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Padraic G Fallon

Publications and source records attributed to Padraic G Fallon.

At least 19 recordsLinked to original sources
PubMed2006

Pathogen-derived immunomodulatory molecules: future immunotherapeutics?

The identification of molecules from various pathogens that modulate innate and/or adaptive immunity is a dynamic and rapidly developing area of research. These immunomodulatory molecules (IM) have been optimized during pathogen-host co-evolution, and have a potential application as novel immunotherapeutics. In this review, we illustrate the use of pathogen IM that have been produced as recombinant proteins, with different modes of modulatory activity, and discuss their potential to modulate undesirable immune responses in human diseases.

Animals↗
PubMed2006

Identification of an interleukin (IL)-25-dependent cell population that provides IL-4, IL-5, and IL-13 at the onset of helminth expulsion.

Type 2 immunity, which involves coordinated regulation of innate and adaptive immune responses, can protect against helminth parasite infection, but may lead to allergy and asthma after inappropriate activation. We demonstrate that il25(-/-) mice display inefficient Nippostrongylus brasiliensis expulsion and delayed cytokine production by T helper 2 cells. We further establish a key role for interleukin (IL)-25 in regulating a novel population of IL-4-, IL-5-, IL-13-producing non-B/non-T (NBNT), c-kit+, FcepsilonR1- cells during helminth infection. A deficit in this population in il25(-/-) mice correlates with inefficient N. brasiliensis expulsion. In contrast, administration of recombinant IL-25 in vivo induces the appearance of NBNT, c-kit+, FcepsilonR1- cells and leads to rapid worm expulsion that is T and B cell independent, but type 2 cytokine dependent. We demonstrate that these IL-25-regulated cells appear rapidly in the draining lymph nodes, implicating them as a source of type 2 cytokines during initiation of worm expulsion.

Animals↗
PubMed2006

Helminth-modified pulmonary immune response protects mice from allergen-induced airway hyperresponsiveness.

It has been shown that the presence of certain helminth infections in humans, including schistosomes, may reduce the propensity to develop allergies in infected populations. Using a mouse model of schistosome worm vs worm + egg infection, our objective was to dissect the mechanisms underlying the inverse relationship between helminth infections and allergies. We have demonstrated that conventional Schistosoma mansoni egg-laying male and female worm infection of mice exacerbates airway hyperresponsiveness. In contrast, mice infected with only schistosome male worms, precluding egg production, were protected from OVA-induced airway hyperresponsiveness. Worm-infected mice developed a novel modified type 2 cytokine response in the lungs, with elevated allergen-specific IL-4 and IL-13 but reduced IL-5, and increased IL-10. Although schistosome worm-only infection is a laboratory model, these data illustrate the complexity of schistosome modulation of host immunity by the worm vs egg stages of this helminth, with the potential of infections to aggravate or suppress allergic pulmonary inflammation. Thus, infection of mice with a human parasitic worm can result in reduced airway inflammation in response to a model allergen.

Allergens↗
PubMed2005

Schistosoma mansoni secretes a chemokine binding protein with antiinflammatory activity.

The coevolution of humans and infectious agents has exerted selective pressure on the immune system to control potentially lethal infections. Correspondingly, pathogens have evolved with various strategies to modulate and circumvent the host's innate and adaptive immune response. Schistosoma species are helminth parasites with genes that have been selected to modulate the host to tolerate chronic worm infections, often for decades, without overt morbidity. The modulation of immunity by schistosomes has been shown to prevent a range of immune-mediated diseases, including allergies and autoimmunity. Individual immune-modulating schistosome molecules have, therefore, therapeutic potential as selective manipulators of the immune system to prevent unrelated diseases. Here we show that S. mansoni eggs secrete a protein into host tissues that binds certain chemokines and inhibits their interaction with host chemokine receptors and their biological activity. The purified recombinant S. mansoni chemokine binding protein (smCKBP) suppressed inflammation in several disease models. smCKBP is unrelated to host proteins and is the first described chemokine binding protein encoded by a pathogenic human parasite and may have potential as an antiinflammatory agent.

