Understanding the Role of the Immune System in Improving Tissue Regeneration Proceedings of a Workshop (2022) / Chapter Skim
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7 Tools and Preclinical Models for Monitoring and Optimizing the Host's Pro-Regenerative Environment
7 Tools and Preclinical Models for Monitoring and Optimizing the Host's Pro-Regenerative Environment
Pages 95-112
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From page 95... ...
immunotherapies use engineered T cells with synthetic receptors to treat certain types of cancer; these cells can be designed and manufactured as "living drugs." (Sadelain) • Novel applications of CAR T-cell therapies for regenerative medicine may include removing senescent cells and modulating tissue regen eration.
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From page 96... ...
explore recent advances in monitoring and imaging of the immune system as well as the potential implications of these new approaches for clinical translation of regenerative medicines and (2) discuss challenges and opportunities with regard to preclinical models for studying immune system involvement in response to regenerative medicine.
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From page 97... ...
Advantages of the CODEX approach include its integration with existing microscope platforms, making it broadly accessible to more researchers, and that it does not require coordinating with a tissue analysis core, he said. In the current era, collecting data through the CODEX approach and analysis methods is relatively straightforward; rather, the primary challenges are data analysis and extraction of meaning from large datasets, Nolan remarked.
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From page 98... ...
Lymph Node Cellular Neighborhoods To demonstrate how relational rules can be extracted from CN analysis, Nolan used the example of lymph nodes from the tonsil and spleen, because they provide a standard baseline of a nonactivated immune system. The lymph nodes across the human body are evolutionarily similar, yet the tissues have structural differences, he noted.
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From page 99... ...
Case Study: Colorectal Tumor Immune Microenvironment To illustrate how cellular neighborhoods can be used to study pathology, Nolan and his team conducted a case study of the colorectal tumor immune microenvironment (Schurch et al., 2020)
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Local CNs and the relationships between them can be used to predict which type of tumor a patient has, which may influence therapeutic options, he suggested. In the context of regenerative medicine, mapping the organization of pathologies could inform the development of novel therapeutics to enhance tissue regeneration processes.
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From page 101... ...
T-cell engineering, employs genetic engineering to instruct T-cell functionality and is the primary focus of Sadelain's work. Assembling Chimeric Antigen Receptors for Cell Therapy Sadelain provided an overview of the process by which CARs, or synthetic T-cell receptors, are assembled for cell therapy (Riviere and Sadelain, 2017)
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From page 102... ...
. Therapeutic Potential of Senolytic CAR T Cells in Regenerative Medicine In addition to providing a paradigm for the development of CAR T cells, advances in CD19 CAR therapy have potential to open new avenues BOX 7-1 Impacts of CD19 CAR Therapy • Provides clinical benefit for patients with relapsed B-cell malignancies • Ushered "synthetic biology" (e.g., chimeric proteins)
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From page 103... ...
Regenerative medicine can reciprocally offer new prospects for the development of tools and therapies to the field of T-cell engineering, he noted. For instance, CAR therapy typically relies on autologous T cells collected from patients, but investigators are interested in alternatives like collecting cells from healthy volunteers or using pluripotent stem cells.
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From page 104... ...
BASIC IMMUNOLOGY TO GUIDE REGENERATIVE THERAPEUTIC DESIGN Kaitlyn Sadtler, Earl Stadtman Tenure-Track Investigator and chief of the Section on Immunoengineering at the National Institute of Biomedical Imaging and Bioengineering, discussed how basic immunology can guide regenerative therapeutic design, noting that it is now possible to apply an understanding of mechanistic biology to guide the design of biomaterials. Immunoengineering in Human Health and Disease The various functions of the immune system in human health and disease give rise to the potential of immunoengineering (i.e., engineering the immune system)
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From page 105... ...
Her laboratory and others are looking more deeply into the immune response to the injury and to the material implantation. Both the location of an injury and the type of implanted material can affect immune cell recruitment, activation, and polarization, creating a varied repertoire of different cells and signaling molecules that can then ultimately interact with stem cells, explained Sadtler.
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From page 106... ...
. Modeling the Poles of Innate Immune Responses with Representative Materials To evaluate immune responses to implanted biomaterials, Sadtler and her team model opposing "poles" of immune responses using two representative materials -- one pro-fibrotic and one pro-regenerative -- implanted in a mouse model.
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From page 107... ...
. Human Immune Responses to Trauma and Recovery: Learning from Clinical Data While the context of mouse models can be useful, Sadtler emphasized the importance of learning from clinical models and patients to inform animal models of disease, and vice versa.
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From page 108... ...
Eventually, the aim would be to start with quantitative modeling and perturb the computational system to eliminate approaches that are unlikely to be successful before testing them in vivo or in the clinic, Sadtler described. There are multiple approaches underway to integrate these data and engineer biomaterials for immune-guided regenerative therapeutics -- for example, to prevent fibrosis of the medical devices used in reconstruction and to grow back new tissues using regenerative therapeutics, she explained.
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From page 109... ...
Sadtler was asked whether immune responses change when progenitor stem cells are added to biomaterials before implantation in the host. She replied that her group has not investigated that directly because their work focuses primarily on endogenous repair, but she noted that stem cells themselves can be highly immunomodulatory.
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From page 110... ...
The CD28 domain creates an "explosive" effector cell endowed with maximal effector functions, but this comes at the expense of longevity of the cells, which rapidly proceed into terminal differentiation. Other costimulatory domains, 41BB being the prototype, program a weaker effector profile, but they enhance the persistence of those cells.
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From page 111... ...
Developing New Tools and Preclinical Models Kassim asked each presenter for their perspectives on priorities in developing tools and preclinical models for both monitoring the performance of regenerative medicines and using them to create more effective therapies. In the context of early-stage translational science, Sadtler discussed the potential benefits of collecting more clinical data and conducting more thorough analyses of human responses to materials and trauma.
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From page 112... ...
Although cancer has been a useful starting point for understanding wound repair, he highlighted that the CODEX methodology could be used with other models of wound repair or pathology to search for common rules that guide the immune response. These common rules and cellular complexes might elucidate which immune cells are necessary in a certain organization to carry out a particular function, he added.
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