Immunology in the Arabian desertBasel al-Ramadi, Adrian Hayday & Wilhelm Schwaeble

Increasing evidence suggests that immune mechanisms underlie major inflammatory diseases that show no overt microbial etiology. In this context, a 4-day conference of clinical and nonclinical scientists convened in the United Arab Emirates to consider recent research developments in this fast-moving field.

The Third Al-Ain International Immunology Meeting, organized by the Faculty of

Medicine and Health Sciences of the United Arab Emirates (UAE) University, was held 17–20 March 2008 at the Hotel Intercontinental Resort, Al Ain, UAE. On day 1, a workshop-style preconference meeting was arranged in a small conference pavilion, designed to resemble a large, festive, desert tent. This created an exotic and relaxed meeting atmosphere that encour-aged the participants to forego the constraints of their usual familiar contexts and to think creatively. The preconference was then split into three clinical workshops: Inflammatory and Autoimmune Diseases, Autoimmune Connective Tissue Diseases, and Hepatitis. These clinical workshops allowed detailed panel discussions and usefully set the human health context for the science to follow.

On 18 March, approximately 200 delegates were welcomed to the elaborate Conference Hall by His Excellency Sheikh Nahayan Mabarak Al Nahayan (Fig. 1), Chancellor of the United Arab Emirates University and Minister of Higher Education and Scientific Research. His opening speech emphasized the importance of embedding cutting-edge bio-medical research in an international network of collaborations, to which the UAE is increas-ingly committing. In some ways, the ongoing

transition of the emirates from nomadic desert culture to urban modernity highlights a paral-lel transition from immunological interest in diseases of the developing world to interest in the involvement of immunology in major dis-eases of the developed world.

Pathophysiology of innate inflammationIn the first symposium, on the pathophysio-logical effect of inflammatory pathways of the innate immune system, Richard Flavell (New Haven, USA) gave a plenary lecture focus-ing on the macromolecular ‘inflammasome’, which regulates several processes, including caspase activation, infection-induced cell death and release of the proinflammatory cytokine interleukin 1β (IL-1β). By ‘feeding into’ vari-ous members of the intracellular Nod family of innate sensors, such as IPAF and NALP3, microbes such as salmonella and shigella and nonmicrobial stimuli such as silica particles or uric acid crystals may each activate the inflam-masome, thus promoting both positive immu-nity and immunopathology associated with infections processes and with noninfectious processes such as silicosis and gout. One key molecular mediator promoting inflammasome activation is potassium ion efflux, which con-veys information about the state and integrity of the cell membrane. It is notable that some bacteria produce their own proteins that pro-mote potassium ion efflux. In the final part of his talk, Flavell showed data demonstrating that priming of antigen-specific immunoglobulin G1 by alum, the most widely used adjuvant in clinical practice, requires IPAF and NALP3 and inflammasome function1.

Potassium ion efflux is also known to regulate pyroptosis, an inflammatory form of caspase-1-dependent macrophage death that is accompa-nied by the release of IL-1β and other cytokines

and is induced by salmonella, shigella and other bacteria. Emad Alnemri (Philadelphia, USA) described the ‘signature’ of pyroptosis as the activation of caspase-1 by the adaptor protein ASC in macromolecular aggregates (‘pyroptosomes’), whose formation occurs very notably within 2 minutes of stimulation. Alnemri distinguished pyroptosomes from the perhaps better-known inflammasomes; in particular, he discussed the association of the syndrome of pyogenic arthritis, pyoderma gangrenosum and acne, an autoinflammatory disorder, with mutations in the gene encoding the cytoskeletal-organizing protein PSTPIP1 (also called CD2BP1), which activates the familial Mediterranean fever protein pyrin; this activation of pyrin mediates the formation of ASC oligomers that nucleate the pyroptosome. Hence, patients with this syndrome may con-stitutively promote inflammatory pyroptosis in the absence of infection.

