DiPaolo, M. Neale Weitzmann, and Roberto Pacifici. "PTH expands short-term murine hemopoietic stem cells through T cells." Blood 120, no. 22 (November 22, 2012): 4352–62. http://dx.doi.org/10.1182/blood-2012-06-438531.

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Abstract Intermittent parathyroid hormone (iPTH) treatment expands hemopoietic stem and progenitor cells (HSPCs), but the involved mechanisms and the affected HSPC populations are mostly unknown. Here we show that T cells are required for iPTH to expand short-term HSPCs (ST-HSPCs) and improve blood cell engraftment and host survival after BM transplantation. Silencing of PTH/PTH-related protein receptor (PPR) in T cells abrogates the effects of iPTH, thus demonstrating a requirement for direct PPR signaling in T cells. Mechanistically, iPTH expands ST-HSPCs by activating Wnt signaling in HSPCs and stromal cells (SCs) through T-cell production of the Wnt ligand Wnt10b. Attesting to the relevance of Wnt10b, iPTH fails to expand ST-HSPCs in mice with Wnt10b−/− T cells. Moreover, iPTH fails to promote engraftment and survival after BM transplantation in Wnt10b null mice. In summary, direct PPR signaling in T cells and the resulting production of Wnt10b play a pivotal role in the mechanism by which iPTH expands ST-HSPCs. The data suggest that T cells may provide pharmacologic targets for HSPC expansion.

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Alter, B. J., and F. H. Bach. "Cellular basis of the proliferative response of human T cells to mouse xenoantigens." Journal of Experimental Medicine 171, no. 1 (January 1, 1990): 333–38. http://dx.doi.org/10.1084/jem.171.1.333.

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Purified human T cells respond proliferatively to allogenic peripheral blood mononuclear (PBMC) stimulating cells but show no response to murine splenic stimulating cells. Two possible explanations for the lack of xenogeneic response are that human T cells, educated in a human thymus, cannot directly recognize a molecule as disparate as mouse antigen encoded by H-2 and/or that a cytokine(s) produced by the APCs is needed to allow a proliferative response and that the cytokine(s) produced by murine APC do not provide an adequate stimulus to the human T cells under these conditions. We show here that highly purified human T cells can respond directly in an antigen-specific manner to murine stimulating cells if human rIL-1 or rIL-2 or a T cell growth factor (TCGF) preparation are present in the culture. These findings demonstrate that human T cells can recognize murine antigens and that a highly significant response can be obtained if a human cytokine is present to permit that response.

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33

Fanslow, W. C., K. N. Clifford, M. Seaman, M. R. Alderson, M. K. Spriggs, R. J. Armitage, and F. Ramsdell. "Recombinant CD40 ligand exerts potent biologic effects on T cells." Journal of Immunology 152, no. 9 (May 1, 1994): 4262–69. http://dx.doi.org/10.4049/jimmunol.152.9.4262.

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Abstract Murine and human CD40 ligand (CD40L) were recently cloned, expressed, and shown to possess potent activity on human and murine B cells, including stimulation of proliferation and Ig secretion in the presence of cytokines. In addition to its action on B lymphocytes, this report demonstrates that CD40L induced both CD4+ and CD8+ T cells isolated from murine lymphoid tissues to proliferate in the presence of submitogenic dosages of Con A, PHA, CD3 mAb, and TCR-alpha beta mAb. The presence of CD40L during suboptimal TCR stimulation resulted in increased expression of the activation Ags IL-2R alpha and CD69 and increased IL-2 production. Taken together, these results show that CD40L is a potent activator of murine T cells and suggest that CD40L is involved in the regulation of T cell function mediated through T:T cell interaction.

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34

Copelan, EA, SC Johnson, MR Grever, JF Sheridan, and PJ Tutschka. "Pharmacologic marrow purging in murine T cell leukemia." Blood 71, no. 6 (June 1, 1988): 1656–61. http://dx.doi.org/10.1182/blood.v71.6.1656.1656.

