Immunocompetent Organ Models – the Future of Biomedical Research

In recent years, the field of biomedical research has witnessed a revolutionary shift with the advent of cutting-edge technologies such as organ-on-chip models. These miniature replicas of human organs offer a promising platform for drug testing, disease modeling, and personalized medicine. One crucial factor that plays a pivotal role in the success of these models is immunocompetence. In this blog post, we delve into the significance of immunocompetence in organ-on-chip models and how it opens new avenues for advancing medical research.

About Organ-on-Chip Models

Organ-on-chip models aim to simulate human organs and tissues on a microfluidic biochip. Comprehensive models are able to reproduce key functions and responses of organs in vitro and thus replicate molecular processes of the human body in vivo. This allows researchers to gain human-relevant insights for disease modelling, infections studies or drug development.

Most accurate data are produced with highly complex models including:

• • Integration of all relevant cell types
  • Vascularization allowing for blood flow
  • Perfusion promoting physiological differentiation
  • Immunocompetence
  • Microbes to model the microbiome (gut)

Especially the integration of multiple immune cell types, replicating the cellular complexity of the immune system is of high relevance for medical research. In the following chapters, we will go into further detail why immunocompetence is so important in organ models.

Why immunocompetence matters

The immune system is a critical component of the human body, playing a vital role in protecting against infections, eliminating diseased cells, and maintaining tissue homeostasis. Replicating the immune response in organ-on-chip models is something that has previously been overlooked, but is crucial for several reasons.

1. Inflammation and Chronic Diseases

Autoimmune diseases, such as rheumatoid arthritis and inflammatory bowel disease, develop when the adaptive immune system no longer tolerates self-antigens and instead establishes an immune response against them. Autoimmune diseases can affect almost all organs (Mello 2019 et al.). Triggers are complex, but usually involve a combination of genetic and environmental factors. Due to their complex nature, most, inflammatory diseases cannot faithfully be replicated in animal models, creating the need for physiological human in vitro models to advance research in this field. Immunocompetent organs-on-chip offer a potent model to study chronic inflammatory processes, paving the way for a deeper understanding of these diseases and the development of targeted therapies. At Dynamic42, we have a developed a colitis-on-chip model that simulates characteristics of inflammatory bowel disease observed in vivo (Figure below).

The intestine-on-chip model incorporates a vascular and an intestinal compartment, which are separated by a porous membrane. Compartments are bidirectionally perfused. Vascular perfusion mimics blood flow and is used to apply treatments, while epithelial perfusion is crucial to induce an intestinal villus- and crypt-like cytoarchitecture.

2. Tissue-resident immune cells

The impact of primary and secondary lymphoid organs on infection, injury, autoimmune or inflammatory diseases has been studied extensively. But what has been less studied is the immune responses in organs such as liver, lung, skin, kidney, intestine and even tumors (Maharjan 2020 et al., Wang 2023 et al.).

Numerous investigations (Prete 2022 et al., Gray 2022 et al., Ardain 2019 et al., Mueller 2015 et al., Shin 2013 et al.) have highlighted the existence of both adaptive and innate immune cells within non-lymphoid tissue, commonly referred to as tissue-resident immune cells. These cells engage with their immediate environment either through direct cell-cell interactions or indirectly via cytokines and assume a crucial role in orchestrating organ specific immune, tissue damage and inflammatory responses (Maharjan 2020 et al.). Therefore, it is paramount for truly comprehensive organ models to contain a tissue resident immune component for gaining profound insights into the physiology of organs and tissues. This in turn will aid to improve disease research as well as enhance therapeutic approaches for a spectrum of pathologies.

3. Accurate Disease Modeling

Diseases often involve complex interactions of different cell type. This is specifically true for immune cell interactions in autoimmune and inflammatory diseases. Importantly, even pathologies such fatty liver disease that at first glance are not connected to immune surveillance often have an immune component (Huby and Gautier 2021 et al.)

Pathologies modelled without the presence of immune cells frequently fall short in predicting the human response in vivo, highlighting the need for immunocompetent organ models  (Van Os 2023 et al.). Incorporating immunocompetence in organ-on-chip models allows for a more accurate representation of disease conditions, enabling researchers to study the dynamics of pathologies like cancer, inflammatory and autoimmune conditions, infectious diseases and neurological disorders (Wang 2023 et al.).

