Long-Lived Plasma Cells in Mice and Men.

Even though more than 30 years have passed since the eradication of smallpox, high titers of smallpox-specific antibodies are still detected in the blood of subjects vaccinated in childhood. In fact, smallpox-specific antibody levels are maintained in serum for more than 70 years. The generation of life-long immunity against infectious diseases such as smallpox and measles has been thoroughly documented. Although the mechanisms behind high persisting antibody titers in the absence of the causative agent are still unclear, long lived plasma cells (LLPCs) play an important role. Most of the current knowledge on LLPCs is based on experiments performed in mouse models, although the amount of data derived from human studies is increasing. As the results from mouse models are often directly extrapolated to humans, it is important to keep in mind that there are differences. These are not only the obvious such as the life span but there are also anatomical differences, for instance the adiposity of the bone marrow (BM) where LLPCs reside. Whether these differences have an effect on the function of the immune system, and in particular on LLPCs, are still unknown. In this review, we will briefly discuss current knowledge of LLPCs, comparing mice and humans.

Interleukin-5 facilitates lung metastasis by modulating the immune microenvironment.

Although the lung is the most common metastatic site for cancer cells, biologic mechanisms regulating lung metastasis are not fully understood. Using heterotopic and intravenous injection models of lung metastasis in mice, we found that IL5, a cytokine involved in allergic and infectious diseases, facilitates metastatic colonization through recruitment of sentinel eosinophils and regulation of other inflammatory/immune cells in the microenvironment of the distal lung. Genetic IL5 deficiency offered marked protection of the lungs from metastasis of different types of tumor cells, including lung cancer, melanoma, and colon cancer. IL5 neutralization protected subjects from metastasis, whereas IL5 reconstitution or adoptive transfer of eosinophils into IL5-deficient mice exerted prometastatic effects. However, IL5 deficiency did not affect the growth of the primary tumor or the size of metastatic lesions. Mechanistic investigations revealed that eosinophils produce CCL22, which recruits regulatory T cells to the lungs. During early stages of metastasis, Treg created a protumorigenic microenvironment, potentially by suppressing IFNγ-producing natural killer cells and M1-polarized macrophages. Together, our results establish a network of allergic inflammatory circuitry that can be co-opted by metastatic cancer cells to facilitate lung colonization, suggesting interventions to target this pathway may offer therapeutic benefits to prevent or treat lung metastasis.

Immunotherapeutic approaches for the treatment of eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is a clinical pathologic disease characterized by symptoms of esophageal dysfunction and eosinophilia of the esophagus. When the diagnosis is confirmed, it is important to treat the eosinophilic inflammation not only to control the presenting symptoms, but also to prevent acute and chronic complications. The pathogenesis of EoE is most likely a mixed IgE and non-IgE food-mediated reaction, where Th2 cytokines drive esophageal eosinophilia as in other atopic diseases. Hence, it is not surprising that therapy is based on inflammation control, with steroids (oral or topical) and/or food antigen avoidance. However, these treatment options are not specific, reduce the quality of life of patients and have significant side effects, therefore, there is an ongoing effort to design more specific immunotherapies. In this review, we review standard and immunotherapeutic options for EoE treatment, such as anti-IL-5, anti-TNFα, anti-IgE, anti-CRTH, oral allergy desensitization and environmental immunotherapy.

Signalling by the ßc family of cytokines.

The GM-CSF, IL-3 and IL-5 family of cytokines, also known as the ßc family due to their receptors sharing the signalling subunit ßc, regulates multiple biological processes such as native and adaptive immunity, inflammation, normal and malignant hemopoieis, and autoimmunity. Australian scientists played a major role in the discovery and biological characterisation of the ßc cytokines and their recent work is revealing unique features of cytokine receptor assembly and signalling. Furthermore, specific antibodies have been generated to modulate their function. Characterisation of the structural and dynamic requirements for the activation of the ßc receptor family and the molecular definition of downstream signalling pathways are providing new insights into cytokine receptor signalling as well as new therapeutic opportunities.

Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages.