Animals↗
PubMed2005

Identification of a functioning mitochondrial uncoupling protein 1 in thymus.

We present evidence that rat and mouse thymi contain mitochondrial uncoupling protein (UCP 1). Reverse transcriptase-PCR detected RNA transcripts for UCP 1 in whole thymus and in thymocytes. Furthermore, using antibodies to UCP 1 the protein was also detected in mitochondria isolated from whole thymus and thymocytes but not in thymus mitochondria from UCP 1 knock-out mice. Evidence for functional UCP 1 in thymus mitochondria was obtained by a comparative analysis with the kinetics of GDP binding in mitochondria from brown adipose tissue. Both tissues showed equivalent B(max) and K(D) values. In addition, a large component of the nonphosphorylating oxygen consumption by thymus mitochondria was inhibited by GDP and subsequently stimulated by addition of nanomolar concentrations of palmitate. UCP 1 was purified from thymus mitochondria by hydroxyapatite chromatography. The isolated protein was identified by peptide mass mapping and tandem mass spectrometry by using MALDI-TOF and LC-MS/MS, respectively. We conclude that the thymus contains a functioning UCP 1 that has the capacity to regulate metabolic flux and production of reactive oxygen-containing molecules in the thymus.

Amino Acid Sequence↗
PubMed2004

Lethal, neonatal ichthyosis with increased proteolytic processing of filaggrin in a mouse model of Netherton syndrome.

Netherton syndrome is an autosomal recessive multisystemic disorder characterized by congenital ichthyosiform erythroderma, hair shaft defects and atopy, caused by mutations within the human SPINK5 gene. To investigate the development of this disease, we have cloned mouse spink5 and created mice with a mutated premature stop codon at amino acid R820X, to produce an allele that closely mimics a point mutation (E827X) in human SPINK5. Newborn spink5(R820X/R820X) mice develop a lethal, severe ichthyosis with a loss of skin barrier function and dehydration, resulting in death within a few hours of birth, similar to that observed in patients with severe Netherton syndrome. Epidermal barrier function is compromised because of the stratum corneum becoming spontaneously detached in the newborn mice, and this is probably compounded by the reduced mechanical strength detected in the cornified envelopes. Biochemical analysis of skin from newborn wild-type and spink5(R820X/R820X) mice revealed a substantial increase in the proteolytic processing of profilaggrin into its constituent filaggrin monomers. Filaggrin functions to organize keratin filaments into highly ordered macrofibrils that crisscross the cornified cells of the stratum corneum imparting structural integrity, and defects in filaggrin processing occur in a number of forms of congenital ichthyosis. These data suggest that in the absence of the serine protease inhibitor spink5, there is an abnormal increase in the processing of profilaggrin, resulting in an overabundance of filaggrin monomers, and that this may play a direct role in the observed deficit in the adhesion of the stratum corneum and the severely compromised epidermal barrier function.

Amino Acid Sequence↗
PubMed2004

SIGN-R1 contributes to protection against lethal pneumococcal infection in mice.

Rapid clearance of pathogens is essential for successful control of pyogenic bacterial infection. Previous experiments have shown that antibody to specific intracellular adhesion molecule-grabbing nonintegrin (SIGN)-R1 inhibits uptake of capsular polysaccharide by marginal zone macrophages, suggesting a role for SIGN-R1 in this process. We now demonstrate that mice lacking SIGN-R1 (a mouse homologue of human dendritic cell-SIGN receptor) are significantly more susceptible to Streptococcus pneumoniae infection and fail to clear S. pneumoniae from the circulation. Marginal zone and peritoneal macrophages show impaired bacterial recognition associated with an inability to bind T-independent type 2 antigens such as dextran. Our work represents the first evidence for a protective in vivo role for a SIGN family molecule.

Animals↗
PubMed2004

Helminth infection protects mice from anaphylaxis via IL-10-producing B cells.