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Abstract Deoxycoformycin in combination with deoxyadenosine was used to purge 6C3HED malignant T cells from murine marrow in vitro. Adenosine deaminase activity of 6C3HED cells was ablated by incubation with 10(- 6) mol/L deoxycoformycin (dCF). During a 12-hour incubation with 10(-6) mol/L dCF and 10(-4) mol/L deoxyadenosine, tumor cells sequentially accumulated dATP, became depleted of NAD followed by ATP, then died. More than 5 logs of 6C3HED cells were killed as measured by survival of mice injected with treated tumor cells. Identical incubation of 5 x 10(6) marrow cells did not interfere with rescue of syngeneic lethally irradiated mice. Long-term survival was demonstrated in 12 of 14 mice that received marrow that had been contaminated with 5% 6C3HED cells, incubated with deoxycoformycin and deoxyadenosine, then used to rescue lethally irradiated mice. This murine model provides information not available from in vitro assays and may be useful in the development of strategies to purge malignant T cells from marrow.

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35

Copelan, EA, SC Johnson, MR Grever, JF Sheridan, and PJ Tutschka. "Pharmacologic marrow purging in murine T cell leukemia." Blood 71, no. 6 (June 1, 1988): 1656–61. http://dx.doi.org/10.1182/blood.v71.6.1656.bloodjournal7161656.

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Deoxycoformycin in combination with deoxyadenosine was used to purge 6C3HED malignant T cells from murine marrow in vitro. Adenosine deaminase activity of 6C3HED cells was ablated by incubation with 10(- 6) mol/L deoxycoformycin (dCF). During a 12-hour incubation with 10(-6) mol/L dCF and 10(-4) mol/L deoxyadenosine, tumor cells sequentially accumulated dATP, became depleted of NAD followed by ATP, then died. More than 5 logs of 6C3HED cells were killed as measured by survival of mice injected with treated tumor cells. Identical incubation of 5 x 10(6) marrow cells did not interfere with rescue of syngeneic lethally irradiated mice. Long-term survival was demonstrated in 12 of 14 mice that received marrow that had been contaminated with 5% 6C3HED cells, incubated with deoxycoformycin and deoxyadenosine, then used to rescue lethally irradiated mice. This murine model provides information not available from in vitro assays and may be useful in the development of strategies to purge malignant T cells from marrow.

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36

Prat, M., S. Bretti, M. Amedeo, S. Landolfo, and P. M. Comoglio. "Monoclonal antibodies against murine IFN-gamma abrogate in vivo tumor immunity against RSV-induced murine sarcomas." Journal of Immunology 138, no. 12 (June 15, 1987): 4530–33. http://dx.doi.org/10.4049/jimmunol.138.12.4530.

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Abstract Previous work has shown that immunization of syngeneic mice with v-src-induced sarcomas gives rise to specific protection against a lethal dose of v-src-transformed fibroblasts. This immune response is mediated by Lyt-1+, Lyt-2,3+ T lymphocytes, with no apparent involvement of cytotoxic T cells, as shown in Winn-type assays. Immune cells mediating tumor rejection in this system have now been further characterized, and it was found that L3T4+ T lymphocytes alone provided full protection against v-src-induced sarcomas. Moreover, the role of interferon-gamma (IFN-gamma) in the tumor rejection was analyzed. A monoclonal antibody directed against this lymphokine was able to reverse the protective effect displayed by immune T lymphocytes, by eliciting highly effective T suppressor cells. It was thus concluded that T cells with L3T4 surface marker are the main thing responsible for the adoptive immunity in this tumor system, and the activity of these cells is positively modulated by lymphokines such as IFN-gamma.

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37

Davodeau, F., M. A. Peyrat, A. Necker, R. Dominici, F. Blanchard, C. Leget, J. Gaschet, et al. "Close phenotypic and functional similarities between human and murine alphabeta T cells expressing invariant TCR alpha-chains." Journal of Immunology 158, no. 12 (June 15, 1997): 5603–11. http://dx.doi.org/10.4049/jimmunol.158.12.5603.

