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Effects of rhlL-7 on Leukocyte Subsets in Mice: Implications for Antitumor Activity
Published in Ronald H. Goldfarb, Theresa L. Whiteside, Tumor Immunology and Cancer Therapy, 2020
Kristin L. Komschlies, Timothy T. Back, Theresa A. Gregorio, M. Eilene Gruys, Giovanna Damia, Robert H. Wiltrout, Connie R. Faltynek
Interleukin 7 (IL-7) is a 25 kDa glycoprotein that was originally characterized as a product of a cloned murine bone marrow stromal cell line (1,2), and its mRNA has since been detected in the thymus and spleen (3). Human and murine recombinant IL-7 exhibit a 60% homology at the protein level with all of the six cysteine residues conserved (4). in vitro, IL-7 induces the proliferation of pro-B and pre-B lymphocytes (1,2) and affects the growth of both immature and mature cells of the T lymphocyte lineage (5–9). IL-7 also induces lymphokine-activated killer (LAK) activity from human peripheral blood leukocytes (9,10) and mouse splenocytes (11) in vitro. Further, IL-7 affects myeloid progenitor cells since splenic granulocyte-macrophage colony forming units (CFU-GM) and multipotential CFU (CFU-GEMM) are increased in mice treated with IL-7 (12,13), while total bone marrow CFU are decreased (13). Thus, the aims of these studies are to 1) determine whether the administration of recombinant human IL-7 (rhlL-7) to mice could alter the incidence or total number of various lymphoid subsets and 2) assess the effects of IL-7 against experimental metastases in mice.
Progressive multifocal leukoencephalopathy
Published in Avindra Nath, Joseph R. Berger, Clinical Neurovirology, 2020
Eric M. L. Williamson, Joseph R. Berger
Restoration of immune function or perturbation leads to better outcomes in PML, thus approaches focused on boosting immune function have been investigated. Interleukin-2, which can stimulate T-cells, and infusions of adopted cytotoxic T-cells have reportedly been successful in battling PML in patients with T-cell deficiencies unrelated to HIV [282]. Interleukin-7 (CYT) [107] stimulates all cells in the lymphoid lineage and it too has been argued to be of benefit in individual case reports when given as recombinant IL-7 with JCV capsid protein to boost JCV-specific T cell responses [283]. Such strategies of increasing T cell responses cannot be recommended in the setting of multiple sclerosis though, not only because of the anecdotal nature of such reports but also due to concern that stimulating the immune system could worsen underlying MS.
Overview of the mucosal immune system structure
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Reinhard Pabst, Per Brandtzaeg
The cellular interactions involve lymphotoxins (LTs), which are members of the tumor necrosis factor (TNF) superfamily, as well as the two TNF receptors (TNF-Rs) I and II (55 and 75 kDa). A crucial differentiating event is membrane expression of LTα1β2 on the CD3−CD4+CD45+IL-7R+ LTi cells after stimulation of the receptor activator of nuclear factor (NF) κB (RANK)–TNF receptor associated factor family 6 (TRAF6) pathway and—especially in PPs—alternative cytokine signaling through the interleukin-7 receptor (IL-7R). This event is followed by LTi cell interaction with the LTβ receptor (LTβR)−positive stromal cells, which are positive for vascular cell adhesion molecule (VCAM)-1 and are called lymphoid tissue organizer cells but display a different activation profile in the organogenesis of lymph nodes and PPs. Knockout mice deficient in LTα or LTβ virtually lack lymph nodes and have no detectable PPs. The organ development also involves several feedback loops with chemokines and adhesion molecules such as CXC chemokine ligand 13 (CXCL13)–CXCR5 and CXCR5-induced α4β1integrin–VCAM-1 interactions.
