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Saudi Journal of Kidney Diseases and Transplantation
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SPECIAL ARTICLE-BOOK REVIEW  
Year : 2012  |  Volume : 23  |  Issue : 3  |  Page : 538-544
Innate alloimmunity part 2: Innate immunity and allograft rejection


Director-General, Saudi Center for Organ Transplantation, Riyadh, Kingdom of Saudi Arabia

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Date of Web Publication7-May-2012
 

How to cite this article:
Shaheen F. Innate alloimmunity part 2: Innate immunity and allograft rejection. Saudi J Kidney Dis Transpl 2012;23:538-44

How to cite this URL:
Shaheen F. Innate alloimmunity part 2: Innate immunity and allograft rejection. Saudi J Kidney Dis Transpl [serial online] 2012 [cited 2020 Jul 12];23:538-44. Available from: http://www.sjkdt.org/text.asp?2012/23/3/538/95794
Walter Gottlieb Land

Baskent University Ankara, Turkey and Pabst Science Publishers Lengerich, Germany

This book is Part 2 of the two-part mono­graph in which the emerging role of innate immunity in organ transplantation (Innate Alloimmunity) is comprehensively presented and described for the first time worldwide. In a Prologue, the author outlines modern notions in immunology claiming that the innate immune defense system is not only directed against pathogen-mediated tissue injury but against any tissue injury, including allograft injury. In this context, the author emphasizes that, during the last decade, accumulating experimental and clinical evidence has been published in favor and support of his original 'Injury Hypo­thesis' holding that it is the primary allograft injury that - in addition to its foreignness - induces innate immune pathways (1) leading to alloimmune-mediated allograft rejection, and (2) contributing to the development of alloatherosclerosis and allofibrosis as major pathohistological features of chronic allograft dysfunction. Accordingly, in this book, the author has collected and meticulously des­cribed a wealth of supporting evidence that have recently led to those revolutionizing notions in transplant medicine.

The book is presented in eight chapters headed (1) 'Early appreciation in the 1990s: The injured allograft as an acutely inflamed organ and the first clues to the existence of innate alloimmunity', (2) 'Oxidative allograft injury revisited at the beginning of the new millennium', (3) 'Oxidative injury-induced, damage-associated molecular pattern molecules and their pattern recognition receptors', (4) 'Role of pattern recognition receptors in me­diating oxidative tissue injury via activation of dendritic cells, innate lymphocytes, and T lymphocytes', (5) 'Experimental and clinical findings in direct and indirect support of the existence of innate alloimmunity', (6) 'Chronic allograft dysfunction: a model disease of innate immunity', (7) 'Immunosuppressive strategies in light of innate alloimmunity' and (8) 'Appendix: Innate alloimmunity and blood coagulation'. These chapters are self-contained although coherent with each other and close up each with a separate extensive reference section.

Chapter 1 is a very readable report on early appreciation of the injured allograft as an acutely inflamed organ (163 references). In particular, the story of the Munich SOD trial in kidney transplant patients -decorated with a few anecdotes - is attractively told, a history that provided the first clues to the existence of innate alloimmunity and represents the hour of birth of the 'Injury Hypothesis'. Also in this chapter, the reader is reminded that, in the 1990s, interrelations between postischemic allograft reperfusion injury and early clinical events such as delayed graft function and acute rejec­tion episodes/immune-mediated graft loss were already well recognized. In addition, the reader learns of early notions in the 1990s, already holding that the allograft reperfusion injury contributes to T-cell alloactivation via up-regulation of costimulatory molecule expression on antigen-presenting cells such as dendritic cells.

