RESUMEN
The pathophysiological importance of the immunogenicity of damage-associated molecular patterns (DAMPs) has been pinpointed by their identification as triggers of allograft rejection following release from dying cells, such as after ischemia-reperfusion injury. In cancers, however, this strong trigger of a specific immune response gives rise to the success of cancer immunotherapy. Here, we review the recently literature on the pathophysiological importance of DAMP release and discuss the implications of these processes for allograft rejection and cancer immunotherapy, revealing a striking mechanistic overlap. We conclude that these two fields share a common mechanistic basis of regulated necrosis and inflammation, the molecular characterization of which may be helpful for both oncologists and the transplant community.
Asunto(s)
Rechazo de Injerto/inmunología , Inflamación/fisiopatología , Neoplasias/inmunología , Daño por Reperfusión/inmunología , Aloinjertos , Animales , Rechazo de Injerto/patología , Humanos , Necrosis , Neoplasias/patología , Daño por Reperfusión/patologíaRESUMEN
Upon solid organ transplantation and during cancer immunotherapy, cellular stress responses result in the release of damage-associated molecular patterns (DAMPs). The various cellular stresses have been characterized in detail over the last decades, but a unifying classification based on clinically important aspects is lacking. Here, we provide an in-depth review of the most recent literature along with a unifying concept of the danger/injury model, suggest a classification of DAMPs, and review the recently elaborated mechanisms that result in the emission of such factors. We further point out the differences in DAMP responses including the release following a heat shock pattern, endoplasmic reticulum stress, DNA damage-mediated DAMP release, and discuss the diverse pathways of regulated necrosis in this respect. The understanding of various forms of DAMPs and the consequences of their different release patterns are prerequisite to associate serum markers of cellular stresses with clinical outcomes.
Asunto(s)
Estrés del Retículo Endoplásmico , Rechazo de Injerto/etiología , Inflamación/fisiopatología , Trasplante de Órganos/efectos adversos , Animales , Humanos , NecrosisRESUMEN
The EuroSPK Study group was created during the 4th Spitzingsee 1997 workshop in Kühtai, Austria. Thanks to W. Land for the incentive to gather European Centres--with Switzerland and Israel--and propose them to joint efforts and share data in the field of pancreas transplantation. Today, two prospective randomized studies have been already performed; a lot of data and results have been generated and worldwide spread. The spirit of the group will continue with a new interest in innate immunity and prevention of the ischemic reperfusion injury in pancreas transplantation.
Asunto(s)
Congresos como Asunto , Trasplante de Páncreas/historia , Austria , Protocolos Clínicos , Historia del Siglo XX , Humanos , Trasplante de Páncreas/métodosRESUMEN
An emerging body of evidence suggests that the innate immune system plays a critical role in allograft rejection. Any injury to the donor organ, e.g. the reperfusion injury, induces an inflammatory milieu in the allograft which appears to be the initial event for activation of the innate immune system. Injury-induced intragraft damage- associated molecular patterns (DAMPs) are recognized by donor-derived and recipient-derived, TLR4/2-bearing immature dendritic cells (iDCs). After recognition, these cells mature and initiate allorecognition/alloactivation in the lymphoid system of the recipient. Indeed, the key "innate" event, leading to activation of the adaptive alloimmune response, is the injury-induced, TLR4-triggered, and NFkappaB-mediated maturation of DCs ("innate alloimmunity"). Time-restricted treatment of innate immune events would include 1) treatment of the donor during organ removal, 2) in-situ/ex-vivo treatment of the donor organs alone, and 3) treatment of the recipient during allograft reperfusion and immediately postoperatively. Treatment modalities would include 1) minimization of the oxidative allograft injury with the use of antioxidants; 2) prevention of the TLR4-triggered maturation of DCs with the use of TLR4-antagonists; 3) inhibition of complement activation with the use of complement inhibiting agents. According to data from clinical and experimental studies it can be assumed that successful suppression of innate alloimmune events results in either subsequent significant reduction in, or