Granulocyte-macrophage colony-stimulating factor augmentation of T-cell receptor-dependent and T-cell receptor-independent thymocyte proliferation

Stewart-Akers, AM; Cairns, JS; Tweardy, DJ; Sa, McCarthy

doi:10.1182/blood.v83.3.713.bloodjournal833713

Cited by 4 publications

(3 citation statements)

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“…Therefore, these reported data are insufficient to explain why the tumor-induced thymic atrophy was prevented by intratumoral injection of the oncolytic Ad expressing IL-12. Furthermore, although it has been previously reported that GM-CSF is able to augment thymocyte proliferation, 38 our data showed that GM-CSF is less effective than IL-12 in preventing tumor-induced thymic atrophy.…”

Section: Discussioncontrasting

confidence: 88%

Strengthening of antitumor immune memory and prevention of thymic atrophy mediated by adenovirus expressing IL-12 and GM-CSF

et al. 2011

Gene Ther

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Interleukin (IL)-12 and granulocyte-monocyte colony-stimulating factor (GM-CSF) have recently been used as immunotherapeutic agents in cancer gene therapy. IL-12 and GM-CSF have differential roles in the antitumor immune response, as IL-12 targets T, NK and natural killer T (NKT) cells and GM-CSF principally targets antigen-presenting cells (APCs). To strengthen the therapeutic efficacy of these two cytokines, we generated an oncolytic adenovirus (Ad), Ad-ΔB7/IL12/GMCSF, coexpressing IL-12 and GM-CSF. Using a murine B16-F10 syngeneic tumor model, we show that Ad-ΔB7/IL12/GMCSF promoted antitumor responses and increased survival compared with an oncolytic Ad expressing IL-12 or GM-CSF alone (Ad-ΔB7/IL12 or Ad-ΔB7/GMCSF, respectively). By measuring cytotoxic T lymphocyte activity and interferon-γ production, we show that the enhanced therapeutic effect was mediated by the induction of immune cell cytotoxicity. In situ delivery of Ad-ΔB7/IL12/GMCSF resulted in massive infiltration of CD4(+) T cells, CD8(+) T cells, NK cells and CD86(+) APCs into the tissue surrounding the necrotic area of the tumor. Moreover, GM-CSF effectively promoted antitumor immune memory, which was significantly augmented by IL-12. Lastly, IL12-expressing oncolytic Ads prevented tumor-induced thymic atrophy and was associated with reduced apoptosis and increased proliferation in the thymus. Taken together, these data demonstrate that an oncolytic Ad coexpressing IL-12 and GM-CSF is a potential therapeutic tool for the treatment of cancer.

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Section: Discussioncontrasting

confidence: 88%

Strengthening of antitumor immune memory and prevention of thymic atrophy mediated by adenovirus expressing IL-12 and GM-CSF

et al. 2011

Gene Ther

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“…However, its effect might be indirect by increasing IL-6 production by thymocytes, since it is one of the major inducers with IL-1 (36). The main role of GM-CSF might be to increase thymocyte survival by playing a protective role against apoptosis, as shown in various hematopoietic systems (4,25,27), and/or to induce proliferation of certain subpopulations of thymocytes, as shown for the CD4 Ϫ CD8 Ϫ subset in the murine thymus (43). IL-1 might also participate in a proliferative effect, as shown in the mouse model (32).…”

Section: Discussionmentioning

confidence: 98%

Contact with Thymic Epithelial Cells as a Prerequisite for Cytokine-Enhanced Human Immunodeficiency Virus Type 1 Replication in Thymocytes

Rothe

Chêne

Nugeyre

et al. 1998

J Virol

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We report here that human immunodeficiency virus type 1 (HIV-1)-infected human thymocytes, in the absence of any exogenous stimulus but cocultivated with autologous thymic epithelial cells (TEC), obtained shortly (3 days) after thymus excision produce a high and sustained level of HIV-1 particles. The levels and kinetics of HIV-1 replication were similar for seven distinct viral strains irrespective of their phenotypes and genotypes. Contact of thymocytes with TEC is a critical requirement for optimal viral replication. Rather than an inductive signal resulting from the contact itself, soluble factors produced in the mixed culture are responsible for this effect. Specifically, the synergistic effects of tumor necrosis factor, interleukin-1 (IL-1), IL-6, and granulocyte-macrophage colony-stimulating factor may account by themselves for the high level of HIV-1 replication in thymocytes observed in mixed cultures. In conclusion, the microenvironment generated by TEC-thymocyte interaction might greatly favor optimal HIV-1 replication in the thymus.

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“…Antigen‐presenting cell (APC) populations respond to GM‐CSF by expansion and activation with increased circulation to lymph nodes (LNs)13–15. Furthermore, naïve T cells can be stimulated by GM‐CSF16, 17. An important caveat, however, is that any direct influence that human GM‐CSF has on the immune system must proceed through the APCs, as T cells do not have GM‐CSF receptors18.…”

Section: Introductionmentioning

confidence: 99%

Granulocyte macrophage‐colony stimulating factor (GM‐CSF) recruits immune cells to the pancreas and delays STZ‐induced diabetes

Krakowski

Abdelmalik

Mocnik

et al. 2001

The Journal of Pathology

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Granulocyte macrophage-colony stimulating factor (GM-CSF) is one of the most widely used growth factors for enhancing immune responses and is known to recruit and activate antigen-presenting cells (APCs). This study hypothesized that overexpression of this cytokine within the pancreatic beta-cells would recruit, expand, and activate APCs. The question was whether this would lead to tolerance or autoimmunity to pancreatic antigens. This possibility was tested by preparing transgenic mice (ins-GM-CSF) whose islets expressed murine GM-CSF. By 6-8 weeks of age, these mice developed a profound mononuclear cell infiltration that often overwhelmed the exocrine pancreas, although no changes in enzyme or hormone function were apparent. The majority of the mononuclear infiltrate within the pancreas was identified as F4/80+ macrophages. Transgenic ins-GM-CSF mice had splenomegaly due to a massive increase in the macrophage population. Additionally, mononuclear cells were found within the livers of transgenic mice, with F4/80+ cells also identified within the infiltrate, indicating that GM-CSF-activated mononuclear cells circulated to organs other than the pancreas. To assess the disease potential, this study tested whether macrophage recruitment to the pancreas might accelerate or protect the islets from diabetes. It was found that the induction of diabetes by low-dose streptozotocin (STZ) was delayed and reduced within ins-GM-CSF transgenic mice, in comparison with negative littermates. Together, these data highlight the role of GM-CSF in recruiting APCs such as macrophages. Advanced cellular infiltration does not overtly harm, and may even protect, pancreatic function, as seen with the delay in chemically induced diabetes.

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Granulocyte-macrophage colony-stimulating factor augmentation of T-cell receptor-dependent and T-cell receptor-independent thymocyte proliferation

Cited by 4 publications

References 0 publications

Strengthening of antitumor immune memory and prevention of thymic atrophy mediated by adenovirus expressing IL-12 and GM-CSF

Strengthening of antitumor immune memory and prevention of thymic atrophy mediated by adenovirus expressing IL-12 and GM-CSF

Contact with Thymic Epithelial Cells as a Prerequisite for Cytokine-Enhanced Human Immunodeficiency Virus Type 1 Replication in Thymocytes

Granulocyte macrophage‐colony stimulating factor (GM‐CSF) recruits immune cells to the pancreas and delays STZ‐induced diabetes

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