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Abstract Several studies have demonstrated the existence of a murine NK1.1+ alphabeta T cell subset expressing V alpha14+ TCR alpha-chains with highly conserved invariant junctional sequences and able to secrete Th2 cytokines when exposed to CD1+ stimulator cells. In humans, alphabeta T cells carrying invariant V alpha24+ TCR alpha-chains highly homologous to those expressed by murine NK1.1 cells have been recently described. Here we show that these cells (referred to as V alpha24inv T cells) and murine NK1.1+ alphabeta T cells resemble each other in several ways. First, like their murine counterparts, T cells expressing high levels of V alpha24inv TCRs can be either CD4- CD8- double negative (DN) or CD4+, but they never express heterodimeric CD8 molecules. Second, most V alpha24inv T cells are brightly stained by NKRP1-specific mAb but not by mAb directed against other type II transmembrane proteins of the NK complex. Third, DN and particularly CD4+ V alpha24inv T cells are greatly enriched for IL-4 producers. The concomitant expression of highly conserved TCRs of a particular set of NK markers and of Th2 cytokines in human and murine alphabeta T cells suggests a coordinate acquisition of these phenotypic and functional properties. Furthermore, the relatively high frequency of human V alpha24inv T cells, which are presently shown to represent on average 1/500 PBL, and the high interindividual variations of the size of this cell subset under physiologic conditions go for a major role played by alphabeta T cells carrying invariant TCR in a large array of immune responses.

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38

Fowler, Daniel. "T cells helping GVHD: take-away lessons." Blood 114, no. 14 (October 1, 2009): 2858–59. http://dx.doi.org/10.1182/blood-2009-07-234179.

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Using double cytokine knockout donor CD4 cells, in this issue of Blood, Yi and colleagues help clarify the complex role of IFN-γ and the tissue specificity of Th1, Th17, and Th2 subsets in murine GVHD.1

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39

Gross, J. A., T. St John, and J. P. Allison. "The murine homologue of the T lymphocyte antigen CD28. Molecular cloning and cell surface expression." Journal of Immunology 144, no. 8 (April 15, 1990): 3201–10. http://dx.doi.org/10.4049/jimmunol.144.8.3201.

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Abstract The human T lymphocyte Ag CD28 (Tp44) is a homodimeric glycoprotein expressed on the surface of a majority of human peripheral T cells and thymocytes. Although exposure of T cells to anti-CD28 mAb does not activate T cells, stimulation of CD28 can synergize with signals transmitted through the TCR or other stimuli to augment proliferation and lymphokine production. We have used a portion of the human CD28 cDNA to isolate a homologous murine cDNA from an EL4 T lymphoma library. The murine clone has 61% nucleotide identity with the human cDNA. Both human and murine sequences exhibit homology with members of the Ig supergene family and CTLA-4, a T cell specific murine gene. Many characteristics of the human CD28 molecule are conserved within the putative murine CD28 polypeptide. The murine cDNA sequence encodes a polypeptide of 218 amino acids that has 68% identity with the human sequence. Both the murine and human molecules are integral membrane glycoproteins with hydrophobic signal peptide sequences and transmembrane region. All five potential N-linked glycosylation sites are conserved and six of the seven cysteine residues of the mouse protein are found in the human CD28 polypeptide. The murine cDNA is encoded by a single copy nonrearranging gene whose expression at the mRNA level is restricted to T cells. A rabbit antiserum was raised against a synthetic peptide corresponding to a hydrophilic portion of the translated murine cDNA sequence. This antiserum identifies an 80-kDa homodimer consisting of disulfide-bonded subunits of 40 kDa that is expressed on splenic T cells, thymocytes, and several T cell tumors, but not on B cells. deglycosylation studies indicate that four of the five N-linked glycosylation sites are used and that the mature core protein has a molecular mass of 25 kDa, close to that predicted by the cDNA sequence. Transfection of the murine cDNA into Chinese hamster ovary cells resulted in the expression of an 80-kDa dimeric molecule that was immunoprecipitated by the antipeptide antiserum. Taken together, these data provide strong support that we have identified the murine homologue of CD28.

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40

Ranges, G. E., M. P. Bombara, R. A. Aiyer, G. G. Rice, and M. A. Palladino. "Tumor necrosis factor-alpha as a proliferative signal for an IL-2-dependent T cell line: strict species specificity of action." Journal of Immunology 142, no. 4 (February 15, 1989): 1203–8. http://dx.doi.org/10.4049/jimmunol.142.4.1203.