4. Drug discovery and development

As much as the immune system is involved in the regulation of the hosts defense against pathogens and cancerous cells it can also cause detrimental tissue damage when the immune response is exaggerated (Wang 2023 et.al.). It is because of this double-edged sword that in vitro models used to study novel drugs and therapies, especially those modulating the immune response, need to contain an immune component. The immune response influences the efficacy and safety of drugs, and understanding these interactions is essential for developing therapeutics that are both effective and well-tolerated by the human body.

An example is drug safety testing for T-cell bispecific antibodies (TCBs) used in the treatment of cancers. Due to low levels of expression of tumor antigens in healthy tissues TCBs are associated with an on-target, off-tumor risk.

At Dynamic42, we have developed a 3D microphysiological model of the human blood vessel to test for toxicity and immune-related adverse events caused by immunomodulatory antibodies (Figure below). We tested the model using TGN1412, an antibody deemed save and highly effective in pre-clinical studies conducted on macaques. Clinical trials, however, had to be terminated after six volunteers experienced a life-threatening CD4 T cell/IL2-driven cytokine storm and blood vessel inflammation followed by vascular leakage. When tested in our in vitro model, TGN1412 induced the release of IL-2 from CD4+ T cells, leading to a breakdown of the endothelial barrier and subsequent vascular leakage.

5. Personalized Medicine

Personalized medicine aims to tailor medical treatment to an individual’s unique characteristics, including their immune profile. Immunocompetent organ-on-chip models have the potential to contribute to personalized medicine by allowing researchers to assess how an individual’s immune system responds to specific drugs or treatments. Sharifi 2019 et al. developed a foreign body response biochip that allows for integration of human donor derived monocytes to model the immune cells response to implant material with the aim to identify suitable ones for the patient.

6. Cancer research

Developing microphysiological models of a person’s tumor microenvironment (TME) is crucial, especially for advancing cancer immunotherapy. The lack of representative preclinical models to predict clinical efficacy and safety outcomes poses a major impediment for widespread adoption of novel immunotherapies (Maulana 2021 et al.).

The TME significantly influences an individual’s immune profile through the creation of an immunosuppressive milieu, ultimately impacting the response of the immune system to cancer cells. It is noteworthy that the TME possesses human-specific biophysical and biochemical factors, as highlighted in studies such as Liu 2021 et al. Furthermore, the involvement of monocytes, macrophages, and neutrophils in tumor development, as emphasized by Binnewies 2018 et al., adds complexity to the overall understanding.

Considering these challenges and complexities, the development of microphysiological models that faithfully replicate the tumor composition of individual patients, including the immune component, becomes imperative. This approach opens avenues for the creation of personalized drug methods tailored to the unique characteristics of a patient’s tumor. At Dynamic42, we are actively addressing this need by establishing a pancreatic cancer spheroid-on-a-chip model containing patient-derived TME (fibroblasts, figure below). These models not only ensure immunocompetence but also incorporate an embedded tumor microenvironment, providing a robust platform for screening novel therapeutic approaches in a personalized manner.

Conclusion

The integration of immunocompetence in organ-on-chip models represents a groundbreaking advance in biomedical research. These models, simulating human organs on microfluidic biochips, have proven instrumental in drug testing, disease modeling, and personalized medicine. The immune system, often overlooked, plays a pivotal role in protecting against infections and maintaining tissue homeostasis. Immunocompetence is crucial, where its inclusion in organ-on-chip models enhances research and therapeutic development.

Accurate disease modeling benefits from immunocompetent organ-on-chip models, faithfully replicating complex interactions between different cell types, especially immune cells. This ensures a more accurate representation of disease conditions, enabling researchers to study various pathologies and improve predictions of human responses in vivo.

Immunocompetence’s role extends to drug discovery, understanding the dual nature of the immune system in regulating host defense and potentially causing tissue damage. Microphysiological models contribute to a better understanding of drug efficacy and safety, crucial for developing therapies modulating the immune response.

Personalized medicine stands to benefit significantly from immunocompetent organ-on-chip models, allowing researchers to assess an individual’s immune system response to specific drugs or treatments. Ongoing efforts, such as developing patient-derived pancreatic cancer spheroid-on-a-chip models, showcase the promising future of these innovative approaches in shaping biomedical research.

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