Eosinophils in visceral adipose tissue (VAT) have been implicated in metabolic homeostasis and the maintenance of alternatively activated macrophages (AAMs). The absence of eosinophils can lead to adiposity and systemic insulin resistance in experimental animals, but what maintains eosinophils in adipose tissue is unknown. We show that interleukin-5 (IL-5) deficiency profoundly impairs VAT eosinophil accumulation and results in increased adiposity and insulin resistance when animals are placed on a high-fat diet. Innate lymphoid type 2 cells (ILC2s) are resident in VAT and are the major source of IL-5 and IL-13, which promote the accumulation of eosinophils and AAM. Deletion of ILC2s causes significant reductions in VAT eosinophils and AAMs, and also impairs the expansion of VAT eosinophils after infection with Nippostrongylus brasiliensis, an intestinal parasite associated with increased adipose ILC2 cytokine production and enhanced insulin sensitivity. Further, IL-33, a cytokine previously shown to promote cytokine production by ILC2s, leads to rapid ILC2-dependent increases in VAT eosinophils and AAMs. Thus, ILC2s are resident in VAT and promote eosinophils and AAM implicated in metabolic homeostasis, and this axis is enhanced during Th2-associated immune stimulation.

IL-5-induced migration via ERK1/2-mediated MMP-9 expression by inducing activation of NF-κB in HT1376 cells.

Interleukin-5 (IL-5) plays an important role in the growth and differentiation of human B cells and eosinophils. However, little is known about the effect of IL-5 on cancer cells. In this study, we investigated the molecular mechanisms involved in the IL-5-induced migration of HT1376 bladder cancer cells. Our results indicated that IL-5 significantly enhanced migration and MMP-9 expression in HT1376 cells. We also found that IL-5 induces transcriptional activation of the binding of NF-κB and AP-1, which are two important nuclear transcription factors that are linked to MMP-9 expression in HT1376 cells. In subsequent experiments, we found activation of ERK1/2 in IL-5-treated HT1376 cells. To examine the involvement of the ERK1/2 signaling pathway on IL-5-induced cell responses, we pretreated HT1376 cells with the ERK1/2 inhibitor U0126 followed by IL-5 treatment. The results showed that U0126 treatment inhibited migration of IL-5-treated HT1376 cells. Moreover, IL-5-stimulated MMP-9 expression was suppressed by the addition of U0126. Inhibition of ERK1/2 function consistently rescued transcriptional activity of NF-κB, without altering AP-1 activation, in IL-5-treated cells. Finally, inhibition of the IL-5-specific receptor IL-5Rα by small interfering RNA (siRNA) suppressed migration, ERK1/2 activation, MMP-9 expression and binding activation of NF-κB in IL-5-treated HT1376 cells. The results of the present study indicate that the IL-28A/IL-28AR1 dyad induces cell migration through ERK1/2-mediated expression of MMP-9 by binding activation of NF-κB in bladder cancer cells. In conclusion, these novel findings indicate that binding of IL-5 to IL-5Rα plays a critical role in MMP-9 expression, which may be involved in the migration of bladder cancer.

Identification of JAK2 as a mediator of FIP1L1-PDGFRA-induced eosinophil growth and function in CEL.

The Fip1-like1 (FIP1L1)-platelet-derived growth factor receptor alpha fusion gene (F/P) arising in the pluripotent hematopoietic stem cell (HSC),causes 14% to 60% of patients with hypereosinophilia syndrome (HES). These patients, classified as having F/P (+) chronic eosinophilic leukemia (CEL), present with clonal eosinophilia and display a more aggressive disease phenotype than patients with F/P (-) HES patients. The mechanisms underlying predominant eosinophil lineage targeting and the cytotoxicity of eosinophils in this leukemia remain unclear. Given that the Janus tyrosine kinase (JAK)/signal transducers and activators of transcription (Stat) signaling pathway is key to cytokine receptor-mediated eosinophil development and activated Stat3 and Stat5 regulate the expression of genes involved in F/P malignant transformation, we investigated whether and how JAK proteins were involved in the pathogenesis of F/P-induced CEL. F/P activation of JAK2, Stat3 and Stat5, were confirmed in all the 11 F/P (+) CEL patients examined. In vitro inhibition of JAK2 in EOL-1, primary F/P(+) CEL cells (PC) and T674I F/P Imatinib resistant cells(IR) by either JAK2-specific short interfering RNA (siRNA) or the tryphostin derivative AG490(AG490), significantly reduced cellular proliferation and induced cellular apoptosis. The F/P can enhance the IL-5-induced JAK2 activation, and further results indicated that JAK2 inhibition blocked IL-5-induced cellular migration and activation of the EOL-1 and PC cells in vitro. F/P-stimulation of the JAK2 suppressed cells led to a significantly reduction in Stat3 activation, but relatively normal induction of Stat5 activation. Interestingly, JAK2 inhibition also reduced PI3K, Akt and NF-κB activity in a dose-dependent manner, and suppressed expression levels of c-Myc and Survivin. These results strongly suggest that JAK2 is activated by F/P and is required for F/P stimulation of cellular proliferation and infiltration, possibly through induction of c-Myc and Survivin expression via activation of multiple signaling pathways, including NF-κB, Stat3, and PI3K/Akt.