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Abstract The ability of TNF-alpha to stimulate T cell proliferation was examined. We demonstrate that murine rTNF-alpha induces the proliferation of CT6, a murine T cell line previously thought to be responsive only to IL-2. This activity appears to be the result of the direct action of murine rTNF-alpha on the CT6 cells because neither 1) murine IL-2 or murine IL-4, lymphokines also capable of inducing CT6 proliferation, were detected in culture supernatants from murine rTNF-alpha-treated CT6 cells nor 2) did antibodies specific for IL-2 or IL-4 inhibit murine rTNF-alpha-induced CT6 proliferation. Unlike many of the activities displayed by TNF-alpha, its ability to induce CT6 cell proliferation shows strict species specificity as indicated by the failure of human rTNF-alpha to stimulate these cells. Flow cytometric analysis and binding of radiolabeled TNF-alpha have indicated that receptors for TNF-alpha on these cells are specific for murine TNF-alpha. The ability of murine rTNF-alpha to induce the proliferation of certain T cell lines further indicates that this molecule plays an important role in regulation of T cell-mediated immune responses.

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41

Kapur, Rick, Michael Kim, Rukhsana Aslam, Mark J. McVey, Arata Tabuchi, Alice Luo, Jonathan Liu, et al. "T regulatory cells and dendritic cells protect against transfusion-related acute lung injury via IL-10." Blood 129, no. 18 (May 4, 2017): 2557–69. http://dx.doi.org/10.1182/blood-2016-12-758185.

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Key PointsCD4+CD25+FoxP3+ T regulatory cells and CD11c+ dendritic cells protect against antibody-mediated murine TRALI. Murine TRALI is associated with reduced IL-10 levels, and IL-10 administration prevents and rescues TRALI development.

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42

Karpati, R. M., S. M. Banks, B. Malissen, S. A. Rosenberg, M. A. Sheard, J. S. Weber, and R. J. Hodes. "Phenotypic characterization of murine tumor-infiltrating T lymphocytes." Journal of Immunology 146, no. 6 (March 15, 1991): 2043–51. http://dx.doi.org/10.4049/jimmunol.146.6.2043.

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Abstract Tumor infiltrating lymphocytes (TIL) can be isolated from solid tumors and selectively expanded in long term culture with IL-2 and autologous irradiated tumor. Such long term cultured cells express anti-tumor activity in vitro, mediate the regression of established tumor in murine models of cancer, and have been used for the treatment of cancer in humans. We have characterized freshly isolated mouse Thy-1+ TIL populations, as well as long term TIL cultures, from several different C57BL/6 (B6) tumors. Freshly isolated Thy-1+ TIL include both CD4+ and CD8+ cells, as well as cells bearing NK markers. These cells are predominantly TCR alpha beta+, with a smaller population of TCR gamma delta+ cells. The TCR alpha beta+ cells expressed a broad distribution of V beta phenotypes that was statistically different from that expressed in normal B6 splenic Thy-1+ cells or CD8+ cells, presumably reflecting in vivo selection in the host anti-tumor response. NK cells are present in these tumors at a greater frequency than noted in splenic T cells. Cultured TIL populations rapidly became exclusively Thy-1+/CD8+/CD4- and TCR alpha beta+/gamma delta-. Individual long term TIL populations initially expressed multiple V beta products, but rapidly restricted their V beta expression, frequently expressing a single dominant V beta. The identity of this dominant V beta varied among different TIL lines, but the overall representation of V beta phenotypes in these cultures was statistically different from that seen in Thy-1+ or CD8+ splenocytes. No statistical difference was noted between lines derived from antigenically distinct tumors. The selection of tumor specific T cells in vitro is therefore not reflected in any simple predominance of V beta usage. The complexity of TCR usage in the anti-tumor response may result from the involvement of multiple alpha- and beta-chain regions in the response to a single antigenic determinant, or may reflect multiple antigenic determinants expressed on a single syngeneic tumor.

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43

Erdei, A. "C1q receptor on murine cells." Journal of Immunology 145, no. 6 (September 15, 1990): 1754–60. http://dx.doi.org/10.4049/jimmunol.145.6.1754.

