Transplantation and Damage-Associated Molecular Patterns (DAMPs)

Land, W.; Agostinis, Patrizia; Gasser, Stephan; Garg, Abhishek D.; Linkermann, Andreas

doi:10.1111/ajt.13963

Cited by 131 publications

(120 citation statements)

References 392 publications

(526 reference statements)

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“…Our results also explain other reported connections of defective TLR signaling in mice deficient in complement components (77, 78). Since emerging evidence suggests that early post-transplant sterile inflammation is triggered by DAMP/TLR ligations (15, 79) our findings raise the possibility that peri-transplant blockade of C3ar1/C5ar1 signaling could attenuate the deleterious effects of early inflammation on enhancing alloimmunity so as to improve graft survival and function.…”

Section: Discussionmentioning

confidence: 71%

TLR-Induced Murine Dendritic Cell (DC) Activation Requires DC-Intrinsic Complement

Sheen

Strainic

Wang

et al. 2017

The Journal of Immunology

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Induction of pro-inflammatory T cell immunity is augmented by innate dendritic cell (DC) maturation commonly initiated by Toll-like receptor (TLR) signaling. We demonstrate that ligation of TLR3, 4, and 9 induces murine DC production of complement components and local production of the anaphylatoxin C5a. In vitro, ex vivo, and in vivo analyses show that TLR-induced DC maturation as assessed by surface phenotype, expression profiling by gene array, and functional ability to stimulate T cell responses, requires autocrine C3a- and C5a-receptor (C3ar1/C5ar1) signaling. Studies employing bone marrow chimeric animals and Foxp3-GFP/ERT2-Cre/dTomato fate mapping mice show that TLR-initiated, DC autocrine C3ar1/C5ar1 signaling causes expansion of effector T cells and instability of regulatory T cells and contributes T cell-dependent transplant rejection. Together, our data position immune cell-derived complement production and autocrine/paracrine C3ar1/C5ar1 signaling as crucial intermediary processes that link TLR-stimulation to DC maturation and the subsequent development of effector T cell responses.

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Section: Discussionmentioning

confidence: 71%

TLR-Induced Murine Dendritic Cell (DC) Activation Requires DC-Intrinsic Complement

Sheen

Strainic

Wang

et al. 2017

The Journal of Immunology

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“…Some researchers reported various instances where SNS model seemed to fail e.g. MHC‐mismatched kidney transplants from living donors performing better than MHC‐compatible kidneys from deceased donors or graft‐vs‐host disease being less severe in recipients that had gentle (rather than harsh) preconditioning treatments . Moreover, it was still not clear why adjuvants were mandatory to make bacterial or viral vaccines work effectively, despite latter's obvious microbial non‐self composition …”

Section: Historical Background: From Self/non‐self Model To Anti‐tumomentioning

confidence: 99%

Cell death and immunity in cancer: From danger signals to mimicry of pathogen defense responses

Garg

Agostinis

2017

Immunological Reviews

339

275

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The immunogenicity of cancer cells is an emerging determinant of anti-cancer immunotherapy. Beyond developing immunostimulatory regimens like dendritic cell-based vaccines, immune-checkpoint blockers, and adoptive T-cell transfer, investigators are beginning to focus on the immunobiology of dying cancer cells and its relevance for the success of anticancer immunotherapies. It is currently accepted that cancer cells may die in response to anti-cancer therapies through regulated cell death programs, which may either repress or increase their immunogenic potential. In particular, the induction of immunogenic cancer cell death (ICD), which is hallmarked by the emission of damage-associated molecular patterns (DAMPs); molecules analogous to pathogen-associated molecular patterns (PAMPs) acting as danger signals/alarmins, is of great relevance in cancer therapy. These ICD-associated danger signals favor immunomodulatory responses that lead to tumor-associated antigens (TAAs)-directed T-cell immunity, which paves way for the removal of residual, treatment-resistant cancer cells. It is also emerging that cancer cells succumbing to ICD can orchestrate "altered-self mimicry" i.e. mimicry of pathogen defense responses, on the levels of nucleic acids and/or chemokines (resulting in type I interferon/IFN responses or pathogen response-like neutrophil activity). In this review, we exhaustively describe the main molecular, immunological, preclinical, and clinical aspects of immunosuppressive cell death or ICD (with respect to apoptosis, necrosis and necroptosis). We also provide an extensive historical background of these fields, with special attention to the self/non-self and danger models, which have shaped the field of cell death immunology.

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“…Moreover, graft cells injured during the ischemia/reperfusion (I‐R) process release various damage‐associated molecular patterns (DAMPs) into the perfusate . DAMPs are a heterogeneous collection of molecules released by injured and dying cells that bind to distinct pattern‐recognition receptors on tissue resident leukocytes and graft cells, initiating proinflammatory responses …”

mentioning

confidence: 99%

Damage‐Associated Molecular Patterns Induce Inflammatory Injury During Machine Preservation of the Liver: Potential Targets to Enhance a Promising Technology

et al. 2019

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Machine preservation (MP) has emerged as a promising technology in liver transplantation, but the cellular processes occurring during MP have not been characterized. Recent studies have noted the presence of inflammatory molecules generated during MP. We hypothesized that there is a metabolism‐dependent accumulation of damage‐associated molecular patterns (DAMPs) and inflammatory cytokines during MP and that these molecules provoke inflammation in the graft. To stratify groups by metabolic rate, MP was performed on rat livers from standard donors at 3 different temperatures: room temperature (RT), subnormothermic (30°C), and normothermic (37°C). Static cold storage at 4°C was included as a reference group. Following a 4‐hour preservation period, graft reperfusion was performed ex vivo at 37°C (n = 6 for all groups). Levels of DAMPs and inflammatory cytokines were measured, and their biological activity was assessed by determining toll‐like receptor (TLR) stimulation, inflammatory gene expression, and activation of cell death pathways. There was a time‐dependent increase in levels of DAMPs during MP with high‐mobility group box 1 and extracellular DNA levels increasing for all groups ( P < 0.05, 30 versus 240 minutes). Tumor necrosis factor α levels in the perfusate also increased during MP for all groups ( P < 0.05, 30 minutes versus 240 minutes). Levels of inflammatory molecules correlated with increased activation of TLRs (TLR3, P = 0.02, normothermic machine preservation [MP37] versus machine preservation at room temperature [MPRT]; TLR9, P = 0.02, MP37 versus MPRT). Priming of the NLRP3 inflammasome and activation of cell death pathways were reduced in grafts preserved by MP at room temperature. In conclusion, inflammatory molecules produced during MP have a biological impact on the graft. Therapies to attenuate DAMP‐mediated inflammation during MP may further enhance this promising technology.

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Transplantation and Damage-Associated Molecular Patterns (DAMPs)

Cited by 131 publications

References 392 publications

TLR-Induced Murine Dendritic Cell (DC) Activation Requires DC-Intrinsic Complement

TLR-Induced Murine Dendritic Cell (DC) Activation Requires DC-Intrinsic Complement

Cell death and immunity in cancer: From danger signals to mimicry of pathogen defense responses

Damage‐Associated Molecular Patterns Induce Inflammatory Injury During Machine Preservation of the Liver: Potential Targets to Enhance a Promising Technology

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