Identification of innate IL-5-producing cells and their role in lung eosinophil regulation and antitumor immunity.

IL-5 is involved in a number of immune responses such as helminth infection and allergy. IL-5 also plays roles in innate immunity by maintaining B-1 B cells and mucosal IgA production. However, the identity of IL-5-producing cells has not been unambiguously characterized. In this report, we describe the generation of an IL-5 reporter mouse and identify IL-5-producing non-T lymphoid cells that reside in the intestine, peritoneal cavity, and lungs in naive mice. They share many characteristics with natural helper cells, nuocytes, and Ih2 cells, including surface Ags and responsiveness to cytokines. However, these phenotypes do not completely overlap with any particular one of these cell types. Innate non-T IL-5-producing cells localized most abundantly in the lung and proliferated and upregulated IL-5 production in response to IL-25 and IL-33. IL-33 was more effective than IL-25. These cells contribute to maintaining sufficient numbers of lung eosinophils and are important for eosinophil recruitment mediated by IL-25 and IL-33. Given that eosinophils are shown to possess antitumor activity, we studied lung tumor metastasis and showed that innate IL-5-producing cells were increased in response to tumor invasion, and their regulation of eosinophils is critical to suppress tumor metastasis. Genetic blockade or neutralization of IL-5 impaired eosinophil recruitment into the lung and resulted in increased tumor metastasis. Conversely, exogenous IL-5 treatment resulted in suppressed tumor metastasis and augmented eosinophil infiltration. These newly identified innate IL-5-producing cells thus play a role in tumor surveillance through lung eosinophils and may contribute to development of novel immunotherapies for cancer.

Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study.

RATIONALE: Eosinophilic asthma is a phenotype of asthma characterized by the persistence of eosinophils in the airways. IL-5 is involved in the activation and survival of eosinophils. OBJECTIVES: To evaluate the effect of the antibody to IL-5, reslizumab, in patients with eosinophilic asthma that is poorly controlled with high-dose inhaled corticosteroid. METHODS: Patients were randomly assigned to receive infusions of reslizumab at 3.0 mg/kg (n = 53) or placebo (n = 53) at baseline and at Weeks 4, 8, and 12, with stratification by baseline Asthma Control Questionnaire (ACQ) score less than or equal to 2 or greater than 2. The primary efficacy measure was the difference between the reslizumab and placebo groups in the change in ACQ score from baseline to end of therapy (Week 15 or early withdrawal). MEASUREMENTS AND MAIN RESULTS: Mean changes from baseline to end of therapy in ACQ score were -0.7 in the reslizumab group and -0.3 in the placebo group (P = 0.054) and in FEV(1) were 0.18 and -0.08 L, respectively (P = 0.002). In those patients with nasal polyps, the changes in ACQ score were -1.0 and -0.1, respectively (P = 0.012). Median percentage reductions from baseline in sputum eosinophils were 95.4 and 38.7%, respectively (P = 0.007). Eight percent of patients in the reslizumab group and 19% of patients in the placebo group had an asthma exacerbation (P = 0.083). The most common adverse events with reslizumab were nasopharyngitis, fatigue, and pharyngolaryngeal pain. CONCLUSIONS: Patients receiving reslizumab showed significantly greater reductions in sputum eosinophils, improvements in airway function, and a trend toward greater asthma control than those receiving placebo. Reslizumab was generally well tolerated.

