Abstract
Granulysin (GNLY) is a cytolytic and proinflammatory protein expressed in activated human cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Conventional mouse models cannot adequately address the triggering mechanism and immunopathological pathways in GNLY-associated diseases due to lack of the GNLY gene in the mouse genome. Therefore, we generated a humanized immune system (HIS) mouse model by transplanting human umbilical cord blood mononuclear cells into NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice after sublethally irradiation. We examined the GNLY expression and its effects on tumor growth using this system. Our HIS mice expressed human CD45+, CD4+, CD8+ and CD56+ cells in the peripheral blood and spleen. A high expression level of human Th1/Th2 and NK cytokines was detected, indicating the activation of both T and NK cells. Importantly, we found an elevated level of GNLY in the serum and it was produced by human CTLs and NK cells obtained from the peripheral blood mononuclear cells and spleen cells in the HIS mice. The serum level of GNLY was negatively correlated with the proliferation of transplanted tumor cells in HIS mice. Collectively, our findings strongly supported that HIS mouse as a valuable model for studying human cancer under an intact immune system and the role of GNLY in tumorigenesis.
Highlights
Granulysin (GNLY), a member of the saposinlike protein (SAPLIP) family, is produced by activated human cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells [1, 2]
Prior to the engraftment of human cord blood mononuclear cells (CBMCs), the hematological profiles of the peripheral blood obtained from naïve male Balb/c, NOD-SCID and NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice (8 and 24 weeks of age) were examined and compared
This suggested that aging process did not change the lymphocyte counts in NSG mice resulting from no leakiness (Figure 1A)
Summary
Granulysin (GNLY), a member of the saposinlike protein (SAPLIP) family, is produced by activated human cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells [1, 2]. GNLY exhibits a broad spectrum of antimicrobial activities and potent cytotoxic action against tumor cells [3, 4]. GNLY protein is shown to activate antigen presenting cells and serve as immune alarmin [5]. GNLY acts as a chemoattractant for T cells, monocytes, and other inflammatory cells and to stimulate the expression of several cytokines, including RANTES, IL1, IL-6, IL-10, and IFN-γ [6], indicating GNLY helps recruit immune cells to sites of inflammation. GNLY has been www.impactjournals.com/oncotarget shown as a lytic agent against various human tumors [4, 7] and may be useful as a diagnostic and therapeutic agent in clinics [8]. The conventional mouse model cannot be used to study the triggering mechanism and immunopathological pathways mediated by GNLY due to lack of the GNLY gene in the mouse genome [6, 9]
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