The ability of nonmicrobial stress to pro-mote ‘immune reactions’ proved a common topic of discussion inside and outside the for-mal sessions, and it was taken up in the context of Toll-like receptor (TLR) pathways by David A. Brenner (San Diego, USA), who delivered a plenary talk focusing on fibrosis of the liver. Hepatic stellate cells in the liver express TLR4, and polymorphisms in this gene are associated with a higher risk of fibrosis after infectious hepatitis. In this context, Brenner described a pathway from TLR4 through the adaptor protein MyD88 to the transcription factor NF-κB that downregulates the transforming growth factor-β pseudoreceptor BAMBI. This sensitizes cells to differentiate into myofibro-blasts in response to transforming growth factor-β produced by liver Kupffer cells (mac-rophages), thus leading to fibrosis2. Disruption of this proinflammatory loop may reverse the

Basel al-Ramadi is in the Department of

Microbiology and Immunology, United Arab

Emirates University, Al Ain, United Arab Emirates.

Adrian Hayday is in the Peter Gorer Department

of Immunobiology, Kings College London School

of Medicine, London, SE1 9RT UK. Wilhelm

Schwaeble is in the Department of Infection,

Immunity & Inflammation, University of Leicester,

Leicester, lE1 9HN UK.

e-mail: ws5@le.ac.uk.

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fibrogenic process. Brenner also showed that the proliferation of hepatic stellate cells in response to platelet-derived growth factor and inflammatory mediators such as reactive oxy-gen species can be suppressed by the adminis-tration of high-molecular-weight adiponectin, an adipocyte-derived ‘adipocytokine’, which acts by means of adenosine monophosphate–activated protein kinase3. TLR-mediated fibro-sis may underlie the actions of many agents of liver toxicity, such as carbon tetrachloride, that have no inherent microbial component, which reiterates the possibility that there are endogenous TLR ligands.

Moving from the liver to another organ, Marc Donath (Zurich) conveyed how his studies of mouse models of type 2 diabetes have informed clinical trial design. He reminded the audience that the pancreas is in part an immunological organ in which glucagon-producing cells can synthesize IL-6 and in which glucose promotes IL-1β production by insulin-producing β-cells. These effects are associated with upregulation of the death receptor Fas, which is involved in β-cell apoptosis or proliferation, depending on the activity of the caspase-8 inhibitor FLIP. FLIP-mediated proliferation of β-cells leads to more production of IL-1β and IL-8, which drives leukocyte infiltrates. These are increas-ingly recognized features of type 2 diabetes that may gradually shift the balance toward β-cell death and fibrosis. Encouragingly, a clinical trial of 312 patients has shown that treatment with anakinra, a recombinant human IL-1 receptor antagonist, produces impressive slow-ing of disease progression4.

Fuelled by lunch al fresco in the exquisite March sun, the meeting participants listened to Ruslan Medzhitov (New Haven, USA) discuss how the specificity of various TLRs and Nod proteins contributes to an orches-trated response to a variety of noxious insults.

Medzhitov showed that plasma membrane–localized TLR4 ‘preferentially’ induces signal-ing through the adaptors TIRAP and MyD88, whereas endocytosed TLR4 complexes signal through a pathway mediated by the pathway of the adaptors TRAM and TRIF5. This type of differential regulation by location permits physiologically appropriate responses to differ-ent inflammatory stimuli. For example, high-grade inflammatory responses to microbial and viral agents promote tumor necrosis factor (TNF) as well as cytolytic and antimicrobial effectors, whereas tissue injury, signaled by uric acid and other ‘alarmins’, promotes tissue-re-pair responses and IL-1β. Another reflection of the orchestrated responses is provided by the finding that distinct sets of response genes can be selectively regulated in different chro-matin modules, as shown by their differential response to repeated TLR stimulation. Thus, although macrophage expression of IL-6 and IL-12p40 can be suppressed after repeated treatment with lipopolysaccharide, antimicro-bial genes such as the one encoding C-RAMP can be more rapidly induced. Selective ‘toler-ization’ may therefore optimize antimicrobial protection, which decreases the predisposition to septic shock and other immunopathologies. Of clinical importance, ‘tolerizable’ genes are those that can be suppressed by steroids and IL-10, whereas ‘nontolerizable’ genes are those that cannot.

