The T cell as a bridge between innate and adaptive immune systems: Implications for the kidney

Kidney International, Vol. 61 (2002), pp. 1935–1946

PERSPECTIVES IN BASIC SCIENCE

The T cell as a bridge between innate and adaptive immune systems: Implications for the kidney HAMID RABB Nephrology Division, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

The T cell as a bridge between innate and adaptive immune systems: Implications for the kidney. The immune system is classically divided into innate and adaptive components with distinct roles and functions. T cells are major components of the adaptive immune system. T cells are firmly established to mediate various immune-mediated kidney diseases and are current targets for therapy. Ischemic acute renal failure, a major cause of native kidney and allograft dysfunction, is mediated in part by inflammatory components of the innate immune system. However, recent data from experimental models in kidney as well as liver, intestine, brain and heart implicate T cells as important mediators of ischemia reperfusion injury. These data reveal new insights into the pathogenesis of ischemic acute renal failure, as well as identify novel and feasible therapeutic approaches. Furthermore, the identification of T cells as a mediator of early alloantigenindependent tissue injury demonstrates that the functional capacity of T cells spreads beyond adaptive immunity into the realm of the innate immune response.

There is increasing evidence for the immunopathogenesis of renal diseases that were previously not recognized to have an immune basis [1]. Ischemia-reperfusion injury (IRI) to the kidney, a major cause of acute native kidney and allograft dysfunction, is now established to involve components of the immune system [2–7]. In addition, there is increasing awareness of the interrelationship between immunologic and non-immunologic factors in kidney diseases previously felt to be solely of immune or non-immune etiology [8–10]. Chronic progressive renal dysfunction in native kidneys, as well as allografts, typifies conditions where these interrelationships are becoming evident. A broad overview of the immune response is therefore important for those studying or caring for the patient with renal disease. At the same time, immune paradigms developed from in vitro studies may not fully Key words: T cell, acute renal failure, ischemia reperfusion, innate immunity, adaptive immunity. Received for publication July 11, 2001 and in revised form February 4, 2002 Accepted for publication February 5, 2002

 2002 by the International Society of Nephrology

explain in vivo observations in kidney disease. Thus, immunologic studies of kidney diseases can lead to new treatments, as well as expand current immunologic models. Classically, the immune system has been divided into innate and adaptive components with distinct roles and functions [11]. The innate immune system comprises the nonspecific resistance to pathogens, whereas adaptive immunity is characterized by antigen specificity and immunologic memory. In this review, key components of the innate and adaptive immune responses will be discussed, including recent data supporting significant crossover functions of select components of each system. New data will then be presented supporting a role for the T cell as a newly recognized mediator of the innate immune response both in kidney and extrarenal organs. I apologize in advance for the inadvertent omission of key references. INNATE IMMUNE SYSTEM Although it has been long appreciated that host defense depends on both innate and adaptive immune responses, the main focus of immunology research over the 30 years has been on the adaptive response [12]. More recently, there has been renewed interest in the innate immune response. Much of the basic work on the innate system has been performed in insects. Drosophila has been a particularly fertile model, with a well-characterized resistance to microbes employing effector molecules with overlapping functions during morphogenesis. Many Drosophila genes are up-regulated by septic injury, activating transcription factors of the nuclear factorkappa B (NF-␬B) and Rel families [12]. Close evaluation of these proteins elucidated striking similarities with cytokine-induced NF-␬B dependent acute phase response genes in mammals. Another insect, the moth, was the original source of discovery of inducible antimicrobial peptides [13]. Over 400 antimicrobial peptides of the innate immune system subsequently have been identified in different species. Study of the response of the African mosquito Anopheles, which harbors the deadly Plasmo-

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dium malaria parasite, has also yielded considerable information on mechanisms through which the innate immune system mounts successive multisite responses both locally and systemically [14]. These comparative studies with the human innate response have had a major impact in our current understanding of this field. The innate “hard-wired” immune system mounts an immediate response that is stereotypic, generic in nature, and is felt to lack immunologic memory. Innate immunity has evolutionary links to invertebrate phyla. The mammalian innate system is composed of plasma proteins (such as complement), cells [neutrophils, macrophages and natural killer (NK) cells] and physical barriers (Fig. 1) [15]. The neutrophil is the major phagocyte that responds rapidly to infection or trauma. Neutrophil mobility to sites of inflammation and the ensuing phagocytosis are enhanced by specific IgG antibodies and complement (C3) [16]. These opsonins facilitate phagocytosis. Low molecular weight cytokines (chemokines) attract and activate neutrophils, as well as initiate and mediate inflammatory responses for both innate and adaptive immune systems [17]. Complement amplifies the innate immune response through three different pathways: two independent of antibody (Ab)-antigen (Ag) complexes, and the third requiring Ab-Ag complexes for activation. The final effector mechanism for all three is the formation of the active membrane attack complex. The alternative pathway is activated via interaction with specific membrane components of pathogens, while the classic pathway requires specific Ab bound to antigen for activation. Complement also serves as an immunoregulator of the immune response. Complement activation is tightly controlled by inactivation of free complement in plasma. In addition, complement is regulated by several inhibitory proteins, such as C1 inhibitor and decay-accelerating factor. Defects in these inhibitors lead to diseases such as hereditary angioedema and paroxysmal nocturnal hemoglobinuria. Complement also has been linked to the pathogenesis of ischemic injury in kidney [18] as well as other organs [19, 20]. Other leukocytes comprising the innate system that have cytotoxic abilities include monocytes and NK cells. These cells can manifest cytotoxicity without prior sensitization to the target. Natural killer cell-mediated killing appears to involve specific HLA recognition [21]. Killing occurs when the NK cell encounters cells devoid of specific HLA molecules normally responsible for cytotoxicity-inhibiting signal. NK cells also produce cytokines that directly affect B and T cell function. The innate immune system recognizes and responds to a restricted set of highly conserved structures common to different pathogens [11]. These common structures, called pathogen-associated molecular patterns, include lipopolysaccharide, peptidoglycan, bacterial DNA, doublestranded RNA, lipoteichoic acid, mannans and glucans