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Abstract Different cells and cell lines of murine origin were tested for their capacity to bind the C subcomponent C1q by using biotinylated human C1q and streptavidin-FITC. Cytofluorometric analysis of splenocytes and thymocytes shows that the majority of C1q-reactive cells reside in the population of B cells and macrophages. There is a significant difference in the C1q-binding capacity of in vitro activated cells; although more than half of the B cell blasts bind the C subcomponent, T cell blasts are virtually negative. It is shown that pre-B lymphomas and cell lines of myeloid origin bind C1q strongly (90 to 98%), whereas in the case of mature B cell lymphomas, plasmocytomas, and the tested T cell lines, the percentage of C1q binding cells varies from 0 to 56. C1q affinity chromatography of the detergent extracts from P388D1 and WEHI-3 cells followed by SDS-PAGE of the eluted proteins under reducing conditions reveals a band at approximately 80 kDa. Analysis of splenocytes shows two additional minor C1q-binding molecules with apparent molecular masses of 50 and 45 kDa, whereas in the case of B cell blasts three bands of similar density are seen at approximately 95, 50 and 45 kDa. C1q-receptors of murine cells are shown to be antigenically related to their human counterpart, because a polyclonal antibody (266A) raised against the human C1q receptor reacts with them.

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44

Telander, David G., Erika-Nell Malvey, and Daniel L. Mueller. "Evidence for Repression of IL-2 Gene Activation in Anergic T Cells." Journal of Immunology 162, no. 3 (February 1, 1999): 1460–65. http://dx.doi.org/10.4049/jimmunol.162.3.1460.

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Abstract The induction of clonal anergy in a T cell inhibits IL-2 secretion because of the development of a proximal signal transduction defect. Fusion of anergic murine T cells to human Jurkat T leukemia cells and formation of heterokaryons failed to result in a complementation of this signaling defect and restoration of murine IL-2 mRNA inducibility. Instead, signal transduction to the human IL-2 gene became disrupted. Heterokaryons formed by the fusion of anergic murine T cells to normal murine T cells also failed to accumulate intracellular IL-2 protein in response to stimulation either with the combination of CD3 and CD28 mAbs or with ionomycin plus a protein kinase C-activating phorbol ester. The results argue against a loss-of-function signaling defect as the sole basis for clonal anergy induction and document the presence of a dominant-acting repressor molecule that inhibits signal transduction to the IL-2 gene within viable anergic T cells.

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45

Andrews, Alex, Gavin Thurston, Jessica R. Kirshner, and David J. DiLillo. "Exploring mechanisms of tumor resistance to CAR T cell therapy in immunocompetent mouse models." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 170.24. http://dx.doi.org/10.4049/jimmunol.204.supp.170.24.

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Abstract Chimeric antigen receptor (CAR) T cell therapies have shown striking clinical efficacy in the treatment of hematological malignancies, but limited success so far against solid tumors, suggesting that solid tumors may harbor mechanisms of resistance. To investigate mechanisms of CAR T cell therapy resistance in solid tumors, we developed immunocompetent mouse models to explore immune cell interactions and the effect of an immunosuppressive tumor microenvironment on CAR T cell behavior. We generated murine CAR T cells against a model antigen that contained a CD3z intracellular signaling domain linked to either a CD28 or a 4-1BB signaling domain. We found that murine CAR T cells exhibited a predominantly central memory phenotype together with potent cytotoxic activity and antigen-dependent cytokine release in vitro. Further, we found that murine CAR T cells exhibited strong anti-tumor efficacy against both disseminated (EL4) and subcutaneous (MC38) murine tumors in vivo, whereas non-binding control CAR T cells had no anti-tumor effect. However, in both the disseminated and subcutaneous models, tumors were suppressed but not completely eradicated. Although murine CAR T cells possessing either CD28 or 41BB co-stimulatory domains demonstrated similar in vitro activities, they exhibited strikingly different efficacies and resistance mechanisms in vivo. Collectively, these results highlight the contributions of specific co-stimulatory signaling pathways to CAR T cell therapy in immunocompetent murine models and provide a platform to explore resistance mechanisms to CAR T therapy against solid tumors.

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46

Chiarantini, Laura, Robert E. Droleskey, and John R. DeLoach. "In vivo targeting of erythrocytes to circulating T-cells." Proceedings, annual meeting, Electron Microscopy Society of America 50, no. 1 (August 1992): 606–7. http://dx.doi.org/10.1017/s042482010012343x.