Wilhelm Schwaeble (Leicester, UK), rep-resenting something of a ‘renaissance’ of the complement field, considered how the lectin pathway of complement activation, a pat-tern-recognition–driven proinflammatory pathway, can be a critical factor in the initia-tion and maintenance of acute and chronic inflammatory diseases. Mice deficient in the serine protease MASP-2, a key enzyme of the lectin pathway, are protected from inflam-matory tissue loss in experimental models of myocardial infarction and renal ischemia-rep-erfusion injury. Apparently, the carbohydrate-recognition molecules of the pathway bind to oxygen-deprived cells, and the consequent MASP-2-mediated complement activation elicits considerable localized inflammation, which leads to loss of tissue and organ func-tion. Inhibition of the scarce, plasma-resident enzyme MASP-2 may prove to be an effective new therapeutic approach in the treatment of ischemia-induced inflammatory disease.

Next, Mercedes Rincon (Burlington, Vermont, USA) focused on the interlinked regulation of IL-6, IL-21 and IL-17. She con-sidered that IL-17 production is unaffected by IL-21 deficiency, viewing IL-21 and IL-17 as independent responses ‘downstream’ of IL-6 signaling. Because IL-21 is a chief B cell–dif-

ferentiation factor, there may be a common thread underlying the emerging efficacy of IL-6 blockade and rituximab therapies for certain inflammatory diseases. Soluble IL-6 receptor produced by T cells can confer responsive-ness to IL-6 on chondroytes and fibroblasts, which themselves lack endogenous receptors. Notably, large amounts of IL-6 may confer in an autocrine way high expression of multidrug-resistance gene 1 and P-glycoprotein on breast cancer lines. However, a clinical trial involv-ing 469 women with metastatic breast cancer has shown that large amounts either IL-6 or P-glycoprotein were not predictive markers of tumor progression or survival. Moreover, IL-6 amounts did not obviously influence the response to paclitaxel, an anticancer agent affected by the P-glycoprotein pathway.

Although the main focus of the confer-ence was on innate mechanisms, attendees were treated to a technologically impressive presentation by Yuri Sykulev (Philadelphia, USA), who demonstrated the use of quantum dot technology to investigate the sensitivity of CD8+ T cells to very low-dose antigen. His data showed CD8-dependent spread of signals from T cell receptors engaging complexes of cognate peptide and major histocompatibility complex to those engaging noncognate antigen. Such data may have profound implications for the accentuation of autoimmune responses after the activation of T cells through innate immune functions.

The conference dinner was held on the hotel lawns in a balmy 30 °C, a potent reminder that the intense irrigation was not solely cerebral!

The second symposium, on inflammatory innate immune responses in organ dysfunc-tion, began with a presentation by Foo Y (Eddy) Liew (Glasgow, UK) on the antiatherosclerotic activities of IL-33, an IL-1-like cytokine. Liew showed that IL-33 induces T helper type 2 cells expressing the receptor ST2 to produce IL-13 and IL-5, which promote B cells to produce antibodies to oxidized low-density lipopro-teins; the induction of such antibodies blocks the production of foam cells containing low-density lipoproteins. The importance of this mechanism in vivo was demonstrated by data showing that IL-33 treatment of apolipo-protein E–deficient mice, which have severe hypercholesterolaemia, profoundly decreases the formation of severe atherosclerotic plaques in the aortic sinus in response to a fatty diet. IL-33 treatment may therefore have therapeu-tic potential in the treatment of atheroscle-rotic vascular disease, thus emphasizing the broad and profound roles that immunological approaches may have in the clinic.

Hamid Rabb (Baltimore, USA) then presented compelling data indicating the

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Figure 1 His Excellency Sheikh Nahayan Mabarak Al Nahayan, Chancellor of the United Arab Emirates University and Minister of Higher Education and Scientific Research.

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involvement of innate immune mechanisms in renal ischemia-reperfusion injury in the absence of alloantigens, a topic that con-tinued among the short talks that followed. Heitham Hassoun (Al Ain, UAE), for exam-ple, demonstrated how organs other than the kidney may be pathologically affected by ischemia-reperfusion injury, showing that pulmonary endothelial cell apoptosis may be elicited by acute kidney ischemia and may contribute to mortality.

