Transplantation
Abstract
Hypothermia is commonly used to protect donor hearts during transplantation. However, patients transplanted with aged donor hearts still have severe myocardial injury and decreased survival rates, but the underlying mechanism remains unknown. Because aged hearts are not considered suitable for donation, the number of patients awaiting heart transplants is increasing. In this study, we examined whether hypothermic cardioprotection was attenuated in aged donor hearts during transplantation and evaluated potential therapeutic targets. Using a rat heart transplantation model, we found that hypothermic cardioprotection was impaired in aged donor hearts but preserved in young donor hearts. RNA-Seq showed that cold-inducible RNA-binding protein (Cirbp) expression was decreased in aged donor hearts, and these hearts showed severe ferroptosis after transplantation. The young donor hearts from Cirbp-KO rats exhibited attenuated hypothermic cardioprotection, but Cirbp overexpression in aged donor hearts ameliorated hypothermic cardioprotection. Cardiac proteomes revealed that dihydroorotate dehydrogenase (DHODH) expression was significantly decreased in Cirbp-KO donor hearts during transplantation. Consequently, DHODH-mediated ubiquinone reduction was compromised, thereby exacerbating cardiac lipid peroxidation and triggering ferroptosis after transplantation. A cardioplegic solution supplemented with CIRBP agonists improved hypothermic cardioprotection in aged donor hearts, indicating that this method has the potential to broaden the indications for using aged donor hearts in transplantation.
Authors
Yifan Zhu, Chenyu Jiang, Jian He, Chen He, Xingliang Zhou, Xu Huang, Yi Shen, Liwei Wu, Yongnan Li, Bei Feng, Yi Yan, Jun Li, Hao Zhang, Yiwei Liu
Abstract
Neuroinflammation is a recognized complication of immunotherapeutic approaches such as immune checkpoint inhibitor treatment, chimeric antigen receptor therapy, and graft versus host disease (GVHD) occurring after allogeneic hematopoietic stem cell transplantation. While T cells and inflammatory cytokines play a role in this process, the precise interplay between the adaptive and innate arms of the immune system that propagates inflammation in the central nervous system remains incompletely understood. Using a murine model of GVHD, we demonstrate that type 2 cannabinoid receptor (CB2R) signaling plays a critical role in the pathophysiology of neuroinflammation. In these studies, we identify that CB2R expression on microglial cells induces an activated inflammatory phenotype which potentiates the accumulation of donor-derived proinflammatory T cells, regulates chemokine gene regulatory networks, and promotes neuronal cell death. Pharmacological targeting of this receptor with a brain penetrant CB2R inverse agonist/antagonist selectively reduces neuroinflammation without deleteriously affecting systemic GVHD severity. Thus, these findings delineate a therapeutically targetable neuroinflammatory pathway and has implications for the attenuation of neurotoxicity after GVHD and potentially other T cell-based immunotherapeutic approaches.
Authors
Alison Moe, Aditya Rayasam, Garrett Sauber, Ravi K. Shah, Ashley Doherty, Cheng-Yin Yuan, Aniko Szabo, Bob M. Moore II, Marco Colonna, Weiguo Cui, Julian Romero, Anthony E. Zamora, Cecilia J. Hillard, William R. Drobyski
Abstract
Endothelial function and integrity are compromised after allogeneic bone marrow transplantation (BMT), but how this affects immune responses broadly remains unknown. Using a preclinical model of CMV reactivation after BMT, we found compromised antiviral humoral responses induced by IL-6 signaling. IL-6 signaling in T cells maintained Th1 cells, resulting in sustained IFN-γ secretion, which promoted endothelial cell (EC) injury, loss of the neonatal Fc receptor (FcRn) responsible for IgG recycling, and rapid IgG loss. T cell–specific deletion of IL-6R led to persistence of recipient-derived, CMV-specific IgG and inhibited CMV reactivation. Deletion of IFN-γ in donor T cells also eliminated EC injury and FcRn loss. In a phase III clinical trial, blockade of IL-6R with tocilizumab promoted CMV-specific IgG persistence and significantly attenuated early HCMV reactivation. In sum, IL-6 invoked IFN-γ–dependent EC injury and consequent IgG loss, leading to CMV reactivation. Hence, cytokine inhibition represents a logical strategy to prevent endothelial injury, thereby preserving humoral immunity after immunotherapy.