Chapter 2 (390 references) covers the modi­fication and extension of the 'Injury Hypo­thesis' during 2002-2005 as well as focuses on the oxidative allograft injury in terms of the canonical allograft injury able to activate the innate immune system of the donor and the recipient. Sources and mechanisms of reactive oxygen species (ROS) production during post-ischemic reperfusion injury and the role of antioxidative defense systems are extensively described. Emphasis is put on the initial gene­ration of ROS in vascular cells of the reperfused donor organ and their secondary gene­ration by allograft-invading phagocytes (e.g., neutrophils) of recipient origin during reper­fusion. The crucial role of the 3 hypoxiasensing, ROS-producing enzyme systems (mitochondria-derived complex I and III of the electron transport chain, NADPH-related oxidases, xanthine oxidoreductase) for intracellular ROS generation is particularly stressed and decorated with self-explaining impressive color figures. Indeed, - as emphasized in separate sections - increasing evidence suggests that the generation of ROS is necessary and respon­sible for the stabilization and accumulation of the transcription factor HIF (hypoxia-inducing factor), and that all 3 enzyme systems are involved in the process of the sensing of low oxygen tension. Thus, - as also discussed in this chapter - the evolutionary advantage of ROS production during tissue reperfusion seems to be clear: to survive life-threatening hypoxic conditions via up-regulation of HIF-induced expression of target genes responsible for the induction of hypoxia survival mecha­nisms such as increased glucose transport, glycolysis, erythropoiesis, and angiogenesis. And transplant clinicians are well aware of two pe­riods of hypoxia affecting a transplant: during organ removal in the donor and reperfusion in the recipient. So the 'evolutionary sense' here is primarily to lead to a stabilization and accu­mulation of HIF, which evokes an efficient anti-hypoxia response program. However, as discussed by the author, the 3 ROS-producing enzyme systems, located in the donor organ vessels and extemporaneous and unprepared for sensing such a 'strange' hypoxic pattern of hypoxia-anoxia-hypoxia, overreact by produ­cing ROS in excess: a superoxide 'flash' that leads to oxidative allograft injury associated with the generation of DAMPs.

Chapter 3 and 4, covering the description of injury -induced damage-associated molecular patterns (DAMPs) (366 references) and the role of their corresponding pattern recognition receptors (PRRs) (330 references), actually reflect the core of the book. These chapters, divided into topically ordered sections and subsections, inform the reader about the prin­ciples of current notions on innate immunity holding that any tissue injury, including stress­ful oxidative injury, primarily leads to the induction of DAMPs that are recognized by PRRs located either on or in mobile/circulating or immobile/resident cells of the innate immune system such as macrophages, dendritic cells, neutrophils, vascular cells, epithelial cells, myofibroblasts, etc. After recognition of DAMPs, PRR-triggered signaling pathways are initiated leading -via recruitment of adapter molecules and activation of transcription factors- to distinct functionalities of the cells, at each case depending on their programmed function, for example, macrophages secret cytokines or chemokines thereby mounting tissue inflammation and immature dendritic cells (DCs) mature to immunostimulatory antigen-presenting cells able to initiate and elicit an adaptive T-/B-cell immune response. Clearly, these two chapters, equipped with a variety of self-explaining impressive and instructive color figures, will be most useful, instructive and informative to transplant clinicians entering the arena of innate immunity and to scientists undertaking future experimental and clinical research in this field. In more detail:

Chapter 3 covers the description of DAMPs that are believed to play a role in allograft injuries leading to rejection. DAMPs are injury-induced endogenous molecules that are nor­mally hidden in non-injured tissue. For didac­tic reasons, they have been divided by the author into four different classes: (1) class I DAMPs such as 'high mobility group box 1' (HMGB1) are referred to as injury-induced endogenous molecules recognized by and interacting with Toll-like receptors (TLRs) and RAGE, the receptor for advanced glycation end-products, expressed for example on/in dendritic cells; (2) class II DAMPs, such as MHC class I chain-related proteins (MICs) recognized by and interacting with special recognition receptors expressed on innate lym­phocytes; (3) class III DAMPs such as extra­cellular adenosine-5'- triphosphate (eATP), recognized by and interacting with PRRs such as nucleotide-binding domain leucine-rich repeats (NLR) -containing family of PRRs and AIM2, expressed for example on macrophages and preferentially responsible for the activa­tion of inflammasomes; and (4) class IV DAMPs such as nonmuscle myosin heavy chain II (NMHC-II), that is neo-antigens, recognized by preexisting natural IgM antibodies.

