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<p>This study evaluated the ability of ELISpot to identify potential immuno-modulatory drug therapies in sepsis. ELISpot was performed ex vivo on whole blood from septic patients and healthy controls. Innate and adaptive immunity were evaluated by production of TNF-α and IFN-γ, respectively. Drug efficacy was determined by their effects to modulate the both the number of cytokine-producing cells and amount of cytokine produced per cell. The corticosteroid dexamethasone was evaluated for its ability to down modulate TNF-α and IFN-γ production. The TLR7/8 agonist resiquimod (R848) and T cell stimulants IL-7 and anti-PD-1 mAb were tested for their ability to enhance immunity. LPS and resiquimod increased total TNF-α production in septic patients by 1,549% and 1,829%, respectively. Conversely, dexamethasone diminished the responses to LPS or resiquimod by 75% and 61%, respectively. IL-7, but not anti-PD-1 mAb markedly increased IFN-γ production in both healthy subjects (121%) and septic patients (82%). Dexamethasone also reduced anti-CD3/CD28 mAb stimulated IFN-γ production by 69%; while IL-7 ameliorated dexamethasone-induced suppression. IL-7 significantly enhanced lymphocyte function in over 90% of septic patients. ELISpot can reveal host immune response patterns and the effects of drugs to selectively down- or up-regulate patient immunity. Furthermore, the ability of ELISpot to detect the effect of specific immuno-modulatory drugs to independently regulate the innate and adaptive host response could enable precision-based immune drug therapies in sepsis.</p>

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Determining potential immunomodulatory drug efficacy in sepsis using ELISpot

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月18日

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  • Andrew H. Walton,
  • Monty B. Mazer,
  • Kenneth E. Remy,
  • Dale F. Osborne,
  • Ethan B. Davitt,
  • Thomas S. Griffith,
  • Robert W. Gould,
  • Vladimir P. Badovinac,
  • Scott C. Brakenridge,
  • Anne M. Drewry,
  • Ricardo F. Ungaro,
  • Ivanna L. Rocha,
  • Tyler J. Loftus,
  • Philip A. Efron,
  • Lyle L. Moldawer,
  • Charles C. Caldwell,
  • Richard S. Hotchkiss

摘要

This study evaluated the ability of ELISpot to identify potential immuno-modulatory drug therapies in sepsis. ELISpot was performed ex vivo on whole blood from septic patients and healthy controls. Innate and adaptive immunity were evaluated by production of TNF-α and IFN-γ, respectively. Drug efficacy was determined by their effects to modulate the both the number of cytokine-producing cells and amount of cytokine produced per cell. The corticosteroid dexamethasone was evaluated for its ability to down modulate TNF-α and IFN-γ production. The TLR7/8 agonist resiquimod (R848) and T cell stimulants IL-7 and anti-PD-1 mAb were tested for their ability to enhance immunity. LPS and resiquimod increased total TNF-α production in septic patients by 1,549% and 1,829%, respectively. Conversely, dexamethasone diminished the responses to LPS or resiquimod by 75% and 61%, respectively. IL-7, but not anti-PD-1 mAb markedly increased IFN-γ production in both healthy subjects (121%) and septic patients (82%). Dexamethasone also reduced anti-CD3/CD28 mAb stimulated IFN-γ production by 69%; while IL-7 ameliorated dexamethasone-induced suppression. IL-7 significantly enhanced lymphocyte function in over 90% of septic patients. ELISpot can reveal host immune response patterns and the effects of drugs to selectively down- or up-regulate patient immunity. Furthermore, the ability of ELISpot to detect the effect of specific immuno-modulatory drugs to independently regulate the innate and adaptive host response could enable precision-based immune drug therapies in sepsis.