[11]. These pathogen-associated structures are produced by pathogens, are usually essential to the microorganism, and are usually present throughout entire classes of pathogens. Receptors for pathogen-associated molecules are found on macrophages, dendritic cells, and B cells. Once bound, these receptors directly activate effector functions. Well-characterized receptors of the innate immune system include mannan-binding lectin (which promotes complement activation) [22], and the macrophage mannose receptor (facilitates endocytosis of pathogens and presents the derived proteins by MHC molecules on the surface) [23]. Recently, a new family of receptors, called “toll” receptors, has been invoked in the initiation of innate immunity. These transmembrane proteins were originally identified in Drosophila as regulators of dorsoventral polarity [24]. At least 10 mammalian toll receptors have been identified, and the toll-like receptor-4 (TLR-4) is important in lipopolysaccharide recognition and responsiveness [25, 26]. TLR-4 also plays an important role in innate immunity to respiratory syncytial virus [27] and Treponema family bacteria [28]. Furthermore, this receptor mediates macrophage migration inhibitory factor (MIF) signaling in macrophages [29]. TLR-4 and other toll-like receptors are fertile area of investigation for new insights into innate immunity. ADAPTIVE IMMUNE SYSTEM The adaptive immune response is felt to have developed approximately 450 million years ago when a transposon that carried the primitive variants of the recombinase activating genes, RAG-1 and RAG-2, became inserted into the germ line of jawed vertebrates [30]. The adaptive immune system responds to antigenic challenge with specificity that requires antigen receptors that can recognize millions of different molecular structures. At rest, the population of lymphocytes expressing a particular antigen receptor specific to a particular antigen is relatively small. These lymphocytes constitute memory cells for that specific antigen. Upon re-exposure to a particular antigen there is enormous expansion of the specific lymphocytes. Conversely, after resolution of the antigenic challenge, reductions in lymphocyte population occur with residual memory cells that store information. Such learning augments the rapidity and vigor with which the organism responds to subsequent antigenic challenge. The adaptive response is localized with precise homing mechanisms of lymphocytes [31]. T and B cells are the major components of the adaptive immune system, and both express highly specific antigen receptors on their surface (Fig. 2). B cells produce specific antibodies which neutralize pathogens, facilitate phagocytosis by opsonization, and activate complement. The T cell response is mediated by the T cell receptor

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Fig. 1. Innate immunity. The innate system provides the initial defense against infection and injury. The primary components of innate immunity are: (1) physical and chemical barriers; (2) phagocytic cells (neutrophils and macrophages), natural killer (NK) cells and possibly dendritic cells; (3) blood proteins, including members of the complement system and other mediators of inflammation; and (4) cytokines that regulate and co-ordinate many of the activities of the cells of innate immunity. (Reproduction of this figure in color was made possible by Texas Biotech Corp., Houston, Texas.)

Fig. 2. Adaptive immunity. There are two types of adaptive immunity: humoral and cellmediated. Humoral immunity is mediated by antibodies that are produced by B lymphocytes. It is the principal defense mechanism against extracellular microbes and their toxins, with secreted antibodies binding to microbes and toxins to assist in their elimination. Cell mediated immunity is mediated by T cells, with dendritic cells playing important roles in antigen presentation. T cells can function by various methods: (1) activating macrophages to kill phagocytosed microbes; (2) directly destroy infected cells; and (3) by releasing cytokines and alter the milieu around them. (Reproduction of this figure in color was made possible by Texas Biotech Corp., Houston, Texas.)

(TCR). The TCR responds to antigen peptides presented on macrophages following phagocytosis of pathogens (such as bacteria), and to peptides from cytosolic pathogens (such as viruses) presented on infected cells. Most T cells produce a multimeric TCR with ␣ and ␤ chain, while a few express the gamma (␥) and delta (␦) chains. The enormous repertoire of antigen receptors is generated during immunologic development by rearrangements

among individual genes for the receptor domains referred to as variable (V), diversity (D) and joining (J) regions of the TCR and immunoglobulin, a process denoted somatic recombination [32]. The association of multiple different V, D and J regions leads to the formation of up to 1012 or more specific receptors. This random process occurs early in the process of B and T cell development prior to contact with antigen. When a specific

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Fig. 3. Antigen dependent and antigen independent T cell activation. Several integral membrane proteins are involved in antigen recognition and functional responses expressed on T cells. They specifically bind ligands present on antigen presenting cells (APCs) and increase the strength of adhesion between a T cell and an APC. Many accessory molecules may transduce biochemical signals to the interior of the T cell and they are able to regulate immune responses. Recent evidence suggests that T cells also can be activated by antigen independent pathways. Oxygen free radicals, cytokines and RANTES have all been implicated in directly causing T cell activation. (Reproduction of this figure in color was made possible by Texas Biotech Corp., Houston, Texas.)