Chemoattractant-induced signaling via the Ras-ERK and PI3K-Akt networks, along with leukotriene C4 release, is dependent on the tyrosine kinase Lyn in IL-5- and IL-3-primed human blood eosinophils.

Human blood eosinophils exhibit a hyperactive phenotype in response to chemotactic factors after cell "priming" with IL-5 family cytokines. Earlier work has identified ERK1/2 as molecular markers for IL-5 priming, and in this article, we show that IL-3, a member of the IL-5 family, also augments fMLP-stimulated ERK1/2 phosphorylation in primary eosinophils. Besides ERK1/2, we also observed an enhancement of chemotactic factor-induced Akt phosphorylation after IL-5 priming of human blood eosinophils. Administration of a peptide antagonist that targets the Src family member Lyn before cytokine (IL-5/IL-3) priming of blood eosinophils inhibited the synergistic increase of fMLP-induced activation of Ras, ERK1/2 and Akt, as well as the release of the proinflammatory factor leukotriene C(4). In this study, we also examined a human eosinophil-like cell line HL-60 clone-15 and observed that these cells exhibited significant surface expression of IL-3Rs and GM-CSFRs, as well as ERK1/2 phosphorylation in response to the addition of IL-5 family cytokines or the chemotactic factors fMLP, CCL5, and CCL11. Consistent with the surface profile of IL-5 family receptors, HL-60 clone-15 recapitulated the enhanced fMLP-induced ERK1/2 phosphorylation observed in primary blood eosinophils after priming with IL-3/GM-CSF, and small interfering RNA-mediated knockdown of Lyn expression completely abolished the synergistic effects of IL-3 priming on fMLP-induced ERK1/2 phosphorylation. Altogether, our data demonstrate a central role for Lyn in the mechanisms of IL-5 family priming and suggest that Lyn contributes to the upregulation of the Ras-ERK1/2 and PI3K-Akt cascades, as well as the increased leukotriene C(4) release observed in response to fMLP in "primed" eosinophils.

Mesenchymal stem cell transplantation modulates neuroinflammation in focal cerebral ischemia: contribution of fractalkine and IL-5.

Mesenchymal stem cells (MSCs) are reported to possess immunomodulatory properties. Previous reports have demonstrated the beneficial effects of MSC-transplantation in focal cerebral ischemia animal models. In this study, we have investigated the neuroimmunomodulatory functions of human MSCs, transplanted in a rat focal ischemia model of transient middle cerebral artery occlusion (MCAO). Our results revealed that in a human mesenchymal stem cell line, B10 cell transplantation decreased the accumulation of Iba-1(+) microglia and GFAP(+) astrocytes, and inhibited proinflammatory gene expression in the core and ischemic border zone (IBZ). Among the proinflammatory genes iNOS, which was expressed in microglia/macrophage, was persistently inhibited up to 7days after MCAO. In vivo laser capture microdissection and double immunofluorescence staining, and in vitro B10 cell culture experiments showed that, in inflammatory conditions, B10 cells expressed cytokines and growth factors including IL-5, fractalkine, IGF-1, GDNF and VEGF. Fractalkine and IL-5 inhibited cytokine-induced proinflammatory gene expression including iNOS in a human microglia cell line. Thus, our results demonstrate that MSC transplantation suppresses MCAO focal ischemia-induced inflammation, possibly through expression of fractalkine and IL-5.

Exacerbation of oxazolone colitis by infection with the helminth Hymenolepis diminuta: involvement of IL-5 and eosinophils.