Authors
Ping Zhang, Peter Fleming, Christopher E. Andoniou, Olivia G. Waltner, Shruti S. Bhise, Jose Paulo Martins, Benjamin A. McEnroe, Valentina Voigt, Sheridan Daly, Rachel D. Kuns, Adaeze P. Ekwe, Andrea S. Henden, Alda Saldan, Stuart Olver, Antiopi Varelias, Corey Smith, Christine R. Schmidt, Kathleen S. Ensbey, Samuel R.W. Legg, Tomoko Sekiguchi, Simone A. Minnie, Mark Gradwell, Irma Wagenaar, Andrew D. Clouston, Motoko Koyama, Scott N. Furlan, Glen A. Kennedy, E Sally Ward, Mariapia A. Degli-Esposti, Geoffrey R. Hill, Siok-Keen Tey
Abstract
Antibodies can initiate lung injury in a variety of disease states such as autoimmunity, transfusion reactions, or after organ transplantation, but the key factors determining in vivo pathogenicity of injury-inducing antibodies are unclear. Harmful antibodies often activate the complement cascade. A model for how IgG antibodies trigger complement activation involves interactions between IgG Fc domains driving assembly of IgG hexamer structures that activate C1 complexes. The importance of IgG hexamers in initiating injury responses was unclear, so we tested their relevance in a mouse model of alloantibody and complement-mediated acute lung injury. We used three approaches to block alloantibody hexamerization (antibody carbamylation, the K439E Fc mutation, or treatment with domain B from Staphylococcal protein A), all of which reduced acute lung injury. Conversely, Fc mutations promoting spontaneous hexamerization made a harmful alloantibody into a more potent inducer of acute lung injury and rendered an innocuous alloantibody pathogenic. Treatment with a recombinant Fc hexamer ‘decoy’ therapeutic protected mice from lung injury, including in a model with transgenic human FCGR2A expression that exacerbated pathology. These results indicate an in vivo role of IgG hexamerization in initiating acute lung injury and the potential for therapeutics that inhibit or mimic hexamerization to treat antibody-mediated diseases.
Authors
Simon J. Cleary, Yurim Seo, Jennifer J. Tian, Nicholas Kwaan, David P. Bulkley, Arthur E. H. Bentlage, Gestur Vidarsson, Éric Boilard, Rolf Spirig, James C. Zimring, Mark R. Looney
Abstract
Long-term organ transplant survival remains suboptimal, and life-long immunosuppression predisposes transplant recipients to an increased risk of infection, malignancy, and kidney toxicity. Promoting the regulatory arm of the immune system by expanding Tregs may allow immunosuppression minimization and improve long-term graft outcomes. While low-dose IL-2 treatment can expand Tregs, it has a short half-life and off-target expansion of NK and effector T cells, limiting its clinical applicability. Here, we designed a humanized mutein IL-2 with high Treg selectivity and a prolonged half-life due to the fusion of an Fc domain, which we termed mIL-2. We showed selective and sustainable Treg expansion by mIL-2 in 2 murine models of skin transplantation. This expansion led to donor-specific tolerance through robust increases in polyclonal and antigen-specific Tregs, along with enhanced Treg-suppressive function. We also showed that Treg expansion by mIL-2 could overcome the failure of calcineurin inhibitors or costimulation blockade to prolong the survival of major-mismatched skin grafts. Validating its translational potential, mIL-2 induced a selective and sustainable in vivo Treg expansion in cynomolgus monkeys and showed selectivity for human Tregs in vitro and in a humanized mouse model. This work demonstrated that mIL-2 can enhance immune regulation and promote long-term allograft survival, potentially minimizing immunosuppression.
Authors
Orhan Efe, Rodrigo B. Gassen, Leela Morena, Yoshikazu Ganchiku, Ayman Al Jurdi, Isadora T. Lape, Pedro Ventura-Aguiar, Christian LeGuern, Joren C. Madsen, Zachary Shriver, Gregory J. Babcock, Thiago J. Borges, Leonardo V. Riella
Abstract
Tissue-intrinsic mechanisms that regulate severity of systemic pathogenic immune-mediated diseases, such as acute graft-versus-host disease (GVHD), remain poorly understood. Following allogeneic hematopoietic stem cell transplantation, autophagy, a cellular stress protective response, is induced in host nonhematopoietic cells. To systematically address the role of autophagy in various host nonhematopoietic tissues, both specific classical target organs of acute GVHD (intestines, liver, and skin) and organs conventionally not known to be targets of GVHD (kidneys and heart), we generated mice with organ-specific knockout of autophagy related 5 (ATG5) to specifically and exclusively inhibit autophagy in the specific organs. When compared with wild-type recipients, animals that lacked ATG5 in the gastrointestinal tract or liver showed significantly greater tissue injury and mortality, while autophagy deficiency in the skin, kidneys, or heart did not affect mortality. Treatment with the systemic autophagy inducer sirolimus only partially mitigated GVHD mortality in intestine-specific autophagy-deficient hosts. Deficiency of autophagy increased MHC class I on the target intestinal epithelial cells, resulting in greater susceptibility to damage by alloreactive T cells. Thus, autophagy is a critical cell-intrinsic protective response that promotes tissue tolerance and regulates GVHD severity.
