Monday, 08 June 2020 10:29

Immunocompetent 3-organ chip model for immune studies in multisystemic diseases Featured

A peer-reviewed study by Hesperos Inc. based in Florida reports on how the company's human-on-a-chip technology can be used to study immune responses to treatment with biological therapeutics in multi-organ systemic diseases.


The immune system plays an important role in combating infections and to eliminate damaged cells as well as repairing tissue. However, despite an increasing number of available multi-organ systems on microfluidic chips, the integration of required immune cells is still a challenge and not yet widespread.

For this work, Hesperos has cooperated with Hoffmann-La Roche Pharmaceuticals and is describing a pump-free in vitro system consisting of the functional human heart muscle, skeletal muscle, and liver cells in a serum-free medium. Recirculating human monocyte THP-1 immune cells were added to the culture. Monocytes are vital cells of the immune system that are involved in wound healing and pathogen elimination as well as activation of the innate immune response. However, monocyte THP-1 immune cells are also responsible for the cytokine storm that can occur, for example, in sepsis.

The researchers investigated how tissue-specific damage to heart muscle cells caused by the cardiotoxic substance amiodaran1 triggers an indirect activation of THP-1 cells and to what extent the THP-1 immune cells influence the three-organ system. They observed that together with the THP-1 immune cells amiodarone led to a more distinct reduction in heart strength, conduction speed, and a beat rate of the heart cells compared to amiodarone alone. The THP-1 cells also infiltrated the damaged cardiomyocytes and triggered a significantly increased expression of the cytokine IL-6, indicating an M2 macrophage phenotype. However, there was no immune-activated damage in the skeletal muscle or liver cells.

"The most striking feature of our immune-on-a-chip is that it emulates different immune responses for direct tissue damage and acute inflammation and differentiates between M1 and M2 macrophage phenotypes," said James Hickman, Ph.D., Chief Scientist at Hesperos and Professor at the University of Central Florida.

In a second study, the three-organ system was exposed to lipopolysaccharides (LPS) and interferon-gamma (IFN-γ) to stimulate acute inflammation and cytokine storm, respectively, and to trigger monocyte differentiation and activation.  Only the addition of THP-1 immune cells resulted in cellular damage to all components of the three-organ system after treatment with LPS/IFN-γ. The THP-1 immune cells infiltrated the liver tissue and there were significant changes in heart strength, the beat rate of the heart muscle cells, and skeletal muscle strength. In addition, proinflammatory cytokines such as TNF-α, IL-6, and IL-10 were upregulated, indicating an M1 macrophage phenotype analogous to the cytokine storm, the authors concluded.  This occurs during sepsis and during certain reactions to biological therapeutics.

“One application where the immune-system-on-a-chip can be immediately useful is for uncovering how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly affects multi-organ systems by activating the cytokine storm from inflammatory macrophages and to support the rapid development of therapeutics. As the global pandemic of COVID-19 continues to grow, this system has the potential to quickly evaluate antiviral and repurposed drugs to help combat this devastating disease,” said Michael L. Shuler, Ph.D., Chief Executive Officer of Hesperos.

The research was published in the journal Advanced Science:
Sasserath, T., Rumsey, J. W., McAleer, C. W., Bridges, L. R., Long, C. J., Elbrecht, D., Schuler, F., Roth, A., Bertinetti-LaPatki, C., Shuler, M. L. & Hickman, J. J. (2020). Differential Monocyte Actuation in a Three-Organ Functional Innate Immune System-on-a-Chip. Adv. Sci. 2000323, DOI: 10.1002/advs.20200032
https://onlinelibrary.wiley.com/doi/full/10.1002/advs.202000323

Source:
https://hesperosinc.com/

1 Amiodarone is an effective drug for tachycardic arrhythmias, but it is also associated with serious side effects.