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The use of carrier erythrocytes to specifically deliver toxic drugs to cancer cells has been a continuing effort in many laboratories. Carrier erythrocytes offer the advantages of having a large volume, are biodegradable, are easily obtained and prepared, and have the capability of circulating as well as normal erythrocytes. The selective in vivo targeting of drug loaded carrier erythrocytes to the liver and spleen has been demonstrated. By the use of intraperitoneal (IP) injection of carrier erythrocytes DeLoach et al. have demonstrated that carrier erythrocytes can not only be targeted to the lymphatic system but to normal circulation as well. In an attempt to determine the feasibility of targeting carrier erythrocytes to circulating murine T-cells we coupled a monoclonal antibody (Mab) (antimouse Thy 1.2) to murine erythrocytes using chromic chloride as a coupling agent. Murine erythrocytes coupled with antimouse Thy 1.2 have been shown to form rosettes with a cytotoxic T-lymphocyte line (CTLL) in vitro.

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47

Moses, K., and C. Prives. "A unique subpopulation of murine DNA polymerase alpha/primase specifically interacts with polyomavirus T antigen and stimulates DNA replication." Molecular and Cellular Biology 14, no. 4 (April 1994): 2767–76. http://dx.doi.org/10.1128/mcb.14.4.2767-2776.1994.

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Murine cells or cell extracts support the replication of plasmids containing the replication origin (ori-DNA) of polyomavirus (Py) but not that of simian virus 40 (SV40), whereas human cells or cell extracts support the replication of SV40 ori-DNA but not that of Py ori-DNA. It was shown previously that fractions containing DNA polymerase alpha/primase from permissive cells allow viral ori-DNA replication to proceed in extracts of nonpermissive cells. To extend these observations, the binding of Py T antigen to both the permissive and nonpermissive DNA polymerase alpha/primase was examined. Py T antigen was retained by a murine DNA polymerase alpha/primase but not by a human DNA polymerase alpha/primase affinity column. Likewise, a Py T antigen affinity column retained DNA polymerase alpha/primase activity from murine cells but not from human cells. The murine fraction which bound to the Py T antigen column was able to stimulate Py ori-DNA replication in the nonpermissive extract. However, the DNA polymerase alpha/primase activity in this murine fraction constituted only a relatively small proportion (approximately 20 to 40%) of the total murine DNA polymerase alpha/primase that had been applied to the column. The DNA polymerase alpha/primase purified from the nonbound murine fraction, although far more replete in this activity, was incapable of supporting Py DNA replication. The two forms of murine DNA polymerase alpha/primase also differed in their interactions with Py T antigen. Our data thus demonstrate that there are two distinct populations of DNA polymerase alpha/primase in murine cells and that species-specific interactions between T antigen and DNA polymerases can be identified. They may also provide the basis for initiating a novel means of characterizing unique subpopulations of DNA polymerase alpha/primase.

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48

Moses, K., and C. Prives. "A unique subpopulation of murine DNA polymerase alpha/primase specifically interacts with polyomavirus T antigen and stimulates DNA replication." Molecular and Cellular Biology 14, no. 4 (April 1994): 2767–76. http://dx.doi.org/10.1128/mcb.14.4.2767.

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Murine cells or cell extracts support the replication of plasmids containing the replication origin (ori-DNA) of polyomavirus (Py) but not that of simian virus 40 (SV40), whereas human cells or cell extracts support the replication of SV40 ori-DNA but not that of Py ori-DNA. It was shown previously that fractions containing DNA polymerase alpha/primase from permissive cells allow viral ori-DNA replication to proceed in extracts of nonpermissive cells. To extend these observations, the binding of Py T antigen to both the permissive and nonpermissive DNA polymerase alpha/primase was examined. Py T antigen was retained by a murine DNA polymerase alpha/primase but not by a human DNA polymerase alpha/primase affinity column. Likewise, a Py T antigen affinity column retained DNA polymerase alpha/primase activity from murine cells but not from human cells. The murine fraction which bound to the Py T antigen column was able to stimulate Py ori-DNA replication in the nonpermissive extract. However, the DNA polymerase alpha/primase activity in this murine fraction constituted only a relatively small proportion (approximately 20 to 40%) of the total murine DNA polymerase alpha/primase that had been applied to the column. The DNA polymerase alpha/primase purified from the nonbound murine fraction, although far more replete in this activity, was incapable of supporting Py DNA replication. The two forms of murine DNA polymerase alpha/primase also differed in their interactions with Py T antigen. Our data thus demonstrate that there are two distinct populations of DNA polymerase alpha/primase in murine cells and that species-specific interactions between T antigen and DNA polymerases can be identified. They may also provide the basis for initiating a novel means of characterizing unique subpopulations of DNA polymerase alpha/primase.