Inflammation and autoimmune diseaseThe late-morning third symposium was opened by Len Harrison (Melbourne, Australia), who reviewed the results of the Melbourne Pre-Diabetes Family Study of the genetic, environmental, inflammatory and metabolic components contributing to the increase in type 2 diabetes. Harrison considered that advanced glycation end-products (modified compounds produced nonenzymatically, which are present in many foods) may induce immune activation driven by the receptor for glycation end-products in the pancreas, which can promote β-cell destruction. On a separate note, Harrison also discussed data from the Intranasal Insulin Trial showing that intranasal administration of insulin leads to fewer anti-bodies to subsequently administered insulin, which indicates the possible utility of experi-mental immunoregulation in humans in vivo. By cloning autoantigen-specific regulatory T cells, Harrison found a consistent increase of three- to eightfold in CD52 expression relative to that of non–autoantigen-specific regulatory T cells. The CD4+CD52hi cells seemed to be

‘preferentially’ generated at low concentrations of the autoantigen, and Harrison hypothesizes that this subset of regulatory T cells may be important in the etiology of diabetes.

Janine Coombes, a researcher in the labora-tory of Fiona Powrie (Oxford), reviewed the immunoregulatory mechanisms responsible for the development of inflammatory bowel disease in mouse models. She emphasized the importance of IL-23, rather than IL-12, by showing that IL-23p19-deficient mice have a milder course of disease. Notably, IL-23 seems to modulate mainly regulatory T cell numbers, which are greater in the lamina propria of p19-deficient mice, with lower amounts of TNF and interferon-γ (IFN-γ). Coombes showed that Foxp3+ regulatory T cells can be induced to develop in the peripheral gut-associated lymphoid tissue after antigen administra-tion; the generation of these cells depends on interaction with CD103+ dendritic cells (DCs), whereas CD103– DCs promote proinflamma-tory responses. Critical distinctions between the two types of DCs include the expression by CD103+ DCs of transforming growth factor-β and enzymes that convert retinal into retinoic acid6. The abilities of CD103+ DCs may be ‘conditioned’ by the epithelial cells with which they engage through E-cadherin. Such data reemphasize the bidirectional information flow between immune and parenchymal cells in the maintenance of tissue homeostasis.

Miodrag Lukic (Al Ain, UAE) showed that IL-23 administration increases the diabeto-genic process in a highly refined version of the streptozotocin-induced mouse model of dia-betes. This exacerbation did not occur in IFN-

γ-deficient mice, which links the IL-23–IFN-γ axis, similar to that described for inflammatory bowel disease (discussed above). Nonetheless, there was also upregulation of IL-17. The idea that pathogenic T helper type 1 effector cells (and perhaps other T helper subsets) were induced by ‘upstream’ TLR signaling is consistent with the exacerbation of disease by the TLR2 agonist PAM3 and supports the finding that TLR2 senses β-cell death, thereby contributing to the initiation of autoimmune disease.

Clearly, identifying the respective functions of inflammatory cytokines in various patho-physiological contexts remains challenging. For example, the mouse gut is one of the main sites where CD4+ IL-17-expressing T helper cells are found, yet any contribution of such cells to inflammatory bowel disease has yet to be formally demonstrated. In contrast, IL-17 has been linked to rheumatoid arthritis in mouse models and in cohorts of human patients. New data on the therapeutic potential of targeting IL-17-expressing T helper cells to decrease the inflammation associated with matrix destruc-tion in rheumatoid arthritis were presented by Pierre Miossec (Lyon, France), who provided compelling evidence that IL-17 acts in synergy with TNF to produce disease. Whether the active IL-17 in a pathophysiological situation is genuinely the product of IL-17-expressing T helper cells needs to be established, as many other cells, including γδ T cells, can express large amounts of IL-17.

Staying in the area of the arthritides, the etio-pathogenesis of systemic lupus erythematosus was reviewed by Martin Herrmann (Erlangen, Germany), who provided a reminder that class-switched autoantibodies specific for nuclear constituents are pathognomonic for systemic lupus erythematosus, which empha-sizes the importance of understanding the breakdown of adaptive tolerance. Although much has been made of the ability of toler-ance to be broken by TLR-dependent recog-nition of immune complexes and nucleic acid from apoptotic cells, Herrmann focused on the many membrane perturbations that may pro-mote TLR-independent recognition of dying cells by innate immune cells that can then fuel an adaptive response7. Such mechanisms may precede any antibody formation and may be particularly important in the context of defects in scavenger recognition systems that occur in patients.

