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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2022. Understanding the Role of the Immune System in Improving Tissue Regeneration: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26551.
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1

Introduction
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The innate and adaptive immune systems are cornerstones of the human body’s response to tissue damage and injury. The innate immune system, which is the body’s nonspecific line of defense against non-self pathogens, is initially activated in response to tissue damage. As part of the healing process, acute inflammation via the innate immune system is associated with tissue repair and regeneration (Julier et al., 2017). Through the recruitment of neutrophils and macrophages, the early immune response clears cellular debris, remodels the extracellular matrix, and induces the production of high levels of cytokines (Julier et al., 2017). The adaptive immune system is subsequently activated, serving a critical role in tissue repair and regeneration through the activity of immune cells and their interactions with tissue-resident stem cells.

During normal homeostasis processes, such as cell turnover, the immune system’s essential role in facilitating tissue repair and regeneration is well characterized. However, in the context of a cell-damaging event, such as injury, less is known about the specific mechanisms that activate the immune system to shift the balance toward tissue regeneration. Moreover, within the adaptive immune system, the specific molecular interactions

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1 The planning committee’s role was limited to planning the workshop, and the Proceedings of a Workshop was prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop. Statements, recommendations, and opinions expressed are those of individual presenters and participants; have not been endorsed or verified by the Health and Medicine Division of the National Academies of Sciences, Engineering, and Medicine; and should not be construed as reflecting any group consensus.

Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2022. Understanding the Role of the Immune System in Improving Tissue Regeneration: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26551.
×

between T cells and tissue-resident stem cells—and how these two cell types contribute to overall tissue healing—have not yet been fully elucidated.

The immune system changes with advancing age. Over time, thymic atrophy can lead to a decline in adaptive immune responses and a state of chronic innate immune system activation, known as age-associated inflammation (Kasler and Verdin, 2021). This state of persistent low-grade immune activation can weaken the immune system’s capacity for tissue repair and lead to the development of degenerative disease. Many regenerative medicine therapies are designed to treat age-related degenerative conditions. The development of these therapies would benefit from better understanding how the immune system is modulated during aging and how those age-related changes affect the overall coordination of endogenous tissue regeneration. A patient’s immune response is also foundational to the clinical success of cell- and tissue-based regenerative medicines (Zakrzewski et al., 2014). For example, the success of allogeneic cell-based therapies can be undermined by immunological challenges, such as graft-versus-host disease and host rejection. Surmounting those challenges will require developing tolerance-inducing strategies, similar to those used to support patients receiving solid organ or hematopoietic stem cell transplants. There may be opportunities to learn from those fields how to assess a patient’s immune system prior to treatment as a way to improve clinical outcomes of cell-based therapies.

Implantable, engineered biomaterials have been shown to be effective in modulating the immune system (Browne and Pandit, 2015; Sridharan et al., 2015). From a clinical perspective, however, important knowledge gaps persist at the intersection of immunology and regenerative medicine. Among the fundamental research questions to be explored are whether modulating a patient’s own immune system could improve regenerative medicine outcomes and, more broadly, whether the use of regenerative medicine approaches to activate the immune response and promote tissue repair could feasibly contribute to therapeutic success.

To address these and other gaps in the understanding of promising approaches to manipulate the immune system and/or the regenerative medicine product to improve outcomes of tissue repair and regeneration in patients, the Forum on Regenerative Medicine at the National Academies of Sciences, Engineering, and Medicine convened a two-day virtual public workshop titled “Understanding the Role of the Immune System in Improving Tissue Regeneration.” During the workshop, participants explored open questions about the role of the immune system in the success or failure of regenerative medicine therapies. They considered potential strategies to effectively “prepare” patients’ immune systems to accept regenerative therapies and increase the likelihood of successful clinical outcomes as well as considered risks associated with modulating the immune system.

Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2022. Understanding the Role of the Immune System in Improving Tissue Regeneration: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26551.
×

Participants also reflected on lessons learned from related fields of research and clinical practice, including organ and bone marrow transplantation and age-associated inflammation. The Statement of Task for the workshop can be found in Box 1-1. A broad array of stakeholders participated in the workshop, including immunologists, cell biologists, bioengineers, industry researchers, regulatory officials, clinicians, product manufacturers, patients, and other experts.