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49

Stevanovic, Sanja, Bart Nijmeijer, Marianke LJ Van Schie, Roelof Willemze, Marieke Griffioen, and J. H. Frederik Falkenburg. "Human T Cells with Distinct Specificities Mediate Graft-Versus-Leukemia Reactivity and Xenogeneic Graft-Versus-Host Disease in a NOD/Scid Mouse Model for Human Acute Leukemia." Blood 114, no. 22 (November 20, 2009): 1330. http://dx.doi.org/10.1182/blood.v114.22.1330.1330.

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Abstract Abstract 1330 Poster Board I-352 Immunodeficient mice inoculated with human leukemia can be used as a model to investigate Graft-versus-Leukemia (GvL) effects of donor lymphocyte infusions (DLIs). In addition to GvL reactivity, treatment with DLI induces xenogeneic Graft-versus-Host Disease (GvHD) in mice, characterized by pancytopenia and weight loss. In patients treated with DLI for relapsed or residual leukemia after allogeneic stem cell transplantation, immune responses against non-leukemic cells may also cause GvHD. It has been suggested that GvL reactivity and GvHD, which co-develop in vivo, can be separated and that distinct T cells exist with the specific capacity to mediate GvL reactivity or GvHD. Since adoptive T cell transfer models that allow analysis of separation of GvL and GvHD are rare, we aimed to establish whether GvL reactivity and xenogeneic GvHD could be separated using our model of human leukemia-engrafted NOD/scid mouse after treatment with human donor T cells. In this study, non-conditioned NOD/scid mice engrafted with primary human acute lymphoblastic leukemic cells were treated with CD3+ DLI. Established tumors were effectively eliminated by emerging human T cells, but also induced xenogeneic GvHD. Flowcytometric analysis demonstrated that the majority of emerging CD8+ and CD4+ T cells were activated (HLA-DR+) and expressed an effector memory phenotype (CD45RA-CD45RO+CCR7-). To investigate whether GvL reactivity and xenogeneic GvHD were mediated by the same T cells showing reactivity against both human leukemic and murine cells, or displaying distinct reactivity against human leukemic and murine cells, we clonally isolated and characterized the T cells during the GvL response and xenogeneic GvHD. T cell clones were analyzed for reactivity against primary human leukemic cells and primary NOD/scid hematopoietic (BM and spleen cells) and non-hematopoietic (skin fibroblasts) cells in IFN-g ELISA. Isolated CD8+ and CD4+ T cell clones were shown to recognize either human leukemic or murine cells, indicating that GvL response and xenogeneic GvHD were mediated by different human T cells. Flowcytometric analysis demonstrated that all BM and spleen cells expressed MHC class I, whereas only 1-3 % of the cells were MHC class II +. Primary skin fibroblasts displayed low MHC class I and completely lacked MHC class II expression. Xeno-reactive CD8+ T cell clones were shown to recognize all MHC class I + target cells and xeno-reactive CD4+ T cells clones displayed reactivity only against MHC class II + target cells. To determine the MHC restriction of xeno-reactive T cell clones, NOD/scid bone marrow (BM) derived dendritic cells (DC) expressing high levels of murine MHC class I and class II were tested for T cell recognition in the presence or absence of murine MHC class I and class II monoclonal antibodies in IFN-g ELISA. Xeno-reactive CD8+ T cell clones were shown to be MHC class I (H-2Kd or H-2Db) restricted, whereas xeno-reactive CD4+ T cell clones were MHC class II (I-Ag7) restricted, indicating that xeno-reactivity reflects genuine human T cell response directed against allo-antigens present on murine cells. Despite production of high levels of IFN-gamma, xeno-reactive CD8+ and CD4+ T cell clones failed to exert cytolytic activity against murine DC, as determined in a 51Cr-release cytotoxicity assay. Absence of cytolysis by CD8+ T cell clones, which are generally considered as potent effector cells, may be explained by low avidity interaction between human T cells and murine DC, since flowcytometric analysis revealed sub-optimal activation of T cells as measured by CD137 expression and T cell receptor downregulation upon co-culture with murine DC, and therefore these results indicate that xenogeneic GvHD in this model is likely to be mediated by cytokines. In conclusion, in leukemia-engrafted NOD/scid mice treated with CD3+ DLI, we show that GvL reactivity and xenogeneic GvHD are mediated by separate human T cells with distinct specificities. All xeno-reactive T cell clones showed genuine recognition of MHC class I or class II associated allo-antigens on murine cells similar as GvHD-inducing human T cells. These data suggest that our NOD/scid mouse model of human acute leukemia may be valuable for studying the effectiveness and specificity of selectively enriched or depleted T cells for adoptive immunotherapy. Disclosures: No relevant conflicts of interest to declare.

