Effect of IL-18 on expansion of gammadelta T cells stimulated by zoledronate and IL-2

Our plain-English summary of Effect of IL-18 on expansion of gammadelta T cells stimulated by zoledronate and IL-2, by W. Li, S. Kubo, A. Okuda, et al (Journal of Immunotherapy, 2010).

The study

• Authors: W. Li, S. Kubo, A. Okuda, H. Yamamoto, H. Ueda, T. Tanaka, H. Nakamura, H. Yamanishi, N. Terada, H. Okamura
• Journal: Journal of Immunotherapy
• Published: 2010;33(3):287-96
• Cited by: 52 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Zoledronate (Zol) has recently been shown to expand gammadelta T cells that play important roles in host defenses against infection and tumors. In this study, we examined effects of interleukin-18 (IL-18) on expansion of gammadelta T cells in human peripheral blood mononuclear cells (PBMCs) stimulated by Zol and IL-2. The expansion of gammadelta T cells stimulated by Zol and IL-2 was strongly promoted by exogenous IL-18, and to the contrary, inhibited by neutralizing anti-IL-18 receptor antibody. The gammadelta T cells that expanded in the presence of Zol, IL-2, and IL-18 exhibited the phenotype of effector memory cells characterized by CD44 (+), CD27 (-), and CD45RA (-). In addition, they expressed NKG2D, perforin, CD94, CD25, and CD122, and 15% to 40% of them were positive for CD56. Incubation of gammadelta T cells in the presence with IL-18 produced GM-CSF, IFN-gamma, and TNF-alpha at much higher levels than those incubated without IL-18. They showed strong cytotoxicity against tumor cells including mesothelioma cells and inhibited growth of xenograft of mesothelioma in mice. These observations indicate that IL-18 can efficiently promote expansion of gammadelta T cells with potent antitumor activity.

In plain English

This was a laboratory study, not a study of people exposed to asbestos. The authors grew immune cells called gamma delta T cells from the blood of healthy donors. They stimulated the cells with the drug zoledronate and the signaling protein IL-2, and tested whether a third protein, IL-18, changed their growth. Blocking the IL-18 receptor with an antibody lowered the share of gamma delta T cells in 14-day cultures from 75% to 45%. With IL-18 added, the cells usually expanded 1000 to 5000 fold, though responses differed between donors. Cells incubated with IL-18 produced markedly higher levels of the immune proteins IFN-gamma, TNF-alpha and GM-CSF. In the dish, the purified cells killed three mesothelioma cell lines but not normal mesothelial cells or Met-5a cells. They also killed hepatoma and osteosarcoma cells. Injected into mice carrying mesothelioma tumors grown from MSTO-211H cells, they significantly suppressed tumor growth. The authors concluded that IL-18 can be a useful tool for preparing these cells for immune cell therapy of cancers resistant to conventional therapies.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (basic) study: human blood cells cultured with drugs and cytokines, tests of tumor cell killing in the dish, and a mouse xenograft experiment
• Who was studied: Peripheral blood mononuclear cells from healthy donors aged 25 to 60 (total number of donors not stated; figures report 3 to 5 samples per experiment). Target cells were mesothelioma cell lines (MESO-1, MESO-4, MSTO-211H), normal mesothelial cells, Met-5a cells, and hepatoma and osteosarcoma cell lines. NOD/SCID mice (n = 6 in the tumor figure) were also used.
• Exposure: No asbestos exposure was studied. Cells were stimulated with zoledronate, IL-2 and IL-18 in various combinations, or with an antibody blocking the IL-18 receptor.
• Main results:
  • In cultures with zoledronate and IL-2, gamma delta T cells rose from about 1% to 2% of cells at the start to 75% after 14 days
  • Adding an antibody that blocks the IL-18 receptor reduced the proportion of gamma delta T cells to 45%
  • With IL-2, IL-18 and zoledronate together, the number of gamma delta T cells usually expanded 1000 to 5000 fold
  • Growth responses differed among cells from different donors
  • Almost all expanded gamma delta T cells had the effector memory phenotype
  • Gamma delta T cells stimulated with IL-18 produced markedly high levels of IFN-gamma, TNF-alpha and GM-CSF
  • The expanded cells strongly killed three mesothelioma cell lines but not normal mesothelial cells or Met-5a cells
  • The expanded cells also killed hepatoma and osteosarcoma cells
  • In NOD/SCID mice with MSTO-211H mesothelioma xenografts, intravenous injection of the expanded cells significantly suppressed tumor growth. Injecting zoledronate along with the cells added no further effect.
• The authors' conclusion: The authors concluded that IL-18 effectively promotes expansion of effector memory gamma delta T cells stimulated by zoledronate and IL-2, and can be a useful tool for preparing these cells for immune cell therapy of cancers resistant to conventional therapies.
• Limitations the authors state:
  • The authors stated that the reasons why cells from different donors responded differently, and why all expanded cells ended up with the same phenotype, remain unclear

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma.

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