OPENING REMARKS

In the workshop welcome, Kathy Tsokas, vice president of Regulatory, Quality, Risk Management and Drug Safety at Janssen Inc. Canada, called for a broader conversation with the public about harnessing the

Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2022. Understanding the Role of the Immune System in Improving Tissue Regeneration: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26551.
×

full potential of the immune system to prepare patients for more successful treatment outcomes. The discussion, she said, should center on the understanding that discoveries are for the benefit of the people who need them. In her remarks, Nadya Lumelsky, chief of the Integrative Biology and Infectious Diseases Branch and director of the Tissue Engineering and Regenerative Medicine Research Program at the National Institutes of Health’s National Institute of Dental and Craniofacial Research, provided an orientation to the workshop. The goal of regenerative medicine is to repair and regenerate tissues compromised by disease, injury, or aging. This field has existed for several decades, but despite many proof-of-principle successes in animal models, relatively few therapies are currently available in clinics. This workshop was designed to address areas that could enable the accelerated translation of therapies into the clinic, with a focus on the immune system—specifically, how to leverage patients’ immune systems to optimize tissue regeneration, she said.

Early attempts to regenerate tissues primarily focused on the identification and isolation of stem and progenitor cells, fueled by the idea that identifying the “right” cells would solve the problem of tissue regeneration, said Lumelsky. Although this continues to be an important area of research, it is now widely recognized that the microenvironment of tissues—often referred to as the stem cell niche—also plays a key role in the outcome of regenerative medicine therapies. Furthermore, the innate and adaptive immune systems that are part of this niche are of paramount importance. In fact, the variability in outcomes seen in the clinic with regenerative medicine therapies is often related to the patient’s own immune system.

Tissue inflammation was once seen as detrimental for tissue healing and regeneration; therefore, inhibiting inflammation was believed to create a permissive environment for regeneration, Lumelsky said. However, it is now recognized that immune system inflammation is critical for effective regeneration. Productive regeneration requires certain elements of the inflammatory response, but inflammation can be problematic when it becomes chronic and initiates cyclical tissue destruction, she explained. Thus, the patterning of the immune system and controlling inflammation at the right time and place become crucial, said Lumelsky.

Lumelsky outlined two overarching themes for the workshop: (1) optimizing graft acceptance and integration of grafted cells with host tissues for cell-based regenerative therapies, and (2) optimizing the tissue microenvironment—or stem cell niche—to both promote endogenous regeneration and inhibit tissue fibrosis and scarring. In addition, participants were encouraged to discuss how to optimize therapies for translation into clinical practice. Kimberlee Potter, scientific program manager for the Biomedical Laboratory Research and Development Service at the U.S. Department of Veterans Affairs Office of Research and Development, encouraged the

Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2022. Understanding the Role of the Immune System in Improving Tissue Regeneration: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26551.
×

workshop participants, and the field at large, to center the patient in the regenerative medicine paradigm. Centering the patient in the care paradigm involves accounting for variability in patient responses to therapies. She recalled compelling stories shared by parents during a previous workshop convened by the Forum on Regenerative Medicine to explore novel clinical trial designs for gene-based therapies, in which parents described experiences their children endured with immune suppression protocols for gene-based therapies (NASEM, 2020).

Potter said that another earlier workshop, Applying Systems Thinking to Regenerative Medicine, explored critical quality attributes in cell manufacturing processes and quality-by-design manufacturing (NASEM, 2021). However, missing from the discussion was information regarding the people receiving advanced therapies and the inability to predict whether the therapy would be safe and effective. A patient-focused perspective might consider variability due to unique underlying biology and health status. With the patient at the center of the care paradigm, it is possible to develop strategies to precisely manipulate the patient’s immune system to optimize graft acceptance or endogenous tissue regeneration, she added.

Keeping the patient voice at the center of the discussion was underscored by comments early in the workshop from Sherilyn George-Clinton, a leader of Multiple Sclerosis: You Are Not Alone. George-Clinton stated that she has lived with autoimmune disorders for more than 20 years. During the 11 years she has been diagnosed with multiple sclerosis, her immune system has been modulated, suppressed, and reset. She shared her enthusiasm about research to harness the immune system’s powers to improve health. In this era of ultra-specialization in research, scientists should share their progress, findings, and ideas with one another, keeping patients always at the forefronts of their minds, George-Clinton remarked.