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50

Zhang, Yinqiang, Mengyi Du, Danying Liao, Wei Xie, Wei Xiong, and Heng Mei. "Long-Term Follow-up of Humanized and Murine CD19 CAR-T Cell Therapy for B-Cell Malignancies." Blood 142, Supplement 1 (November 28, 2023): 3466. http://dx.doi.org/10.1182/blood-2023-180440.

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Aim: CD19 chimeric antigen receptor T cell (CAR-T) therapy is a revolutionary treatment for relapsed/refractory (R/R) B-cell hematologic malignancies. However, the safety and efficacy of murine CAR-T cells which have been widely used as commercialized products still need to be improved. Similarly, murine CAR-T encountered the problem that CAR-related immunogenicity existed after the infusion, which led to the failure of the re-infusion of CAR-T cells. As an improved generation of murine CAR-T cells, whether humanized CAR-T therapy can overcome the above shortcomings remains to be explored. Methods: In this study, the differences in safety, efficacy, and long-term follow-up results of murine and humanized CD19 CAR-T cells in patients with B-cell malignancies were collected and analyzed. A total of 130 patients were enrolled, including 35 patients with murine CAR-T and 95 with humanized CAR-T cells (NCT 02965092, NCT 04008251). Results： The proportion of patients with cytokine release syndrome (CRS) in the murine and humanized groups was 54.3%（19/35） and 61.1%（58/95）, respectively. A significantly higher proportion of patients suffered from severe CRS in the murine group than that in the humanized CAR-T group (17.14% vs. 7.4%, P=0.0233), and one patient in each group died of Grade 5 CRS. The incidence of grade 1-2 Immune effector cell-associated neurotoxicity syndrome (ICANS) was 11.4% (murine: 4/35) and 5.3% (humanized: 5/95), but high-grade ICANS was not observed. Among patients receiving murine CAR-T cells, 80% achieved objective response (OR), 71.43% achieved complete response (CR) and the CR rate of patients with leukemia was 74.19%. The OR rate and CR rate of patients in the humanized group were 75.79% and 63.16%, respectively, while the CR rate of patients with leukemia receiving humanized CAR-T cells was 89.58%. The median follow-up time of patients in the murine and humanized groups was 7 months (0.6-75 months) and 5.5 months (0.5-34 months), respectively. The median progression-free survival (PFS) of patients with murine CAR-T cells was 11 months and that of patients with humanized CAR-T products was 12 months. Both of the median overall survival (OS) were not reached. Among the 48 patients with a bone marrow burden over 20% at baseline, humanized CAR-T therapy was associated with a higher OS rate (84.64% vs. 59.26%, P=0.1479) and a significantly improved PFS (43.94% vs. 33.33%, P=0.0217, Figure 1). Bridging transplantation was an independent factor in prolonging OS (x 2=8.017, p=0.0046) and PFS (x 2=6.584, p=0.0103) of patients with leukemia. Neither species of chimeric antigen receptor nor common risk factors such as age, recurrence, bone marrow burden, BCR-ABL fusion gene had significant effect on patients' long-term follow-up outcomes (Table 1). Four patients received CAR-T therapies more than once. Three of them still achieved varying degrees of long-term remission after multiple humanized CAR-T infusions. However, one patient relapsed as soon as one month after his second infusion of murine CAR-T cells. Conclusion: Results indicate that humanized CAR-T therapy showed better safety and durable efficacy, especially in patients with higher tumor burden in bone marrow. Moreover, it could overcome immunogenicity-induced CAR-T resistance, providing treatment options for patients' failures of CAR-T therapies.

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Journal articles on the topic 'Murine T Cells'

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