In Chapter 4, the role of PRRs, after engage­ment with DAMPs, in mediating and conver­ting tissue injury to full-scale 'sterile' tissue inflammation is thoroughly presented and dis­cussed. With special reference to oxidative allograft injury, emphasis is put on the activa­tion of PRR-bearing phagocytes, DCs, innate lymphocytes such as NK cells, as well as T lymphocytes, that is, cells of the innate immune system involved in the establishment of an inflammatory milieu, for example, as occurring in the course of postischemic reper­fusion injury.

In regard to this scenario, the author convin­cingly attempts to explore the crucial role of donor- and recipient-derived DCs in the initiation of innate alloimmunity by presenting and discussing accumulating evidence from the literature in support of the notion that it is predominantly the oxidative injury to allo-grafts (starting already in the organ donor) that -via induction of class I DAMPs - meta­morphoses PRR-bearing immature DCs into mature immunostimulatory DCs, a process associated with promotion of alloantigen re­presentation and cross-presentation, up-regulation of MHC molecule and costimulatory molecule expression, and secretion of Th1- and Th17- polarizing cytokines (eg, IL-12). Pattern recognition receptor (TLR2/4, RAGE) -triggered intracellular signaling path­ways have been identified that - via recruit­ment of adaptor molecules such as MyD88 and TRIF - activate the three pro-inflammatory master transcription factors NF-κB, AP-1 and IRF3, which, besides others, activate those genes responsible for the metamorphosis of steady-state DCs into potent immunostimulatory antigen-presenting cells capable of promoting the expansion and effector differentiation of naive alloantigen-specific T cells. In separate sections, the phenomenon of a cross-talk bet­ween DCs and innate lymphocytes is des­cribed, a process that contributes to the gene­ration of immunostimulatory DCs.

In the center of this scenario, the author dis­cusses the initial creation of a global intragraft inflammatory milieu beginning in organs to be potentially transplanted from the brain-dead donor and aggravated during allograft reper­fusion injury in the recipient. Obviously, namely, signals from those PRRs mentioned above are not the only prerequisite for full DC activation, but the additional creation of an inflammatory milieu appears to be necessary for DCs to acquire full immunostimulatory capacities. And according to recent leading-edge research work in the field of innate immune-mediated tissue inflammation (the articles concerned cited in this Chapter), the formation of molecular scaffolds termed 'inflammasomes' are those molecular machines of the innate immune system that are responsible for the establish­ment of injury-induced tissue inflammation.

In fact, the PRRs such as TLR4/2 and RAGE appear to operate in concert and collaboration with another family of PRRs predominantly located in macrophages which, after interaction with and recognition by class III DAMPs, are able to activate the 'inflammasomes' such as the most investigated NLRP3-inflammasome that is activated by distinct class III DAMPs and - remarkably- under involvement and participation of ROS. Activation of the NLRP3-inflammasome, as described in detail in this chapter, creates a global inflammatory milieu via autocatalytic cleavage of caspase-1 which ultimately leads to the processing and thus secretion of pro-inflammatory cytokines, most importantly IL-1β and IL-18. Of note, as also discussed in this chapter, recent evidence suggests that those inflammasomes are able to shape an adaptive immune response.

In addition, in this Chapter 4, the author impressively attempts also to explore the po­tential role of donor- and recipient-derived DCs in the induction of innate allotolerance by presenting recent convincing evidence in sup­port of the notion that these antigen-presenting cells may develop into tolerogenic DCs when antigens are presented under subimmunogenic conditions in a non-inflammatory microenvi­ronment. These tolerogenic DCs then, in turn, may induce antigen-specific regulatory T cells (Tregs) able to induce and maintain a tolerant state. In fact, the author's concept that weakly-presented alloantigens in a non-injured allograft, that is, under subimmunogenic condi­tions in the absence of inflammation, may lead to allotolerance induction via induction of Tregs is strongly supported by elegant studies on the murine model of immune responses to Y chromosome-encoded transplantation antigens as quoted in this Chapter.