Substantial data show that infection with helminth parasites ameliorates colitis; however, oxazolone-induced colitis is exaggerated in mice infected with the tapeworm, Hymenolepis diminuta. We tested the hypothesis that the IL-5 response to helminth infection enhances the severity of oxazolone-induced colitis. Mice were infected with H. diminuta and 8 days later were treated with oxazolone ± anti-IL-5 antibodies. Colitis was assessed 72 hours postoxazolone treatment by disease activity scores, myeloperoxidase activity, and histopathology. Other mice received injections of a replication-deficient adenovirus that carried the IL-5 (Ad.IL-5) gene or a control adenovirus (Ad.delete) ± oxazolone. The effect of H. diminuta+oxazolone in CCL11/CCL22 (eotaxin-1 and 2) knockout (KO) mice was determined. Helminth infection and Ad.IL-5 treatment increased IL-5 and eosinophil numbers. In vivo neutralization of IL-5 significantly reduced the severity of colitis in H. diminuta+oxazolone-treated mice, and H. diminuta did not exaggerate oxazolone-induced colitis in CCL11/CCL22 KO mice. Mice receiving Ad.IL-5 only had no colitis, while oxazolone-induced colitis was more severe in animals cotreated with Ad.IL-5 (Ad.delete + oxazolone was not significantly different from oxazolone only). Thus, while there is much to be gleaned about antiinflammatory mechanisms from rodent-helminth model systems, these data illustrate the caveat that infection with helminth parasites as a therapy could be contraindicated in patients with eosinophilia or elevated IL-5 unless coupled to appropriate measures to block IL-5 and/or eosinophil activity.

FTY720 regulates bone marrow egress of eosinophils and modulates late-phase skin reaction in mice.

Eosinophilia in the blood and skin is frequently observed in patients with certain inflammatory skin diseases, such as atopic dermatitis. However, the mechanism underlying eosinophil circulation and the role of eosinophils in cutaneous immune responses remain unclear. In repeated hapten application-induced cutaneous responses in BALB/c mice, the administration of FTY720 before the last challenge decreased the number of skin-infiltrating eosinophils and reduced the late-phase reaction. A similar reduction of the late-phase reaction was observed by a sphingosine-1-phosphate G protein-coupled receptor (S1P1)-selective agonist, SEW2871. We monitored numerous alterations of eosinophils in the blood, spleen, bone marrow, and lymph nodes of interleukin-5 transgenic mice, used as an eosinophilia model, following FTY720 administration. The number of circulating eosinophils was significantly decreased after treatment with FTY720, and eosinophils accumulated in the bone marrow. In addition, eosinophils expressed S1P1, S1P3, and S1P4 mRNAs, and their chemotactic response to S1P was abolished by FTY720 as well as by SEW2871. These findings suggest that FTY720 affects the number of eosinophils in both the blood and skin by inhibiting the egress of eosinophils from the bone marrow and thus downmodulating the late-phase reaction.

Host-derived interleukin-5 promotes adenocarcinoma-induced malignant pleural effusion.

RATIONALE: IL-5 is a T helper 2 cytokine important in the trafficking and survival of eosinophils. Because eosinophils can be found in malignant pleural effusions (MPE) from mice and humans, we asked whether IL-5 is involved in the pathogenesis of MPE. OBJECTIVES: To determine the role of IL-5 in MPE formation. METHODS: The effects of IL-5 on experimental MPE induced in C57BL/6 mice by intrapleural injection of syngeneic lung (Lewis lung cancer [LLC]) or colon (MC38) adenocarcinoma cells were determined using wild-type (il5(+/+)) and IL-5-deficient (il5⁻(/)⁻) mice, exogenous administration of recombinant mouse (rm) IL-5, and in vivo antibody-mediated neutralization of endogenous IL-5. The direct effects of rmIL-5 on LLC cell proliferation and gene expression in vitro were determined by substrate reduction and microarray. MEASUREMENTS AND MAIN RESULTS: Eosinophils and IL-5 were present in human and mouse MPE, but the cytokine was not detected in mouse (LLC) or human (A549) lung and mouse colon (MC38) adenocarcinoma-conditioned medium, suggesting production by host cells in MPE. Compared with il5(+/+) mice, il5⁻(/)⁻ mice showed markedly diminished MPE formation in response to both LLC and MC38 cells. Exogenous IL-5 promoted MPE formation in il5(+/+) and il5⁻(/)⁻ mice, whereas anti-IL-5 antibody treatment limited experimental MPE in il5(+/+) mice. Exogenous IL-5 had no effects on LLC cell proliferation and gene expression; however, IL-5 was found to be responsible for recruitment of eosinophils and tumor-promoting myeloid suppressor cells to MPE in vivo. CONCLUSIONS: Host-derived IL-5 promotes experimental MPE and may be involved in the pathogenesis of human MPE.

What targeting eosinophils has taught us about their role in diseases.

