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Tissue damage, Cell death and Danger signals in Transplantation

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Tissue damages −resulting from either ischemia reperfusion injury in the setting of solid organ transplantation or conditioning regimens before allogeneic hematopoietic cell transplantation− are considered involved in the initiation of deleterious immune responses leading to graft rejection or to the ...

Tissue damages −resulting from either ischemia reperfusion injury in the setting of solid organ transplantation or conditioning regimens before allogeneic hematopoietic cell transplantation− are considered involved in the initiation of deleterious immune responses leading to graft rejection or to the development of graft-versus-host disease (GvHD). These tissue damages lead to the release of alarmins and to the triggering of pathogen-recognition receptors (PRR) that activate innate immune cells and subsequently the adaptive immune system. Heparan sulfate, ATP, High mobility group box-1 (HMGB-1), or defensins may participate to ischemia reperfusion injury or GvHD triggering in experimental models. It has been demonstrated that the activation of PRR −such as the NLPR3/ASC inflammasome complex− or IL-1 receptors triggers experimental acute GvHD. In Humans, single nucleotide polymorphisms of PRR, such as TLR4 or NOD2/CARD15 may impact the outcome of allogeneic hematopoietic cell transplantation or solid organ transplantation. Finally, soluble ST2 −a member of IL-1 receptor family− has been recently identified as a biomarker of steroid-resistant acute GvHD in several patient cohorts. All these data highlight the role of endogenous danger signals resulting from tissue damage as major deleterious factors in transplantation outcome. Different forms/types of cell death have been recently identified and the different signaling pathways that are involved are currently being deciphered. Some of these cell death processes are rather immunologically inert or associated with immune tolerance. For instance, apoptosis is associated with immunomodulatory properties that have been harnessed in different experimental transplantation models to favor tolerance. A recent clinical study reports the use of early donor apoptotic cell infusion in order to prevent GvHD. However, immunogenic apoptotic cell death has also been described, notably after the use of anti-cancer chemotherapeutic drugs that can be used in conditioning regimens. The immunostimulatory effects of immunogenic apoptosis are related to the release of damage-associated molecular pattern (DAMP), such as calreticulin or ATP. Other cell death processes can occur during the transplantation settings, such as necroptosis which plays a role in ischemia reperfusion injury or pyroptosis associated with bioactive IL-1 secretion. Furthermore, while its definitive link with neutrophil cell death is a matter of debate, NETosis can also provide immunostimulatory signals during ischemia reperfusion injury favoring graft rejection. Thus, cell death mechanisms occurring during the transplantation procedures −including either solid organ storage or after conditioning regimens− may influence transplantation outcome. The immunogenicity of cell death is under the control of DAMP and alarmin release.

The goal of this research topic is to link tissue damage, cell death and DAMP in transplantation settings. In other words, the objective of this research topic is to determine how current processes including solid organ storage, conditioning regimens, or other iatrogenic procedures, may generate such DAMP release or a particular cell death process. Another objective is to determine how therapeutic approaches may limit the occurrence of DAMP release or of immunogenic cell death, or may harness it in order to improve transplantation outcome. Indeed, harnessing tolerogenic cell death is an interesting approach to favor transplantation tolerance. The therapeutic effects of extracorporeal photopheresis (ECP) −a therapeutic approach used in both solid organ and in the treatment of GvHD− may be related to its capacity to generate apoptotic cell death. This collection of articles aims to promote interactions between researchers involved in solid organ transplantation (e.g., liver, kidney, heart and composite tissue, such as face transplantation) and in hematopoietic cell transplantati


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