In Chapter 5, experimental and clinical fin­dings in direct and indirect support of the existence of innate alloimmunity are covered by admitting that these findings from targeted studies are still meager. Nevertheless, in a few experiments quoted in this Chapter, it could be shown that blockade or deficiency in one or the other PRRs and/or their agonists/DAMPs, downstream-signaling molecules, or transcrip­tion factors led to prolongation of allograft survival. As cited in this Chapter, this has been shown experimentally for DAMPs such as heat shock protein 72 and HMGB1; the RAGE receptor as well as TLR4/TLR2-recruited adap­tor molecules MyD88 and TRIF; and the trans­cription factor, NF-κB. However, the graft-prolonging effect in these experiments was moderate. However, as concluded by the author, this is not surprising, in view of the considerable redundancy in the innate immune defense system and the action of both direct and indirect allorecognition. In the arena of clinical transplantation, first clinical analyses in lung-, kidney- and heart transplanted pa­tients with TLR4 polymorphisms revealed that these patients were less likely to experience acute and/or chronic rejection.

Chapter 6 of the book (343 references) covers one of the major problems after successful organ transplantation: chronic allograft dys­function that - according to the author's defi­nition - represents a model disease of innate immunity. In the center of this topic, transplant atherosclerosis (alloatherosclerosis) and trans­plant fibrosis (allofibrosis,{including epithelial-mesenchymal transition}), the 2 leading pathognomonic features of chronic allograft dys­function, were chosen as pathohistological examples promoted by activated cells of the innate immune system that - via creation of an inflammatory response -contributes to and maintains atherogenesis and fibrogenesis (in­cluding mechanisms of epithelial-mesenchymal transition).

The chapter starts with some historical remarks referring to observations from the Munich SOD trial assuming that postischemic allograft reperfusion injury contributes to the development of chronic transplant rejection (transplant vasculopathy). Following, this chapter provides substantial information from a growing literature suggesting that acute and chronic allograft injuries, including oxidative injury, via activation of vascular cells of the innate immune system, lead to inflammatory mechanisms within the vasculature as being pathogenetically important in atherosclerosis. The intimate relationship between atheroscle­rosis (and fibrosis) and inflammation is exem­plified in separate sections by the description of interaction of DAMPs with PRRs-bearing vascular cells and myofibroblasts as well as involvement of cytokines and chemokines at all stages of the process of atherosclerosis (and fibrosis). In particular, references are quoted reporting that DAMPs such as oxidized LDL, HMGB1, and cholesterol crystals interacting with PRRs on vascular cells such as LOX-1, TLR4/2, RAGE and NLRP3, are involved in atherogenesis. In this scenario, the NLRP3-inflammasome again seems to play a dominant role.

In a subchapter of this chapter, the author outlines some potential links between iden­tified antigen- dependent and -independent risk factors for chronic allograft dysfunction (including reperfusion injury, hypertension, hyperlipidemia, viral infection, and high donor age) and the activation of the innate immune system of the donor organ. Special emphasis is put on the risk factor high donor age.

In fact, in this section, besides others, the author introduces his remarkable theory of ageing posed in 2004:"Under evolutionary pressure, a strong innate immune system evolved to protect the host as a rapid first line of defense against invading pathogens causing tissue injury. The defense response is provided by PRR-bearing cells of innate immunity that are able to recognize and interact with PAMPs (pathogen-associate molecular pattern). Humans and animals were selected with traits that allowed them, during youth, to resist infections and survive, and thus, to concentrate on repro­duction. After reproductive decline, activation of the same innate immune system is induced by tissue injury, this time caused by ROS generated due to increased mitochondrial leakage during old age. PRR-bearing cells recognize and interact with injury-induced molecules, that is, DAMPs, such as heat shock proteins. The subsequent innate immune response is directed at the organism itself and contributes to aging and age-related diseases. As these negative effects of innate immunity take place in old age, they exert less selective pressure than their positive benefits in youth."