Potter also charged participants and the field to identify knowledge gaps in regenerative medicine to stimulate basic discovery science. In the current post-acute COVID-19 era, centering the immune system in discovery science can serve as a reminder that discoveries should link directly to patients receiving these therapies. Addressing knowledge gaps may involve the development of tools or preclinical models needed to mitigate risk from regenerative medicine therapies. She encouraged participants to consider how advances in fields such as organ transplantation, immunological tolerance, and wound healing can propel regenerative medicine therapies forward.

ORGANIZATION OF THE PROCEEDINGS

This Proceedings of a Workshop summarizes the presentations and discussions that took place at the workshop on November 2 and 3, 2021.

Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2022. Understanding the Role of the Immune System in Improving Tissue Regeneration: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26551.
×

The workshop opened with a keynote presentation on the foundational concepts of tissue homeostasis, inflammation, and repair (Chapter 2). The first session examined lessons learned about immune tolerance and graft acceptance from the field of transplant immunology with applications to regenerative medicine (Chapter 3). Speakers discussed the interaction between the microbiome and graft-versus-host disease, the potential to engineer direct differentiation in pluripotent stem cells to mesenchymal stem cells, and the value of a reverse translation approach—“from bench to bedside and back to the bench”—in developing therapies with better patient outcomes. The second session focused on efforts to engineer allogeneic donor cells for acceptance by the host’s immune system (Chapter 4). Presentations and discussions explored the potential for cell-based transplantation without immunosuppression by protecting allogeneic cells from immune destruction—potentially through hypoimmune cells—and the need to identify and incorporate patient-specific biomarkers that predict outcomes to inform treatment design. The third session concentrated on endogenous regeneration and the role of the local environment in repair, with a focus on approaches that manipulate endogenous modulators of cell regeneration, cell degeneration, and aging (Chapter 5). Participants discussed how biomaterials and B cells can influence wound healing, as well as the roles of molecular mediators, prostaglandin E2 (PGE2) and developmental endothelial locus-1 (DEL-1), in healing and regenerative responses. The fourth session considered strategies to modulate the host immune system to create a pro-regenerative environment (Chapter 6). It included presentations on the applications of cellular senescence and senolytics to organ regeneration and transplantation, the use of the tissue microenvironment as an intervention target in the interdisciplinary field of regenerative immunology and immunotherapies, and the role of specialized pro-resolving mediators in the resolution of inflammation. The fifth session explored advances in developing tools and preclinical models for monitoring and optimizing the host’s pro-regenerative environment (Chapter 7). Presenters described how the local biology of “cellular neighborhoods” can have prognostic and clinical value, the potential to use “living drugs” comprising engineered T cells (e.g., chimeric antigen receptor [CAR] T immunotherapies) to remove senescent cells and modulate tissue regeneration, and rational design for developing anti-fibrotic and pro-healing biomaterials. The final session featured a panel discussion on possibilities for harnessing the immune system to improve outcomes for patients (Chapter 8). The workshop closed with reflections on the future of regenerative medicine with regard to the immune system (see Box 8-1). The workshop agenda is in Appendix A. Appendix B includes speakers’ biographical sketches, and Appendix C contains the approved Statement of Task for the workshop.

Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2022. Understanding the Role of the Immune System in Improving Tissue Regeneration: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26551.
×
Page 1
Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2022. Understanding the Role of the Immune System in Improving Tissue Regeneration: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26551.
×
Page 2
Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2022. Understanding the Role of the Immune System in Improving Tissue Regeneration: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26551.
×
Page 3
Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2022. Understanding the Role of the Immune System in Improving Tissue Regeneration: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26551.
×
Page 4
Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2022. Understanding the Role of the Immune System in Improving Tissue Regeneration: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26551.
×
Page 5
Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2022. Understanding the Role of the Immune System in Improving Tissue Regeneration: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26551.
×
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The Forum on Regenerative Medicine of the National Academies of Sciences, Engineering, and Medicine convened a two-day virtual public workshop to address knowledge gaps in the understanding of promising approaches to manipulate the immune system and/or the regenerative medicine product to improve outcomes of tissue repair and regeneration in patients. The workshop, titled "Understanding the Role of the Immune System in Improving Tissue Regeneration," explored the role of the immune system in the success or failure of regenerative medicine therapies. Participants considered potential strategies to effectively "prepare" patients' immune systems to accept regenerative therapies and increase the likelihood of successful clinical outcomes and also discussed risks associated with modulating the immune system. This Proceedings of a Workshop highlights the presentations and discussions that occurred during the workshop.

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