Fig. 4. Potential mechanisms of T cell involvement in ischemia-reperfusion injury (IRI). Local effect: In the blood vessel T cells can bind to macrophages, platelets, neutrophils and endothelium. This amplifies the microcirculatory sludging and “no-flow” state. Within the interstitium, T cells can contact APCs or be activated by injury signals with an APC. Adjacent to epithelium, T cells can directly damage epithelial cells, as well as regulate epithelial cell function. Distant effect: T cells may be exerting an effect also from a distant site such as the thymus, bone marrow, lymph nodes and spleen. T cells lodged in these sites could release cytokines and chemokines that are having an effect on inflammatory mediators in the kidney. Furthermore, these distant sites are where T cells traffic for education, expansion and deletion. (Reproduction of this figure in color was made possible by Texas Biotech Corp., Houston, Texas.)

receptor has been expressed, it becomes the only antigen recognition structure expressed by that lymphocyte and its progeny. The process of activation and proliferation of a lymphocyte after encountering an antigen is termed clonal selection, which is the basic property of the adaptive immune response. It takes three to five days for enough clones to be produced and differentiate into effector cells [11]. It is in this early phase that effector mechanisms of the innate immune system are activated

and respond to the infection or injury. The innate immune system has traditionally been viewed as a temporizing defense mechanisms, acting until the lymphocyte can take over, and that the innate immune system basically primes the adoptive response [11]. However, the interactions between the two are much more complex. Recent evidence implicates relationships between the innate immune response as determinants whether the antigen, foreign or native, will induce an immune response.

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CD4⫹ cells function as both helper and regulatory cells, fulfilling these roles via direct cell-cell interactions as well as by secretion of many cytokines. One model of T cell activation posits that at least two different signals are necessary to activate T cells. The first signal arises from TCR binding of the complex of antigen fragment and HLA. The second involves a costimulatory signal mediated by, CD80 (B7-1) and CD86 (B7-2) molecules (Fig. 3) [11]. In the absence of CD80 or CD86 costimulation, antigen recognition leads to inactivation or apoptosis of the T cell.

a localized and rapid release of IFN-␥, which precedes ␣␤ T cell activation by hours and days. Thus, it has been felt that ␥␦ responses may influence the ␣␤ response [40]. Gamma delta T cells can also modulate cytokine production by NK cells [41]. Thus, the ␥␦ cell may be an important link between innate and adaptive immunity. There are many other examples of links between innate and adaptive immunity, including the observation that toll receptors of the innate immune system induce the B7 variants, CD80 and CD86, which in turn mediate adaptive immune responses [11].

CURRENTLY ESTABLISHED LINKS BETWEEN THE INNATE AND ADAPTIVE IMMUNE SYSTEM Key links between innate and adaptive immune systems include the antigen presenting dendritic cells (DC), found at the sites of entry into the body, for example, skin, lungs, kidney, and liver, bind and ingest invaders. DCs are components of the innate immune system that then transfer information to the adaptive immune system [33]. DCs also are activated by other components of the innate system, which allow DC to carry antigen to lymph nodes (LNs), where it is presented to T and B cells to initiate the adaptive response. Dendritic cells release interferon-␥ (IFN-␥), which then further triggers a cascade of antigen-nonspecific responses mediated by the innate immune system. Penfield et al have found that during renal IRI, dendritic cells migrate into the kidney [34]. This could be a central event by which the innate and adaptive immune systems are linked in renal IRI. Natural killer cells are a subset of lymphocytes found in blood, lymphoid tissue, and especially spleen [35]. NK cells lack the TCR for antigen recognition and possess the ability to kill tumor cells or host cells infected by virus. NK cells do not require prior contact with target antigens to develop cytolytic properties, though NK cells can acquire specificities using their Fc receptor that binds to IgG-coated target cells. NK cells use numerous pore cell toxins. T cell, particularly CD4⫹ cells, can stimulate NK cell functions. Therefore, NK cells, though members of the innate immune response, have a number of ways of interacting with adaptive immune responses. T cells bearing the gamma-delta (␥␦) form of the T cell receptor are a minor population of T cells in lymphoid organs and the circulation, but a prominent population in skin, intestine and lung [36]. Gamma-delta T cells can recognize structures presented by microorganisms and stressed cells, as do macrophages [37]. Presentation of antigen to ␥␦ T cells bypasses the usual processing pathways required for peptide association to MHC molecules [38]. There is also a primary sequence difference between amino acids that make up ␥␦ TcRs and the conventional ␣␤ T cells [39]. Gamma delta cells are characterized by