The author closes this chapter with the con­clusion that, if one considers chronic allograft dysfunction as a model of a primarily innate immune-mediated disease, one may eventually open the door to novel therapeutic strategies. In vitro/ex vivo manipulation of allograft vascular cells, for example, using genetic engineering methods before implantation of the donor organ or chronic inhibition of the generation of DAMPs in the recipient, may belong to such considerations.

Chapter 7 presents a thoroughly written over­view on potential immunosuppressive stra­tegies in light of innate alloimmunity and, thus, represents a topic likely to have a huge impact on organ transplantation in the future. Clearly, as stressed by the author, the ultimate goal of all those strategies is to harness innate immune pathways in a way to modulate them in terms of negative regulation to induce innate allotolerance. In other words, the ultimate goal of all those strategies is to prevent/inhibit/miti­gate the generation of donor-and recipient-derived immunostimulatory DCs, and instead, to promote the generation of tolerogenic DCs that, in turn, are able to induce alloantigen-specific T regulatory cells associated with the achievement of a state of allotolerance. In this sense, generation of tolerogenic DCs is an active process of the innate immune system that has to be resolutely harnessed by transplantologists in terms of promoting this pro­cess by whatever means.

This trendsetting chapter is presented as seven extensively referenced review subchapters (altogether 245 references), starting with the description of some principles of the use of innate immunity-suppressing drugs and closing up with an outlook dedicated to the question on what can we do tomorrow; a question that is answered with the suggestion to begin tomorrow with a trial in deceased donors, for example, by applying a quintuple treatment consisting of (1) an anti-oxidant, (2) a comple­ment inhibitor, (3) an IL-1β inhibitor, (4) a TLR4 antagonist, and (5) a polyclonal anti-lymphocytic preparation.

The discussion of principles in this chapter 7 includes the fact that the donor's innate immune system mediates the direct pathways of allorecognition/alloactivation, which is mainly responsible for the development of acute rejection episodes during the first weeks and months post-transplant, whereas the recipient's innate immune system mediates the pathways of indirect allorecognition/alloactivation and appears to be predominantly responsible for the processes of chronic allograft rejection. Consequently, transplant clinicians must rea­lize that there is a time-restricted therapeutic window for the suppression of the innate immune system ranging from treatment of the donor before/during organ removal to treat­ment of the recipient before/during allograft implantation and during the first postoperative days. In addition, in view of the considerable pleiotropicity and redundancy in innate allo­immune responses, transplantologists who want to prevent the generation of immunostimulatory donor-derived and recipient-derived DCs within a ROS-mediated inflammatory allograft milieu with the aim to induce allotolerance, have only 2 rational approaches: either they apply an efficient monotherapy at the early level of the inciting allograft oxidative injury, or they apply a combination of multiple inhibiting agents that can act at the level of DAMPs or PRRs and/or effector mediators such as cytokines. The author con­cludes that the latter approach appears still to be questionable in view of those multiple redundant pathways operating in alloimmunity- quite aside from the problem of getting a cli­nical trial with a multiple drug regimen approved by the authorities. What remains the most promising approach, according to the author's opinion, is the rigorous treatment of the initial oxidative injury to an allograft, to prevent all those subsequently induced, redun­dant, innate immune pathways.

In subsequent separate subchapters, potential therapeutic targets of innate immunity-sup­pressing agents are summarized by dividing them into (1) prevention/mitigation of oxidative injury to the donor organ; (2) prevention of development of immunostimulatory DCs; and (3) blockade/inhibition of effector func­tions such as inhibition of inflammasome-mediated secretion of IL-1β. In regard to successful suppression/prevention/inhibition of innate immune responses, potential therapeutics are summarized by dividing them into pharmaceutics/pharmaceuticals (small molecules the­rapeutics), biological agents (biologics, biologicals), and genetic engineering (genetic mani­pulation of a cell, in particular, the use of RNA interference).