even complete avoidance of the currently applied adaptive alloimmunity-suppressing drugs. However, in view of the time-restricted period of treatment, and the fear to potentially destroy its own business with currently applied alloimmunity-suppressing drugs, the pharmaceutical industry is still, but quite legitimately, reluctant to invest in the high cost of clinical development of those drugs for transplant patients because there are no marketing interests. On the other hand, clinical development of innate alloimmunity-suppressing drugs is urgently warranted. But: Who should fund? In this article, three options are explored which may contribute to a solution of the problem: 1) provision of incentives to companies for drug development; 2) conduction of clinical trials in developing countries; and 3) creation of a public-private professional partnership in analogy to the "European Rare Diseases Therapeutic Initiative" (ERDITI). We suggest and recommend the creation of such a partnership which may be called: "The European Initiative for the Suppression of Innate Alloimmunity" ("EISIA"). In analogy to ERDITI, the main goals of this organization should be:--to provide a streamlined facilitated process of collaboration between Academic Teams/Transplant Centres, Study Groups, and Pharma Companies to develop innate alloimmunity-suppressing drugs;--to give Academic Teams/Transplant Centres facilitated access to a large variety of compounds, developed by companies for other indications, which can be evaluated pre-clinically and, if warranted, clinically;--to guarantee the continuity all the way from research to development and commercialisation of the drug. If preclinical studies uncover the potential of a compound for suppressing innate alloimmune events, the Pharma Partner who has rights to this compound will either develop himself the drug for organ transplantation indication or allow its development by the academic team or a third party if he has no intentions of developing himself.
Asunto(s)
Industria Farmacéutica/economía , Ética en Investigación , Inmunidad Innata , Inmunosupresores/economía , Apoyo a la Investigación como Asunto/organización & administración , Ensayos Clínicos como Asunto , Países en Desarrollo , Industria Farmacéutica/ética , Industria Farmacéutica/legislación & jurisprudencia , Europa (Continente) , Rechazo de Injerto/prevención & control , Humanos , Inmunidad Innata/efectos de los fármacos , Inmunidad Innata/inmunología , Propiedad Intelectual , Relaciones Interinstitucionales , Comercialización de los Servicios de Salud , Modelos Inmunológicos , Trasplante de Órganos , Apoyo a la Investigación como Asunto/ética , Trasplante HomólogoRESUMEN
Experimental and clinical evidence has accumulated in support of the notion that oxidative injuries to allografts induce an adaptive alloimmune response which leads to acute rejection. The link between the initial injury and subsequent rejection is the innate immune system represented by injury-activated donor-derived and recipient-derived dendritic cells which interact with naïve T cells of the recipient to induce an alloimmune T-cell response. Therefore, time is mature to consider potential therapeutic strategies that are able to suppress events of innate immunity. Such strategies refer to a "time-restricted therapeutic window" that includes treatment of the donor during organ removal and the recipient during allograft reperfusion. Major targets of such treatment include (1) mitigation of the oxidative allograft injury; (2) inhibition of injury-induced activation of complement; (3) inhibition of Toll-like receptor (TLR)-mediated and innate lymphocyte-triggered maturation of dendritic cells; and (4) blockade of innate effector functions. A considerable variety of promising experimental studies about the prevention/inhibition of innate immune events has already been performed, including the successful experimental use of gene silencing methods, eg, using RNA interference technology with the application of small interfering RNA (siRNA). In addition, a few clinical trials with antioxidants (edaravone, SOD-mimetics), complement inhibitors (pexelizumab, TP-10) in patients with acute myocardial infarction, and TLR4 antagonists (TAK-242, E-5564) in patients with sepsis have been performed or are underway. Performance of similar clinical trials in transplant patients with antioxidative drugs, complement inhibitors, and/or TLR4 antagonists is urgently warranted; siRNAs appear to be extremely attractive for investigation in experimental allogeneic transplant models.