EVIDENCE SUPPORTING A ROLE FOR T CELLS AS A MEDIATOR OF INNATE IMMUNITY IN EXTRARENAL ORGANS The immune response to tissue injury is (1) immediate, and (2) does not require alloantigen stimulation. There are many modes of tissue injury where the innate immune system is activated: ischemia reperfusion injury, burns, crush injuries, envenomation, etc. IRI is becoming increasingly well characterized both clinically and scientifically, and will be the focus of the remainder of this discussion. The pathogenesis of IRI is complex, but inflammation is an established feature. Extensive studies on IRI have been performed in the heart, brain and intestine. It is believed that oxygen free radicals and mitochondrial products are important initiators of cellular and soluble components of the innate immune response during IRI [42]. Complement is activated, particularly via the alternative pathway, generating fragments such as C3a and C5a. This process leads to a release of histamine, platelet activating factor, a host of cytokines, with attendant increase in vascular permeability. Neutrophils and endothelium are activated, with up-regulation of the adhesion molecules including CD11/CD18, ICAM-1 and P-selectin. Neutrophil/platelet aggregates promote microvascular plugging (“white clot”) and emigration of neutrophils into tissue results in local destruction. Macrophages also infiltrate in a more delayed fashion, and likely contribute to repair. Thus, the PMN is the central leukocyte observed in tissue necrosis following ischemia. Based on the above, the T cell, seen only in small numbers during necrosis, would not be expected to play a major role in this process, at least on theoretical grounds. Traditional paradigms concluded that, “the lymphocytes plays very little, if any, role in the acute phases of inflammation, but principally contributes to reactions in chronic long-standing inflammatory processes” [43]. Recent data, however, challenge this model. The persistent clinical dilemmas of managing patients with IRI and new experimental tools have fueled increased research in the early inflammatory response during IRI. There is now both indirect and direct evidence that T cells are important mediators of IRI, even in the

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Rabb: The T cell and innate and adaptive systems Table 1. Evidence for pathogenic role of T cells in gut, heart and lung ischemia/reperfusion injury

Organ

Model

Species

Liver

Cold ischemia

Rat

Liver Intestine Liver

IRI

Rat

Partial lobe subacute phase

Mouse

Liver

IRI

Mice

Liver

IRI

Rat

Liver

Ex vivo cold ischemia

Mouse

Intestine Heart

IRI Transplant

Rat Rat

Heart Lung

Infarction Cold IRI

Rat Canine

Lung

Cold IRI

Swine

Lung

Transplant

Rat

Brain

Focal ischemia

Rat

Intervention/Effect Tacrolimus protective Decreased leukocyte adhesion Tacrolimus protective Decreased leukocyte adhesion T cell deficient (nu/nu) mice protected CD4 depletion protective in wild types T cells modulated neutrophil infiltration T cell deficient (SCID) mice protected CD4⫹ population more important than CD8⫹ cells in this effect FTY 720 with cyclosporine protective, but FTY 720 alone was not protective nu/nu mice protected IL-10 protective Resident T cells important Cyclosporine and rapamycin protective Mycophenolate protective Decreased leukocyte adhesion Cytotoxic T cells activated that kill non-ischemic myocytes Increased natural killer activity in lavage increased MHC II expression in 24 hours Platelet-activating factor blockade protective, possibly by decreasing T cell activation Antithrombin III treatment protective, possibly by decreasing T cell proliferation Tacrolimus but not rapamycin nor cylcosporine protective; immunophilin pathway invoked

absence of alloantigen, and that they act in the early injury period. These observations shift the classical role of the T cell, suggesting that it may play an important role in the early inflammatory response rather than functioning exclusively as a component of the adaptive immune response. There are abundant experimental studies in many nonrenal organs identifying the presence of T cells after IRI. These will not be enumerated. However, it should be noted that though numerous studies have demonstrated a delayed influx occurring after the clear functional deterioration of tissue, T cells have generally not been sought or rigorously identified with definitive techniques. Very early times (first few minutes, hours) have rarely been examined. Furthermore, descriptions do not usually distinguish intravascular accumulation of T cells in the early no-reflow state of IRI, compared to the overt extravasation out of the microcirculation. This is an important distinction, and one that has not been thoroughly addressed to date. Presence or absence of the T cell is further confounded by the potential for T cells to be sequestered in sites of inflammation as “innocent bystanders.” Therefore, the following focus will be on studies that have used techniques to assess cause and effect, as well as transferability. Some of the most convincing evidence for T cell involvement in renal IRI comes from studies of the gut (Table 1) [44–56]. The calcineurin inhibitor FK506 (tacrolimus) used to prevent T cell-mediated allograft rejection as well as other autoimmune diseases, was found

