Understanding the Role of the Immune System in Improving Tissue Regeneration Proceedings of a Workshop (2022) / Chapter Skim
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3 Lessons Learned from Immune Tolerance and Graft Acceptance
3 Lessons Learned from Immune Tolerance and Graft Acceptance
Pages 15-32
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From page 15... ...
de velopment of pluripotent hematopoietic stem cells from human plu ripotent stem cells and (2) durable mixed chimerism with nontoxic conditioning.
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THE MICROBIOME AND IMMUNE TOLERANCE: LESSONS FROM ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION Robert Jenq, deputy department chair of genomic medicine and associate professor of genomic medicine and stem cell transplantation at the University of Texas MD Anderson Cancer Center, stated that allotransplant is a standard treatment for hematological malignancies and is commonly complicated by graft-versus-host disease (GVHD)
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In the 1980s, Rainer Storb at the Fred Hutchinson Cancer Center in Seattle studied the effects of sterilization on bone marrow transplant patients. A 1983 study reported findings on patients with severe aplastic anemia who were conditioned with cyclophosphamide, followed by a bone marrow transplant from matched siblings (Storb et al., 1983)
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Some antibiotic associations were only observed in particular centers, likely due to center-specific practices in first-line treatment for neutropenic fever, Jenq noted. Factors Underlying Loss of Microbiome Diversity Jenq and his colleagues at MD Anderson Cancer Center have further explored the associations between antibiotics and GVHD.
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Jenq noted that an additional advantage of preclinical animal studies is the opportunity to investigate potential mechanisms. Jenq described the work of Eiko Hayase, postdoctoral fellow at MD Anderson Cancer Center, who explored whether the meropenem was depleting beneficial bacteria or contributing to the expansion of harmful bacteria.
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The removal or depletion of the microbiome -- as was done in early studies -- also lowers the inflammatory risk. However, a microbiome that is in an unstable state between the two extremes of healthy or depleted poses the largest risk for GVHD, translocation, or alloimmune rejection of stem cells.
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Tolerance retains normal immune function, preserving the ability to resist infection and cancer. Cell Engineering to Avoid Graft Rejection An alternative strategy to tolerance, Sykes highlighted, is cell engineering to avoid the rejection of tissues, and possibly organs, derived from pluripotent hematopoietic stem cells.
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One approach involves cell therapy of various cell types that have demonstrated a regulatory function in animal models, said Sykes. Multiple clinical trials in HCT and organ transplantation are examining Tregs.
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Pure Deletional Tolerance through Durable Mixed Chimerism Mechanisms of this and other regimens have since been shown to involve depletion of alloreactive T cells in both the peripheral and thymic compartments, said Sykes. Donor hematopoietic stem cells are grafted in the bone marrow, and these hematopoietic stem cells then send progeny and coexisting recipient cells to the recipient thymus.
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While testing a monkey model, she and her colleagues learned that transient mixed chimerism associated with HCT transplantation at the time of kidney transplant from the same donor could lead to tolerance. This discovery led to successful tolerance protocols supported by the Immune Tolerance Network (Kawai et al., 2008; Kawai et al., 2013)
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Applications of Immune Tolerance and Graft Acceptance to Regenerative Medicine Sykes outlined the relevance of immune tolerance and graft acceptance to regenerative medicine. The transplant community is working to develop gentler, non-myeloablative regimens for mixed chimerism induction that foster systemic tolerance to the donor.
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Once the modality is developed, a researcher can be creative in terms of the bacteria that can potentially be made, he added. Effects of Systemic Homeostasis and Inflammation on Immune Response Given that most work on immune response and regeneration focuses on the local niche yet is also influenced by systemic immune homeostasis, Talib asked how systems-level immune function dysregulation can be understood and manipulated to aid local regeneration.
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From page 27... ...
This area of research is emerging, as most knowledge of the immune system is based on antimicrobial functions, Medzhitov commented. Mechanisms of Tolerance in HLA-mismatched Transplants Given that the MGH protocol can generate tolerance in HLA-identical or mismatched transplants, whereas the protocol from Stanford University has only been able to generate tolerance in HLA-matched transplants, Talib asked how these protocols differ and what lessons from the differences can be applied to tolerance induction in HLA-mismatched cases.
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Sykes and her colleagues are currently exploring tolerance induction to xenografts. Immune responses against xenografts are more formidable and involve more mechanisms than responses to allografts, she said.
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Approaches to supporting the survival and stability of infused Tregs are being explored, and clinical trials are conducting safety tests on methods to expand endogenous Tregs via drugs or cytokines and on several cell-based mechanisms. Tolerogenic dendritic cells and mesenchymal stem cells have been shown to be associated with expanded donor-specific Tregs.
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Better understanding of such immune system inputs is necessary to pursue the preferred strategy of preventing activation of the immune system rather than suppressing an ongoing immune response, he said. Organoid Models Given that tissues have specific immune environments with tissueresident immune cells playing an important role, Talib asked how organoid models with induced pluripotent stem cells can be used to understand the local immune system environment and improve methods for tissue and cell transplantation.
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He remarked that making regenerative medicine more attractive through tool development could be a tipping point for the field, given that interesting questions beyond practical implications are already being asked. Sykes emphasized the potential benefits of engineering or directly differentiating pluripotent stem cells into hematopoietic stem cells.
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The approach is fertile ground for generating hypotheses and experimental testing, he continued. Talib added that the California Institute of Regenerative Medicine utilizes this type of approach in "translation going from bench to bedside and from bedside back to the bench" to better understand basic biology or immunology to advance the field.
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