By writing this overview chapter, the author emphasizes those therapeutic strategies that are able to prevent, inhibit or minimize oxidative injury to the donor organ in order to avoid frustrating treatment of redundant innate immune pathways. Plausibly, such an antioxidative treat­ment has to begin in the deceased organ donor where the generation of ROS has been docu­mented and then, perhaps even more justified, in the recipient during allograft reperfusion. Theoretically and as suggested by the author, in regard to injury-induced innate alloimmunity, any attempt to prevent the generation of ROS in a donor organ should start with a strategy to reduce the hypoxic state during both in situ organ perfusion in the donor and allograft reperfusion in the recipient. The next target of therapeutic strategies should include inhibi­tion/blockade of the 3 ROS-producing enzyme systems, followed by methods to scavenge the generated reactive oxygen species, in parti­cular superoxide anions, thereby reducing the oxidative burst. All these suggestions are do­cumented by supportive experimental findings and observations as quoted in the international literature concerned.

In a separate subchapter, the author provides an explanation for the fact that, up to date, that is 16 years after a dramatic beneficial effect of the free radical scavenger SOD on both acute and chronic rejection processes had been proven, no antioxidative agent has been clin­ically developed in the field of organ trans­plantation. In terms of some ethical reflections (by asking the question: Who should fund innate alloimmunity-suppressing drugs?), he discusses that the reason for the failure to develop those agents predominantly lies in a lack of marketing interests on the side of the pharmaceutical industry, however, - as stressed by the author - a quite legitimate reason of 'Big Pharma'.

Chapter 8 is written as an appendix and deals with the topic of innate alloimmunity in relation to blood coagulation, in more detail, with the evolutionary linkage between coagulation and inflammation, a linkage that- as described in this Chapter - is best exemplified by study of the host defenses of the Atlantic horseshoe crab. The mechanisms by which innate inflammatory responses (such as induced by post-ischemic reperfusion injury) promote coagu­lation, are outlined in detail by emphasizing a crucial role of the tissue factor. The author himself asks: "Why do I mention this example here? In terms of 'back to the future,' the question is: Can we perform duct-occluded segmental pancreas transplantation again, this time, by avoiding injury-induced, innate immune-mediated clotting, for example, by suppressing innate immune events using 1 or several approaches mentioned in Chapter 7?"

The book closes up with an optimistic Epilogue that reflects the current opinion of the author on the future role of innate alloimmunity: "Once again, I firmly believe that allograft injury-induced pathways and pro­cesses of innate immunity are not only critical for the induction and direction of the adaptive alloimmune response, leading to allograft rejection, but also for the induction and direc­tion of allotolerance, allowing discontinuation of maintenance immunosuppression in success­fully transplanted patients, as originally dis­cussed in my article in Current Opinion in Organ Transplantation 1999. As the area of innate allotolerance is largely unexplored, we can look forward to new discoveries and many novel findings in this area in the immediate future. Hopefully
!" This book is an up-to-date resource book that provides a valuable summary of the emerging field of innate immunity in transplantation, past, present and future. The book - in conjunction with Part 1 of the monograph on 'Innate Immunity and Host Defense' - also gives an excellent and comprehensive notion about the enormous achievements in this modern field of immunology within the last 10 years. In this sense, the book is an invaluable resource for clinicians and researchers entering the field of innate immunity in organ transplantation, a starting point for reviewing the literature on the various and multifaceted topics of the innate immune system. It would be a good text to hand to new students entering the field, because it is not too daunting in size or complexity, but rich in sources of further information about those various cellular/hu­moral and signaling pathways involved in innate immune responses and valuable for identifying the key players in the development of innate immunity in transplant medicine, past, present and future.

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Correspondence Address:
Faissal Shaheen
Director-General, Saudi Center for Organ Transplantation, Riyadh
Kingdom of Saudi Arabia
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