Reference Kawano 1996 [44] Garcia 1998 [45] Zwacka 1997 [46] Horie 1999 [47] Mizuta 1999 [48] Le Moine 2000 [49] Puglisi 1996 [50] Valentin 2000 [51] Varda 2000 [52] Adoumie 1992 [53] Nikbakht 2000 [54] Okada 1999 [55] Sharkey 1994 [56]

to reduce hepatic IRI injury in rats [44]. These effects appeared to be independent of Kupffer cell phagocytic activity. In a separate study using FK506 in both liver IRI as well as mesenteric IRI in rats, tissue protection correlated with decreased intercellular adhesion molecule-1 (ICAM-1) and P-selectin expression as well as decreased leukocyte rolling [45]. The authors attributed the protection afforded by FK506 to its effect on adhesion molecule expression. However, other interpretations also may be valid, as FK506 is known to exert its effects by altering ischemia-induced ceramide and apoptosis signaling [57]. A study using cyclosporine A and rapamycin, which both impair T cell activation as their main functions, demonstrated attenuated small bowel IRI in rats [50]. The first direct proof of the role for T cells in IRI came from a series of elegant studies on mouse liver. In the subacute phase of liver injury (16 to 20 hours postischemia), a marked preservation of liver function was found in T cell-deficient athymic mice compared to wild type BALB/c strain [46]. This was associated with a marked decrease in neutrophil infiltration. Adaptive transfer of wild type T cells into the athymic (nu/nu) mice restored the neutrophil-mediated injury. In vivo depletion of CD4⫹ cells, but not CD8⫹ cells in wild type mice was also protective. Similarly, mice with severe combined immunodeficiency (SCID) also were protected from liver IRI, and that T cell adoptive transfer, particularly of CD4⫹ cells, restored injury [58]. These results were confirmed and extended by experiments that found that T cell-deficient mice to be relatively resistant

Rabb: The T cell and innate and adaptive systems

to liver IRI. In this ex vivo model of IRI, it was the resident and not infiltrating T cells that played the important role, and interleukin-10 (IL-10) modulated this T cell response [49]. A potential mechanism by which T cells mediated IRI was revealed by examining the effects of CD4⫹ cell reconstitution into severe combined immunodeficient mice (SCID) with bowel inflammation. In this work, CD4⫹ cells, particularly those whose surface expression of CD45RB was high, were found to up-regulate a variety of T helper-1 (Th1) and macrophage-derived cytokines, as well as leukocyte adhesion molecules [59]. Attempts to further elucidate the mechanisms of T cellmediated up-regulation of cell adhesion have been conducted in vitro on hypoxic human umbilical vein cells (HUVEC). T cell adhesion to HUVECs stimulated subsequent neutrophil adhesion to HUVEC, as well as up-regulation of vascular cell adhesion molecule I (VCAM-1). Tumor necrosis factor-␣ (TNF-␣) was felt to be the key factor that linked T cell adhesion to VCAM-1 expression [60]. An early study of the effects of IRI on lung transplantation using canines found that within one to four hours of reperfusion, there was a marked influx of lymphocytes (and neutrophils) accompanied by an increase in lectin-mediated cytotoxicity and natural killer cell cytotoxicity [53]. The authors also found an increase in MHC class II expression, concluding that IRI could render lungs more susceptible to rejection. Another interventional study with indirect evidence that T cells were mediating lung IRI was performed in swine. Pig lung undergoing IRI was protected from edema by platelet activating factor antagonism, which also decreased T cell activation and infiltration [54]. In a separate study using rat lungs undergoing IRI, antithrombin III, with potent antithrombotic and inflammatory properties was found to be protective; however, this agent also decreased T cell proliferation, a mechanism of protection being speculated in the interpretation of the results [55]. In the heart, though much evidence exists for leukocyte mediation of reperfusion events and the presence of lymphocytes postischemia, there is little supportive evidence yet for a direct role of T cells. Abnormalities are found in circulating T cells associated in humans with myocardial ischemia or infarction [61]. An elegant mechanistic study of myocardial infarction using rats found that T cells became activated by the cardiac injury, and also retained a memory response against myocytes [52]. Though there are abundant data on T cell infiltration after brain IRI, only limited data to date found a direct role for the T cell. Administration of FK506 in a rat model of focal cerebral artery occlusion significantly reduced infarct size [56]. Interestingly, the related immunophilin, cyclosporine as well as the T cell activation inhibitor rapamycin did not protect at the doses administered. In fact, rapamycin given together with FK506 blocked the neuroprotective