Modeling yet another inflammatory pathol-ogy, Noel Rose (Baltimore, USA) described an experimental model of mouse autoimmune myocarditis in which IL-13 has a profound ameliorating effect. Although IL-13-deficient mice in this system show enhanced cardiac

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Figure 2 the stunning Arabian Desert near Al Ain.

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infiltration by CD4+ T cells, evidence was pre-sented that the IL-13 modulates mainly mac-rophage activation, promoting alternatively activated CD206+ and CD204+ cells.

The subsequent presentation by Jorge Kalil (Sao Paulo, Brasil) focused on the genetic and molecular predisposition to develop rheumatic fever and rheumatic heart disease, an autoim-mune disease triggered in susceptible children by cross-reactivity between streptococcal antigens and self antigen on heart tissue. His genetic analysis showed that susceptibility cor-relates with specific combinations of HLA and TNF alleles. In the ongoing ‘tussle’ to resolve whether microbes are at the heart of everything (pun intended!) or whether autoimmunity and inflammatory diseases can be initiated entirely through responses to nonmicrobial stress, Jorge Kalil’s talk presented arguably the most convincing case for microbe-driven anti-genic mimicry as an initiating factor. Positions on either side of this issue can be obstinately maintained by various researchers, but such obstinacy met its match in the camels that offered the delegates rides in the desert that evening (Fig. 2).

Inflammatory mediatorsThe next day, the fourth symposium, on inflammatory mediators in infection, sepsis and septic shock, began with a talk by Graham Rook (London), who presented a comprehen-sive review of the present and severe danger posed by multidrug-resistant tuberculosis. Rook outlined several strategies with demon-strated efficacy in animal models that might be realistically tried in humans. Most of these strategies are based on inhibiting IL-4 and/or transforming growth factor-β. IL-4 seems to inhibit all forms of antimycobacterial killing, including autophagy.

Ridha Barbouche (Tunis, Tunisia) reviewed genetic susceptibility to mycobacterial and other infections in a cohort of patients from Tunisia, where the rate of consanguine-ous marriages is high. Consanguinity offers particularly good opportunities for genetic analysis. In addition to the predictable suscep-tibility mutations affecting the IL-12–IFN-γ cytokine pathway, evidence has now linked the genes encoding TLR2 and the C-type lec-tin receptor DC-SIGN to immunity to infec-tion. Immunogenetic studies may identify inflammatory pathways responsive to defined infections.

A complementary field study by Rabia Hussain (Karachi, Pakistan) examined the phenotypes of household contacts of those with acute exposure to tuberculosis. A 2-year longitudinal follow-up study of a cohort of 109 healthy household contacts in 20 families of

patients with smear-positive pulmonary tuber-culosis identified seven new cases, with early evidence indicating that the ratio of IFN-γ to IL-10 may prove to be the inverse correlate of susceptibility.

Narinder Mehra (New Delhi, India) next reviewed the influence of host immunogenet-ics on susceptibility to infection with human immunodeficiency virus. His studies were undertaken in situ on the Indian subcontinent, where genetic data are scarce. He showed that the progression of human immunodeficiency virus disease is influenced by mutations in sev-eral genes, including those encoding chemok-ines and chemokine receptors (CCR2, CCR5, RANTES and SDF1) and cytokines (IFN-γ, IL-10 and IL-4), as well as HLA alleles (HLA-A24 and HLA-B35) that are particularly preva-lent in India.

Michael Ellis (Al Ain, UAE) presented an overview of clinical strategies to protect can-cer patients undergoing chemotherapy from infection and sepsis. On the basis of data obtained from a double-blind, randomized clinical trial in Al Ain, he and his colleagues showed that IL-11 was effective in decreasing infections caused by ‘gut-origin’ organisms that cause chemotherapy-induced mucositis and epithelial cell damage. Additionally, IL-11 was shown to induce synthesis of C-reactive protein, another antimicrobial compound, as well as to limit immunopathological damage by inducing soluble TNF receptor 1 (ref. 8).