Authors
Katherine Oravecz-Wilson, Emma Lauder, Austin Taylor, Laure Maneix, Jeanine L. Van Nostrand, Yaping Sun, Lu Li, Dongchang Zhao, Chen Liu, Pavan Reddy
Abstract
Corticosteroid treatment (CST) failure is associated with poor outcomes for patients with gastrointestinal graft-versus-host disease (GI GVHD). CST is intended to target the immune system, but the glucocorticoid receptor is widely expressed, including within the intestines, where its effects are poorly understood. Here, we report that corticosteroids directly target intestinal epithelium, potentially worsening immune-mediated GI damage. Corticosteroids administered to mice in vivo and intestinal organoid cultures ex vivo reduced epithelial proliferation. Following irradiation, immediate CST mitigated GI damage, but delayed treatment attenuated regeneration and exacerbated damage. In a murine steroid-refractory GVHD model, CST impaired epithelial regeneration, worsened crypt loss, and reduced intestinal stem cell (ISC) frequencies. CST also exacerbated immune-mediated damage in organoid cultures with “steroid-refractory” GR-deficient T cells or Interferon-γ. These findings correlated with corticosteroid-dependent changes in apoptosis-related gene expression and STAT3-related epithelial proliferation. Conversely, Interleukin-22 administration enhanced STAT3 activity and overcame corticosteroid-mediated attenuation of regeneration, reducing crypt loss and promoting ISC expansion in steroid-treated mice with GVHD. Therefore, CST has the potential to exacerbate GI damage if it fails to control the damage-inducing immune response, but this risk may be countered by strategies augmenting epithelial regeneration, thus providing rationale for clinical approaches combining such tissue-targeted therapies with immunosuppression.
Authors
Viktor Arnhold, Winston Y. Chang, Suze A. Jansen, Govindarajan Thangavelu, Marco Calafiore, Paola Vinci, Ya-Yuan Fu, Takahiro Ito, Shuichiro Takashima, Anastasiya Egorova, Jason Kuttiyara, Adam Perlstein, Marliek van Hoesel, Chen Liu, Bruce R. Blazar, Caroline A. Lindemans, Alan M. Hanash
Abstract
Virus-induced memory T cells often express functional cross-reactivity, or heterologous immunity, to other viruses and to allogeneic MHC molecules that is an important component of pathogenic responses to allogeneic transplants. During immune responses antigen-reactive naïve and central memory T cells proliferate in secondary lymphoid organs to achieve sufficient cell numbers to effectively respond whereas effector memory T cell proliferation occurs directly within the peripheral inflammatory microenvironment. Mechanisms driving heterologous memory T cell proliferation and effector function expression within peripheral tissues remain poorly understood. Here we dissected heterologous donor-reactive memory CD8 T cell proliferation and their effector functions following infiltration into heart allografts having low or high intensities of ischemic inflammation. Proliferation within both ischemic conditions requires p40 homodimer-induced IL-15 transpresentation by graft dendritic cells, but expression of effector functions mediating acute allograft injury occurs only in high-ischemic allografts. Transcriptional responses of heterologous donor-reactive memory CD8 T cells are distinct from donor antigen-primed memory CD8 T cells during early activation in allografts and at graft rejection. Overall, the results insights into mechanisms driving heterologous effector memory CD8 T cell proliferation and the separation between proliferation and effector function, that is dependent on the intensity of inflammation within the tissue microenvironment.
Authors
Hidetoshi Tsuda, Karen S. Keslar, William M. Baldwin III, Peter S. Heeger, Anna Valujskikh, Robert L. Fairchild
Abstract
Authors
Maggie E. Jones-Carr, Huma Fatima, Vineeta Kumar, Douglas J. Anderson, Julie Houp, Jackson C. Perry, Gavin A. Baker, Leigh McManus, Andrew J. Shunk, Paige M. Porrett, Jayme E. Locke
Abstract
Ischemia reperfusion injury (IRI)-mediated primary graft dysfunction (PGD) adversely impacts both short- and long-term outcomes after lung transplantation, a procedure which remains the only treatment option for patients suffering from end-stage respiratory failure. While B cells are known to regulate adaptive immune responses, their role in lung IRI is not well understood. Here, we demonstrate by intravital imaging that B cells are rapidly recruited to injured lungs, where they extravasate into the parenchyma. Using hilar clamping and transplant models, we observe that lung-infiltrating B cells produce the monocyte chemokine CCL7 in Toll-like receptor 4 (TLR4)-TRIF-dependent fashion, a critical step contributing to classical monocyte (CM) recruitment and subsequent neutrophil extravasation, resulting in worse lung function. We find that synergistic BCR-TLR4 activation on B cells is required for the recruitment of CMs to the injured lung. Finally, we corroborate our findings in reperfused human lungs, where we observe a correlation between B cell infiltration and CM recruitment after transplantation. This study describes a role for B cells as critical orchestrators of lung IRI. As B cells can be depleted with currently available agents, our study provides a rationale for clinical trials investigating B cell-targeting therapies.
Authors
Khashayar Farahnak, Yun Zhu Bai, Yuhei Yokoyama, Deniz B. Morkan, Zhiyi Liu, Junedh M. Amrute, Alejandro De Filippis Falcon, Yuriko Terada, Fuyi Liao, Wenjun Li, Hailey M. Shepherd, Ramsey R. Hachem, Varun Puri, Kory J. Lavine, Andrew E. Gelman, Ankit Bharat, Daniel Kreisel, Ruben G. Nava
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Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)