Eosinophil-associated disease is a term used to encompass a range of disorders from hypereosinophilic syndrome to asthma. Despite the longstanding belief that eosinophils can be primary contributors to disease pathophysiology, it is only in recent years that direct and selective reduction or elimination of eosinophils can be achieved in animals or human subjects. These developments have been made possible in mice through clever targeting of eosinophil production. Antibodies and other agents that target soluble eosinophil-related molecules, such as IL-5, or cell-surface structures, such as CCR3, have also proved useful in reducing blood and tissue eosinophil counts. In human subjects the only eosinophil-selective agents tested in clinical trials thus far are neutralizing antibodies to IL-5, with promising but mixed results. At the very least, such forms of pharmacologic hypothesis testing of the role of eosinophils in certain airway, gastrointestinal, and hematologic diseases has finally provided us with new insights into disease pathogenesis. At its optimistic best, these and other targeted agents might someday become available for those afflicted with eosinophil-associated disorders. This review summarizes what has been learned in vivo in both preclinical and clinical studies of eosinophil-directed therapies, with an emphasis on recent advances.

Cytokine antagonists for the treatment of asthma: progress to date.

Asthma is a disease of the airways in which several cytokines such as interleukin (IL)-4, IL-5, IL-13 and tumor necrosis factor-alpha (TNFalpha) play a major role in the development and progression of inflammation, airway hyperresponsiveness, mucus production, and airway remodeling. The conventional anti-inflammatory therapies, represented by inhaled corticosteroids and antileukotrienes, are not always able to provide optimal disease control and it is therefore hoped that cytokine antagonists could achieve this goal in such situations. Anticytokine therapies have been tested in preclinical studies and some have entered clinical trials. Anti-IL-4 therapies have been tested in animal models of allergy-related asthma, but because of unclear efficacy their development was discontinued. However, IL-4/IL-13 dual antagonists and IL-13-specific blocking agents are more promising, as they exhibit more sustained anti-inflammatory effects. IL-5 antagonists have been found to be of limited efficacy in clinical studies but might be useful in conditions characterized by severe hypereosinophilia, and in which asthma is one of the disease manifestations. Unlike other chronic inflammatory conditions, such as rheumatoid arthritis, the use of anti-TNFalpha therapies in asthma might be limited by the unfavorable risk/benefit ratio associated with long-term use. The identification of so-called asthma TNFalpha phenotypes and perhaps the use of a less aggressive treatment regimen might address this important aspect. Other cytokine antagonists (for example for IL-9 or IL-25) are currently being evaluated in the asthma setting, and could open new therapeutic perspectives based on their efficacy and safety.

Role of GM-CSF signaling in cell-based tumor immunization.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a potent adjuvant in cancer vaccination; however, the specific role of endogenous GM-CSF remains unknown. We performed cell-based vaccination in 2 tumor models. First, we vaccinated C57BL/6 mice lacking either GM-CSF, IL-5, or beta-common chain (betac), a receptor subunit essential for GM-CSF and IL-5 signaling, with melanoma cells engineered to produce GM-CSF. Tumor vaccination was effective in both GM-CSF(-/-) and IL-5(-/-) mice, showing that protective immunization is independent of both endogenous cytokines. However, all betac(-/-) animals developed tumor. Loss of tumor immunity in betac(-/-) mice does not reflect global impairment in cell-mediated immunity, as contact hypersensitivity reaction to haptens is unaltered. The importance of tumor cell-derived GM-CSF was highlighted by recruitment of dendritic cells at the vaccination site in wild-type, GM-CSF(-/-), and IL-5(-/-) but not in betac(-/-) mice. In the second model, vaccination with unmodified RENCA cells showed similar results with efficient immunization in BALB/c wild-type and GM-CSF(-/-), whereas all betac(-/-) animals died. Altogether, our results strongly suggest that although endogenous GM-CSF and IL-5 are not required to induce tumor immunity, signaling through betac receptor is critically needed for efficient cancer vaccination in both genetically modified GM-CSF-secreting tumor cells and a spontaneously immunogenic models.

Primary eosinophilic disorders of the gastrointestinal tract.