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effect of FK506. Both rapamycin and FK506 compete for the same common binding site on lymphocyte FK binding protein. EVIDENCE SUPPORTING A ROLE FOR T CELLS AS A MEDIATOR OF INNATE IMMUNITY IN THE KIDNEY Unlike heart or gut, where neutrophils are well established to be important mediators of IRI, the role of neutrophils in renal IRI is controversial and not as well established [62]. Treatment of rats [63] and mice [64] with neutrophil depleting antiserum reduced postischemic acute renal failure. However, use of neutrophil depleting serum in rats undergoing renal IRI was not found to be protective by other groups [65, 66]. Elegant ex vivo techniques have demonstrated that infused neutrophils can synergize with ischemia to cause acute renal failure [67]. Certain compounds that protect renal function and tubular structure during experimental acute renal failure attenuate neutrophil influx into injured kidney, prompting the interpretation that the compounds worked by inhibiting neutrophil infiltration. This has been demonstrated in the case of adenosine receptor blockade, which protects renal function after IR and attenuates myeloperoxidase activity, a marker of tissue neutrophils [68]. Interleukin-18 blockade in mice also results in tissue protection and decreased myeloperoxidase levels [69]. Alphamelanocyte stimulating hormone (␣-MSH) markedly reduced renal neutrophils and attenuated renal IRI [7]. However, subsequent study of ␣-MSH demonstrated that the mechanism of action was independent of neutrophils [70]. Others have recently demonstrated that many of the studies that identified neutrophils in acute renal failure mistakenly evaluated macrophages instead: myeloperoxidase, chloroacetate esterase, and “neutrophilspecific mAb HIS-48” all cross-reacted with macrophages [71]. Furthermore, both in sheep [72] and in rats [73] neutrophil infiltration into postischemic kidney has been dissociated from direct role in tissue injury. It is quite possible that the neutrophil has been overestimated as a pathophysiologic factor in renal IRI due to the prominent influx observed in experimental models. A series of experimental studies demonstrated an important role for the leukocyte adhesion molecules CD11/ CD18 and ICAM-1 in renal IRI [3, 4, 64, 74, 75]. These studies also were interpreted as demonstrating an important role for neutrophils during IRI, but this was not conclusive due to the observations of many groups that induction of neutropenia did not lead to protection from IRI [58]. In fact, it was observed that of severe neutropenia was not protective in the identical model that CD11/CD18 and ICAM-1 blockade worked (abstract; Mendiola et al, J Am Soc Nephrol 4:741, 1993). A possible interpretation is that CD11/CD18 or ICAM-1 block-

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Rabb: The T cell and innate and adaptive systems Table 2. Indirect evidence for a role for T cells in renal IRI

Model

Species

Findings

Biopsies IRI IRI

Human Rats Rats

IRI IRI IRI

Rats Rats Mice

IRI Transplant IRI

Rats Human Rats

Mononuclear cells, not neutrophils, in vasa recta during acute renal failure Tacrolimus pretreatment protective, potentially by regulating TNF release CD11/CD18 (expressed on T cells as well as other leukocytes) blockade protective. Neutrophil depletion not protective in parallel studies CD11/CD18 & ICAM-1 blockade protective, need to give intervention early for effect ICAM-1 blockade protective during severe ischemia ICAM-1 knockout protective Reduced myeloperoxidase content of injured kidney ICAM-1 antisense oligonucleotides protective Anti-CD11a/CD18 therapy decreased delayed graft function Mycophenolate protective when combined with bioflavinoids

ade, which has profound effects on T cell function, could have also worked via action on T cells (Table 2) [3, 4, 64, 74–79]. As in liver IRI, FK506 was found to also attenuate experimental renal IRI in rats [77]. In addition, mycophenolate mofetil, which has for the most part replaced azathioprine in most clinical T cell suppression regimens, also confers protection from renal IRI [79]. Furthermore, a significant reduction in early injury after cold renal IRI was afforded by blockade of the T cell CD28-B7 costimulatory pathway with CTLA4Ig (a recombinant fusion protein that contains a homolog of CD28 fused to an IgG1 heavy chain) [80]. This work was extended to a long-term model of progressive proteinuria in uninephrectomized rats that underwent cold IRI [81]. CTLA4Ig treatment on the day of injury, as well as delayed treatment one week beyond ischemia (but not four weeks), was effective in reducing proteinuria [81]. One interpretation was that CTLA4Ig could have had other effects besides involving specific T cell activation [82]. To test the hypothesis if T cells were directly involved in renal IRI, mice deficient in CD4 and CD8 cells were evaluated and found to be protected from renal IRI [83]. Knockout mice, however, can have additional changes besides the targeted disruption. Therefore, another T cell knockout mouse strain was used, the athymic nu/nu mice. This mouse was also protected from renal IRI [84]. Furthermore, adoptive transfer of T cells into these mice restored ischemic injury-potentially fulfilling the “transferability” that Koch required among his classic postulates [85]. To identify the relative contribution of CD4 and CD8 T cell subsets in renal IRI, individual CD4 and CD8 knockout mice were studied, with the CD4 knockout showing a marked protection from both renal injury and mortality after IRI [84]. Adoptive transfer of the wild-type CD4⫹ cells into these knockout mice also led to a worsening injury phenotype, directly demonstrating the importance of CD4⫹ cells in renal IRI. Surprisingly, the neutrophil and macrophage infiltration into postischemic kidney was not affected by either the nu/nu or CD4 knockout, nor the adoptive transfer. Very few infiltrating T cells were seen early