Modulation of the immune system by infection with helminth parasites, including schistosomes, is proposed to reduce the levels of allergic responses in infected individuals. In this study we investigated whether experimental infection with Schistosoma mansoni could alter the susceptibility of mice to an extreme allergic response, anaphylaxis. We formally demonstrate that S. mansoni infection protects mice from an experimental model of systemic fatal anaphylaxis. The worm stage of infection is shown to mediate this protective effect. In vivo depletion studies demonstrated an imperative role for B cells and IL-10 in worm-mediated protection. Furthermore, worm infection of mice increases the frequency of IL-10-producing B cells compared with that in uninfected mice. However, transfer of B cells from worm-infected mice or in vitro worm-modulated B cells to sensitized recipients exacerbated anaphylaxis, which was attributed to the presence of elevated levels of IL-4-producing B cells. Worm-modulated, IL-10-producing B cells from IL-4-deficient, but not IL-5-, IL-9- or IL-13-deficient, mice conferred complete resistance to anaphylaxis when transferred to naive mice. Therefore, we have dissected a novel immunomodulatory mechanism induced by S. mansoni worms that is dependent on an IL-10-producing B cell population that can protect against allergic hypersensitivity. These data support a role for helminth immune modulation in the hygiene hypothesis and further illustrate the delicate balance between parasite induction of protective regulatory (IL-10) responses and detrimental (IL-4) allergic responses.

Adoptive Transfer↗
PubMed2004

Juvenile rhesus monkeys have more colonic granulomas than adults after primary infection with Schistosoma mansoni.

Adults and children have differences in their susceptibility to schistosomiasis. Whether this age-dependent innate susceptibility influences parasite-caused granulomogenesis is difficult to assess in humans. Therefore, we exposed juvenile and adult female rhesus monkeys to primary infection with Schistosoma mansoni. Hepatic and intestinal granuloma formation was observed in both pre-pubescent and adult monkeys. Two distinct stages of granulomas were discerned, the exudative and the productive stage. In the intestine, more granulomas were generated in the colon than in the ileum. In contrast to the adult animals, the juvenile rhesus monkeys had higher numbers of colonic granulomas, these higher numbers being predominantly of the more advanced productive stage. Juvenile animals had a statistically non-significant increased worm burden. These results suggest that juvenile rhesus monkeys have a significantly more intense and advanced colonic response towards entrapped S. mansoni eggs after primary schistosome infections and, thereby, are more susceptible to parasite infection.

Age Factors↗
PubMed2004

Schistosoma mansoni worms induce anergy of T cells via selective up-regulation of programmed death ligand 1 on macrophages.

Infectious pathogens can selectively stimulate activation or suppression of T cells to facilitate their survival within humans. In this study we demonstrate that the trematode parasite Schistosoma mansoni has evolved with two distinct mechanisms to suppress T cell activation. During the initial 4- to 12-wk acute stages of a worm infection both CD4(+) and CD8(+) T cells are anergized. In contrast, infection with male and female worms induced T cell anergy at 4 wk, which was replaced after egg laying by T cell suppression via a known NO-dependent mechanism, that was detected for up to 40 wk after infection. Worm-induced anergy was mediated by splenic F4/80(+) macrophages (Mphi) via an IL-4-, IL-13-, IL-10-, TGF-beta-, and NO-independent, but cell contact-dependent, mechanism. F4/80(+) Mphi isolated from worm-infected mice were shown to induce anergy of naive T cells in vitro. Furthermore, naive Mphi exposed to live worms in vitro also induced anergy in naive T cells. Flow cytometry on in vivo and in vitro worm-modulated Mphi revealed that of the family of B7 costimulatory molecules, only programmed death ligand 1 (PD-L1) was selectively up-regulated. The addition of inhibitory mAb against PD-L1, but not PD-L2, to worm-modulated Mphi completely blocked the ability of these cells to anergize T cells. These data highlight a novel mechanism through which S. mansoni worms have usurped the natural function of PD-L1 to reduce T cell activation during early acute stages of infection before the subsequent emergence of egg-induced T cell suppression in the chronic stages of infection.