Maria J. Fernandez-Cabezudo (Al Ain, UAE) focused on alternative stimulation of mac-rophages by recombinant salmonella strains engineered to express (but not secrete) cytokines under the control of the promoter of the anaer-obic growth–induced gene nirB. Macrophage activation was influenced qualitatively and quantitatively by the expression of cytokines such as IFN-γ and IL-2. Evidence was presented that these cytokines are functionally expressed on the surface of the bacteria and affect mac-rophage function independently of invasion, which perhaps explains previous data show-ing rapid activation in vivo of innate immune responses by the recombinant strains9.

Johann Braun (Al Ain, UAE) presented work undertaken jointly with his colleagues in Germany on the involvement of TLR2 activa-tion by Gram-positive bacteria in cerebrospi-nal inflammation and neuronal damage. After intrathecal administration of a synthetic TLR2 ligand in a rat model of acute exposure, an inflammatory response ensued that was asso-ciated with the identification of neurotoxic activities in the supernatants of microglia. Thus, TLR2 signaling alone may induce host neuronal pathologies that are pathognomic features of acute bacterial meningitis10.

Innate immunity and cancerIn his second talk of the conference, Ruslan Medzhitov discussed inflammation as an etiological agent of malignancy, perhaps as an undesired consequence of uncontrolled wound healing. Intestinal turnover is regulated by the product of the adenomatosis polyposis coli (APC) gene, Wnt (a secreted signaling mol-ecule that regulates cell-to-cell interactions during embryogenesis and cancerogenesis) and β-catenin. Although the tumors that form in APCmin+ mice (a strain highly susceptible to the formation of spontaneous intestinal adenoma) are not obviously dependent on inflammation, APCmin+ mice crossed onto a MyD88-deficient background live much longer with slower pro-gression of early tumorigenic events. None of the three known markers of intestinal adenoma progression, COX2, MMP7 or cPLA2, were upregulated on the MyD88-deficient back-ground, which led to the conclusion that TLR2-MyD88 regulates the tumor-specific expression of key genes required for intestinal tumor pro-gression. It remains to be determined whether this function of the TLR pathway relates to the microbe-rich gut epithelium or applies to car-cinogenesis in other sites as well.

That theme was continued in the fifth and final symposium, on inflammatory innate immune mechanisms in cancer development and progression, which began with a talk by Giorgio Trinchieri (Bethesda, Maryland, USA). He reviewed the conflicting functions of inflammation in tumor development. He considered that in premalignant inflammatory situations, TLR9 may be activated by antibody-DNA complexes, whereas TLR3 may respond to RNA from necrotic cells. Notably, TLR signal-ing apparently can regulate the balance between cell proliferation and apoptosis. Reporting on studies of a chemically induced colitis–associ-ated model of colon carcinoma, he discussed data showing that MyD88-deficient mice are more susceptible to tumor development than are wild-type mice. In experiments with bone marrow chimeras, transfer of MyD88-deficient bone marrow to wild-type mice enhanced tumorigenesis and, conversely, transplanta-tion of wild-type bone marrow protected MyD88-deficient mice. These results suggest that functional expression of MyD88 on bone marrow–derived cells can provide protection from tissue damage and cancer development; conversely, MyD88 is required for some forms of chemically induced skin carcinogenesis. To characterize the function of TNF in tumor pro-gression, mice in which TNF expression is selec-tively ablated in a cell-specific way were used. These studies showed that specific inhibition of TNF expression in gut enterocytes protected mice from chemically induced colon carcino-

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mas. In contrast, ablation of TNF expression in macrophages and T cells enhanced the develop-ment of cancers.

Salem Chouaib (Villejuif, France) identi-fied increased resistance of tumors to being killed by cytotoxic T lymphocytes (CTLs) as one of the central pitfalls in the development of effective anticancer immunity. Therapeutic cancer vaccines aim to induce and maintain effective tumor-specific CTL responses. So far, overall tumor regression rates have been dis-appointingly low, mainly because of resistance mechanisms of the tumors. He discussed the involvement of mutations in the gene encoding the tumor suppressor protein p53 in the resis-tance of tumors to lysis by CTLs. Ordinarily, p53 has a linker function between death recep-tors and the mitochondrial apoptosis pathway. It has been found that CTL-induced stress on target cells is accompanied by an increase in p53 expression. This is mediated by granzyme B, which seems to directly induce the accu-mulation and activation of p53 in target cells. Thus, the induced activation of p53 seems to be critical for regulation of the magnitude of the lysis of tumor targets by CTLs. These data suggest that interventional strategies aimed at restoring p53 expression in tumor targets may well be effective in optimizing CTL-based tumor immunotherapy.