References Solez 1979 [76] Sakr 1992 [77] Rabb 1994 [3] Kelly 1994 [4] Rabb 1995 [74] Kelly 1996 [64] Haller 1996 [75] Hourmant 1996 [78] Jones 2000 [79]

post-ischemia (within 24 hours) despite the use of different antibodies to detect T cells. When CD4⫹ cells deficient in CD28 or IFN-␥ were adoptively transferred, injury was not restored, thus revealing the important role for CD28 and IFN-␥ in renal IRI [84]. To evaluate if alloantigen-independent factors could activate T cells in a nephrotrophic manner, T cells were incubated with renal epithelial cells in hypoxia-reoxygenation conditions, resulting in increased T cell adhesion to renal epithelial cells compared to that in normoxic conditions [83]. More recently, use of the B7-1 Ab to CD80 but not B7-2 Ab to CD86 also abrogated renal IRI in rats, demonstrating that is was likely the B7-1 pathway that was blocked in the CTLA4Ig work [86]. These data further strengthened the argument for role for T cells in renal IRI. Thus, there is now ample evidence from different labs using diverse techniques of an important role for T cells in the immediate response to renal ischemic injury (Table 3) [79–84, 86]. As yet there are insufficient data to extend these conclusions to humans. However, it is important to note that in human kidney biopsies of acute renal failure, mononuclear leukocytes, not neutrophils, have been observed in the vasa recta [76]. In addition, studies using thymoglobulin induction to prevent allograft rejection “serendipitously” reduced delayed graft function, the major manifestation of renal IRI in the cadaveric transplant (abstract; Goltz et al, Transplantation 67:S388, 1999). POTENTIAL MECHANISMS BY WHICH THE T CELL COULD BE A MEDIATOR OF THE INNATE IMMUNE RESPONSE SYSTEM The most widely accepted model of the immune response is the “self–non-self” model, where the immune response recognizes exogenous signals that represent a form of non-self. However, an emerging model is the “danger” model, which proposes that the signals initiating the immune response are inherent in the normal body tissues themselves [87]. The self–non-self model as well as danger model propose that antigen presenting

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Table 3. Direct evidence for a pathogenic role for T cells in renal IRI Model

Species

Findings

Cold ischemia IRI

Rat Mouse

IRI

Mouse

IRI

Rat

CTLA-4 Ig protective, reduced induction of inflammatory genes CD4/CD8 KO mice protected, hypoxia-reanoxia alone sufficient to activate T cells to increase adhesion to kidney Athymic nu/nu & CD4 ⫺/⫺ mice protected, T cell transfer restores injury; neutrophil and macrophage infiltration dissociated from protection Anti-B7-1-Ab protective

cells (APCs) must be activated. However, while the self– non-self model is based on the view that a non-self signal is essential, the danger model proposes that activation of an APC depends on the health of the cells in its neighborhood. Thus, a foreign entity that does no injury will not evoke a response, while a self-entity presented by APCs will evoke response when accompanied by injury. Pre-packaged alarms could be mitochondrial products normally inside the cell, mannose (also found normally inside the cell), RNA, DNA, and inducible signals such as heat shock proteins and toll receptors [87]. The danger model also proposes that each tissue has a set of effector classes it prefers, so that local responses can be tapered. Thus, a T cell being activated and involved in IRI could be interpreted by the danger model as a response to APCs becoming activated by injury, and then traveling to draining lymph nodes and up-regulating costimulatory molecules needed to activate T cells. After the initial reaction by the T cells and other inflammatory pathways, complete remodeling would render the tissue tolerant. However, if remodeling was not adequate, a continued T cell-mediated memory response to the injury would occur, resulting in smoldering inflammation with cycles of repair, which in the long run would lead to fibrosis. This is very consistent with what we observe in the native kidney subject to injury that, once injured, seems to progress inexorably to end stage fibrosis and failure. Similarly, a marginal single kidney allograft with a long cold ischemia time, after the initial acute renal failure, would be expected to gradually deteriorate over time, particularly if other insults were superimposed, such as from hypertension or proinflammatory effects of filtered proteins. One major question that arises when trying to understand the mechanisms underlying the role of the T cell in mediating IRI is the nature of the process by which the T cell gets activated. Normally, one would expect the requirement of an alloantigen in the context of co-stimulatory signals [88]. In IRI without the presence of an alloantigen, such as in native kidney IRI, one could invoke the unveiling of a self-antigen presented by an APC that was normally not exposed to the immune system, but somehow expressed during tissue injury. Recently, T cell activation has been demonstrated to occur totally independently of antigen. The chemokine RANTES has been

Reference Takada 1997 [80] Rabb 2000 [83] Burne 2001 [84] DeGreef 2001 [86]

shown to directly activate T cells [89]. RANTES upregulation has been shown to occur in renal IRI, so this is one possible mechanism for T cell activation in the absence of antigen [90]. Another stimuli now demonstrated to be capable of activation T cells and leading to up-regulation of pro-inflammatory genes are oxygen free radicals [91, 92]. Oxygen free radicals are one of the most widely recognized products of tissue injury, particularly IRI, and could be playing an important role in the T cell activation. T cells, when incubated with renal epithelial cells from the same strain of inbred mouse, C57BL6, become activated when hypoxia-reoxygenation occurs, and increases their adhesion to these renal cells [83]. Similarly, T cells exposed to hypoxic endothelial cells in culture also become activated and increase their adhesive phenotype, in part due to the production of TNF by the hypoxic cells [93]. Thus, a strong theoretical and experimental framework exists to explain the findings of the T cell being an important mediator of IRI. However, what is not clear is how the T cell participates in the injury process. T cell products are important for the optimal expression of endothelial adhesion molecules, which in turn recruit and activate phagocytes [47]. Therefore, it is possible that T cells mediate IRI via amplifying inflammation, in particular facilitating phagocyte recruitment. However, the role of the neutrophil in renal IRI is still not fully defined [58]. Furthermore, neutrophil infiltration into postischemic kidney can be dissociated from the effects of T cell manipulation [84]. Administration of the selectinligand inhibitor, TBC 1269, which acts on both T cells and neutrophils, markedly protected rat kidney structure and function after ischemia without halting neutrophil trafficking to postischemic kidney [94]. The observations that brisk leukocyte trafficking into tissue can occur despite tissue protection from injury has been found in other disease models, including asthma [95]. The T cell has been well established to have an effect on renal tubular epithelial cells, and the damage to these cells is the hallmark of IRI, or acute tubular necrosis. However, very few T cells are seen around the epithelium in IRI, unlike in acute transplant rejection, making it less likely that a direct tubular epithelial toxicity can explain the profound effects. Given the amplification effects of just a few T cells and the microvascular in-