Eosinophils are important effector cells of the innate immune system. Eosinophilic infiltrative disorders of the gastrointestinal tract, though recognised for decades, have recently witnessed a resurgence of interest, particularly for oesophageal disease. A more comprehensive basis for eosinophilic infiltration and activation has identified interleukin 5 (IL5) as a key cytokine for the differentiation and proliferation of eosinophils, while eotaxins promote the recruitment of mature eosinophils to the gut. When activated, eosinophils release multiple cytotoxic agents and immunomodulatory cytokines, resulting in local inflammation and tissue damage. Although eosinophils normally convey a defence against unwanted interlopers such as parasites, in the absence of such inciting agents, their accumulation and activation can elicit the primary infiltrative disorders of the gut: eosinophilic oesophagitis, gastroenteritis and colitis. Diagnosis of these disorders is dependent on the clinical presentation, endoscopic findings (particularly for eosinophilic oesophagitis), and most importantly, histological confirmation. Dietary modifications and topical corticosteroids are first-line treatments for eosinophilic oesophagitis. Systemic corticosteroids are the mainstay of treatment for eosinophilic gastroenteritis; surgery may be required depending on the layer of mucosa involved. Eosinophilic colitis most often occurs in infants; removal of the causative allergen usually results in a complete response. Steroids may be required for older children/adolescents or adults. This review summarises current knowledge on the trafficking of eosinophils to the gastrointestinal tract and the clinical management of the primary disorders of eosinophilic oesophagitis, eosinophilic gastroenteritis and eosinophilic colitis.

Macrophage migration inhibitory factor is critical to interleukin-5-driven eosinophilopoiesis and tissue eosinophilia triggered by Schistosoma mansoni infection.

Macrophage migration inhibitory factor (MIF) participates in the pathogenesis of inflammatory diseases, including asthma, in which it enhances airway hypersensitivity and tissue eosinophilia. Herein, we investigated the role of MIF in eosinophilopoiesis and tissue eosinophilia using Schistosoma mansoni infection. MIF-deficient (Mif(-/-)) mice had similar numbers of adult worms, eggs, and granulomas compared to wild-type mice, but the size of granulomas was strikingly reduced due to smaller numbers of eosinophils. MIF did not affect the acquired response to infection, as Mif(-/-) mice produced normal amounts of Th2 cytokines and IgE. Nevertheless, recombinant MIF (rMIF) behaved as a chemoattractant for eosinophils, what could partially explain the reduced eosinophilia in infected Mif(-/-) mice. Moreover, the percentage of eosinophils was reduced in bone marrows of Mif(-/-) mice chronically infected with S. mansoni compared to wild type. Mif(-/-) had impaired eosinophilopoiesis in response to interleukin (IL)-5 and addition of rMIF to bone marrow cultures from IL-5 transgenic mice enhanced the generation of eosinophils. In the absence of MIF, eosinophil precursors were unable to survive the IL-5-supplemented cell culture, and were ingested by macrophages. Treatment with pancaspase inhibitor z-VAD or rMIF promoted the survival of eosinophil progenitors. Together, these results indicate that MIF participates in IL-5-driven maturation of eosinophils and in tissue eosinophilia associated with S. mansoni infection.

Structure-based rationale for interleukin 5 receptor antagonism.

Human interleukin 5 (IL5) is the major hematopoietin that stimulates the proliferation, migration and activation of eosinophils and is implicated in the pathogenesis of inflammatory and other myeloproliferative diseases. IL5 functions through the signaling of a common receptor subunit beta (beta c), in a receptor activation process that requires initial recruitment of an IL5 specific receptor subunit alpha (IL5Ralpha), for cytokine presentation to beta c. Important advances have been made to understand molecular mechanisms of cytokine recognition and receptor antagonism. Mutational studies indicate that a pair of charge complementary regions play an essential role in specific interaction between IL5Ralpha and IL5. Moreover, peptide studies with the IL5 system have identified a cyclic peptide inhibitor, AF17121, which binds specifically to IL5Ralpha by mimicking the cytokine. A key receptor-recognition pharmacophore has been identified in this peptide inhibitor, and sites of inhibitor recognition can be proposed in the homology-deduced structural model of IL5Ralpha. These results provide an experimental platform to derive enhanced-potency peptidomimetic inhibitors. Such inhibitors have potential use as tools to evaluate the role of eosinophilia in disease and as potential leads to antagonists to treat hyper-eosinophilic diseases such as eosinophilic esophagitis, asthma and chronic myeloproliferative leukemias.