Sherif Karam (Al Ain, UAE) presented a phenotypic analysis of the interaction between gastric progenitor cells and Helicobacter pylori. This organism inhabits gastric tissue in more than 50% of the world’s population and in susceptible hosts causes a dysregulation of acid secretion, which leads to gastritis and stomach cancer. Evidence was presented show-ing that cancer-associated H. pylori strains are selectively able to invade and inhabit actively proliferating gastric stem cell progenitors, but gastritis-associated strains are not. It is plau-sible that this is a causative event in premalig-nant epithelial dysregulation.

Next, Adrian Hayday (London, UK) dis-cussed the function of intraepithelial lympho-cytes (IELs) in immune surveillance. It has been known for some time that stress-related, self-encoded antigens such as mouse Rae-1 and human MICA are rapidly upregulated after inflammatory, microbial or tumorigenic stimuli. These antigens serve as ligands for the activating receptor NKG2D, found on a variety of cytotoxic cells, including γδ T cells, natu-ral killer T cells, natural killer cells and CD8+ T cells. In a transgenic mouse model, higher expression of Rae-1 on normal keratinocytes, in the absence of any confounding inflammatory or malignant transformation signal, induced rapid changes in the organization of NKG2D-expressing intraepithelial T cells, followed rap-idly by reorganization of Langerhans cells and tissue infiltration by unconventional natural killer T cells11. This demonstrated that the ini-tiation of an immune surveillance response can occur in the absence of any non-self antigenic triggers. Moreover, the importance of intraepi-thelial lymphocytes in this process of immune surveillance was demonstrated by the greater susceptibility to squamous cell carcinoma in mice selectively deficient in epidermal intraepi-thelial lymphocytes. The development of these specialized γδ T cells is uniquely dependent on the expression of Skint-1, a member of a newly identified family of proteins expressed in skin, which acts as a positive selecting element by an as-yet-unknown mechanism. Notably, Skint-1 seems to be downregulated by stress, rather than being upregulated by it (as are the NKG2D ligands). This suggests that intraepi-thelial lymphocytes, like natural killer cells, are highly sensitive to signs of normality, such as Skint-1, as well as to ‘alarmins’, such as Rae-1.

In the final talk of the Al-Ain meeting, Basel al-Ramadi (Al Ain, UAE) summarized his group’s work on the use of cytokine-express-ing attenuated salmonella strains in cancer immunotherapy. Systemic administration of

salmonella leads to tumor retardation cor-related with intratumor bacterial accumula-tion, less angiogenesis and more apoptosis. However, data suggest that homing of bacte-ria to tumor tissue may not be a prerequisite for the antitumor effects of salmonella. Oral administration of bacteria leads to tumor inhibition without any detectable bacterial accumulation in tumor tissue, which indi-cates that the antitumor properties of attenu-ated salmonella can be dissociated from their tumor-homing ability.

ConclusionsIn summary, the Third Al-Ain International Immunology meeting emphasized the asso-ciation of immune mechanisms with a seem-ingly growing spectrum of pathophysiological conditions relevant to both the developing and developed worlds. Immunologists’ under-standing can contribute immensely to the elucidation of pathogenesis and to the devel-opment of biomarkers and therapies. This perspective was truly enriching, and a fourth Al-Ain meeting should provide future chances to assess progress in each of these areas of great opportunity.

ACKNOWLEDGMENTSSupported by the Wellcome Trust (A.H.).

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(2008).4. Larsen, C.M. et al. N. Engl. J. Med. 356, 1517–1526

(2007).5. Kagan, J.C. et al. Nat. Immunol. 9, 361–368 (2008).6. Coombes, J.L. et al. J. Exp. Med. 204, 1757–1764

(2007).7. Janssen, E. et al. Immunity 24, 787–799 (2006).8. Ellis, M. et al. Clin. Immunol. 120, 129–137 (2006).9. al-Ramadi, B.K., Mustafa, N., AbouHaidar, M. &

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