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flammation that characterizes IRI, it would not be surprising if the effects of T cells were in the blood vessels themselves, with active engagement of platelets, phagocytes, endothelium and soluble factors (Fig. 4). Increasing evidence has linked T cells with vasoactive substances, including angiotensin II [96], and thus the T cell could have an effect on renal hemodynamics. The T cell lifespan is characterized by circulation through blood and lymphoid tissue. Though it would be conceptually simpler if the T cell had a direct effect in IRI that required adhesion with the cells that were dysfunctional, an indirect and/or distant effect may well be occurring. T cells lodged in spleen, local lymph nodes or bone marrow could well have a role. However, we did not find a protection from renal IRI in the splenectomized aly/aly mouse [97], which lacked spleen and lymph nodes. Therefore, absence of these lymph organs was insufficient to alter the course of IRI (Yokota and Rabb, unpublished data). If T cells did work from a distance, or mediated IRI via the production of cytokines, an obvious question is whether this occurs via the classic T cell TH1 (IL-2, IFG) or TH2 (IL-4) pathway. T cell polarization into one of these pathways underlies the pathogenesis of a number of diseases from leprosy to schistosomiasis. Asthma is characterized by a deleterious TH2 response, while acute transplant rejection is mainly a TH1 response [98]. However, an array of overlapping cytokines is seen in IRI, which clearly does not pinpoint one pathway versus the other. One strategy to evaluate this question is to examine mice that cannot fully polarize into either the TH1 (STAT-4) or TH2 (STAT-6) pathways [99]. Recent data demonstrate that the STAT-6 deficient mouse is markedly susceptible to renal injury and mortality after IRI, suggesting a protective effect of the TH2 pathway in IRI. This suggests the possible existence of a “balancing” T cell phenotype that normally prevents the full expression of IRI–a “yin/yang” homeostatic mechanism (abstract; Yokota et al, J Am Soc Nephrol 12:4158A, 2001). IMPLICATIONS FOR ACUTE AND CHRONIC KIDNEY DISEASES The finding of a pathogenic role for T cells in IRI has profound implications for ischemic injury of the kidney, as well as other organs. T cell manipulation is a clinically established approach in transplantation medicine, thus an earlier application for organ procurement injury is very feasible. For native kidney IRI, often associated with ongoing sepsis, it may be more difficult to design the proper immune intervention. However, increasing data implicate sepsis as an imbalance of immune regulation, and the challenge will be to elucidate the specificity of the deleterious pathways while preserving the function of the helpful pathways in the patient with multiple organ failure.

Chronic allograft nephropathy (CAN), the leading challenge in long term graft function, may be influenced by early changes that result from IRI [100]. Thus, interventions to decrease early necrosis and prevent unwanted T cell activation may be useful to prevent CAN. Native kidney progressive renal disease, be it from diabetes, hypertension, chronic glomerulonephritis or polycystic kidney disease, is characterized by an interstitial mononuclear cell infiltrate that correlates highly with rapid progression. Neither the factors that lead to this lymphocyte infiltration into the interstitium, nor the effects of this smoldering lymphocyte activity are known. In addition, important cytokines implicated in the pathogenesis of progressive renal failure, such as transforming growth factor-␤ (TGF-␤), have a crucial role in T cell functions and may well interplay. Recently, mycophenolate, an immunosuppressive compound widely used in organ transplantation, has been shown to decrease proteinuria and renal injury in chronic progressive renal failure models, suggesting a potential role for T cells in this alloantigen independent process [101–103]. The recognition of an important role for T cells in the early injury response to ischemia also should stimulate new basic research into T cell biology to explain how the T cell is participating in the innate immune response. ACKNOWLEDGMENTS This work was supported by NIH R01 DK54770 and NKF Clinical Scientist Award. The author is indebted to Drs. Joseph Handler, Chris Lu and John Hotchkiss and for helpful suggestions during manuscript preparation, Ms. Vanessa Schlinger and Dr. Melissa Burne with tables and figures, and Ms. Jan Lovick with references. Reproduction of Figures 1 to 4 in color was made possible by Texas Biotech Corp., Houston, Texas. Reprint requests to Hamid Rabb, M.D., Division of Nephrology, Ross 970, 720 Rutland Ave., Johns Hopkins Hospital, Baltimore, Maryland 21205, USA. E-mail: [email protected]

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