The TLR9 agonist (GNKG168) induces a unique immune activation pattern in vivo in children with minimal residual disease positive acute leukemia: Results of the TACL T2009-008 phase I study
Published in Pediatric Hematology and Oncology, 2019
Rebecca Ronsley, Amina Kariminia, Bernard Ng, Sara Mostafavi, Gregor Reid, Peter Subrt, Nobuko Hijiya, Kirk R. Schultz
Interleukin 7 R (IL7R) gene results in transcription of IL-7 protein receptor alpha chain, CD127. IL-7 receptor is found in both B and T lymphocytes and appears to be important in regulation of the inflammatory response.39 IL7R appear to be important in T cell homeostasis in acute GvHD after hematopoietic stem cell transplant, a response important in development of the graft-versus-leukemia response.40 In acute GvHD, the IL-7/sIL-7Rα ratio was significantly higher in patients developing grades II-IV acute GvHD. Moreover, CD8+ T cell engraftment after lymphodepletion such as in HSCT, is IL7Rα dependent.41 Inhibition of IL7R may also act as a checkpoint inhibitor if CD127 (IL7R) expression CD56bright NK regulatory cell populations,42 a population important in suppressing GvHD and viral responses.43
Advances in the genetics of acute lymphoblastic leukemia in adults and the potential clinical implications
Published in Expert Review of Hematology, 2018
Netanel A. Horowitz, Doaa Akasha, Jacob M. Rowe
T cell development is critically dependent on interleukin 7 (IL-7) signaling. The interaction of IL-7 with its receptor (IL7-R) leads to reciprocal JAK1 and JAK3 phosphorylation followed by activation of STAT5. Moreover, the RAS-MAPK and the PI3 kinase (PI3K) are also activated by IL-7 and IL-2. Mutations in the IL-7 signaling pathway (i.e. IL7-R, JAK1, JAK3 and/or STAT5) are relatively common and found in 20–30% of T-ALL cases [53]. JAK1 mutations are associated with chemotherapy refractoriness, while STAT5B mutations have been correlated with an increased risk of recurrence [54,55]. Other mechanisms may also activate this pathway; for example, loss of function mutations in DNM2 leads to an increase in IL7-R expression on thymocytes, promoting T-cell survival [56]. In vitro studies demonstrated that ruxolitinib could reduce the proliferation rate of leukemic cells with JAK1 and ILR-7 mutations [57]. Tofacitinib caused leukemic cell apoptosis in leukemic mice with JAK3 mutations [58].
SALL4 oncogene is an immunogenic antigen presented in various HLA-DR contexts
Published in OncoImmunology, 2018
Marie Kroemer, Laurie Spehner, Patricia Mercier-Letondal, Laura Boullerot, Stefano Kim, Marine Jary, Jeanne Galaine, Emilie Picard, Christophe Ferrand, Thierry Nguyen, Fabrice Larosa, Olivier Adotévi, Yann Godet, Christophe Borg
Responses were assessed by IFN-γ ELISPOT after a long-term in vitro stimulation of fresh or thawed PBMC (viability > 50%) with SALL4-derived peptides during 28 days. Ficoll-isolated PBMCs from healthy donors were cultured with 5 µg/mL of SALL4-derived peptides in pool of 3 peptides in a 24 well plate (4.106 cells per well) (Table 1 and Table 2). Recombinant interleukin 7 (IL-7) (5 ng/mL; Peprotech, 200–07) was added at day 1. Recombinant IL-2 (20 UI/mL, Novartis) was added at day 3, 6, 10, 16, 20, and 24. At day 14, pools of SALL4-derived-peptides were added again to their assigned wells as previously described to stimulate T-cells a second time. For the recall response against viruses, cells were similarly cultured with a mix of 32 peptides from influenza virus, Epstein-Barr virus and cytomegalovirus to a concentration equal to 2 µg/mL (CEF, Cellular Technology Limited, PA-CEF-001). At day 27, pools of SALL4-derived-peptides were added to their assigned wells. At Day 28, the specificity of T-cell was investigated by IFN- γ ELISPOT (Diaclone, 856 051 020P) as detailed below.