Animals↗
PubMed2004

Lymphomagenesis, hydronephrosis, and autoantibodies result from dysregulation of IL-9 and are differentially dependent on Th2 cytokines.

Interleukin-9 is an immunoregulatory cytokine implicated in the development of asthma and allergy. To investigate the role of IL-9 in vivo, we have generated transgenic mice in which IL-9 is expressed from its own promoter. Strikingly, overexpression of IL-9 resulted in premature mortality associated with a complex phenotype characterized by the development of autoantibodies, hydronephrosis, and T cell lymphoma. By intercrossing IL-9 transgenic mice with a panel of Th2 cytokine-deficient mice, we demonstrate that these disorders represent distinct phenotypes that can be dissociated by their differential dependence on Th2 cytokines. Autoantibody production was ablated in IL-9 transgenic animals with a combined absence of IL-4, IL-5, and IL-13, coincident with a reduction in peritoneal B-1 cells. Hydronephrosis arose in 75% of IL-9 transgenic animals and was dependent on the presence of IL-4 and IL-13. In contrast, T cell lymphomas developed independently of the other Th2 cytokines, with the generation of rapidly proliferating CD8(+) or CD4(+)CD8(+) T cell clones that arose in the thymus before infiltrating both lymphoid and nonlymphoid tissues. Our data highlight potentially important new roles for IL-9, through its regulation of downstream Th2 effector cytokines, in autoantibody production and in hydronephrosis.

Animals↗
PubMed2003

Juvenile rhesus monkeys have lower type 2 cytokine responses than adults after primary infection with Schistosoma mansoni.

Adults and children have differences in their susceptibility to schistosomiasis. The relative influences of age-dependent innate resistance and acquired immunity in the differences between susceptibility to schistosomiasis are difficult to assess in humans. Therefore, we exposed juvenile and adult female rhesus monkeys to primary infection with Schistosoma mansoni. In contrast to the adult animals, the juvenile rhesus monkeys had low levels of interleukin (IL)-4 and IL-5 production by peripheral blood mononuclear cells after schistosome infection, as well as lower levels of parasite-antigen-specific antibody (IgG, IgM, and IgA) responses, and produced limited antigen-specific or total IgE. Juvenile animals had statistically nonsignificant increased worm burdens and tissue or fecal egg counts, compared with that of adults, whereas circulating schistosome antigens were significantly higher in infected juvenile monkeys. These results suggest that juvenile rhesus monkeys have reduced type 2 cytokine responses after primary schistosome infections and perhaps are more susceptible to parasite infection.

Age Factors↗
PubMed2003

T helper type-2 cytokine responses: potential therapeutic targets.

T helper (Th)2 cell-mediated immune responses are associated with parasitic helminth infections and atopic disorders. The production of interleukin (IL)-4, IL-5, IL-9 and/or IL-13 by Th2 cells mediates a range of responses that can be protective or pathogenic. Progress has recently been made in elucidating the mechanism of Th2 immunity, which has therapeutic potential for the treatment of allergic diseases.

Animals↗
PubMed2002

Characterization of signaling pathways activated by the interleukin 1 (IL-1) receptor homologue T1/ST2. A role for Jun N-terminal kinase in IL-4 induction.

T1/ST2 is a member of the interleukin (IL)-1 receptor superfamily, possessing three immunoglobulin domains extracellularly and a Toll/IL1R (TIR) domain intracellularly. The ligand for T1/ST2 is not known. T1/ST2 is expressed on Type 2 T helper (Th2) cells, and its role appears to be in the regulation of Th2 cell function. Here, we have investigated T1/ST2 signal transduction, using either transient overexpression of T1/ST2 or a cross-linking monoclonal antibody to activate cells. We demonstrate that T1/ST2 does not activate the transcription factor NF-kappaB when overexpressed in murine thymoma EL4 cells, or in the mast cell line P815 treated with the anti-T1/ST2 antibody. However, a chimera comprising the extracellular domain of the type 1 IL-1 receptor and the intracellular domain of T1/ST2 activates NF-kappaB both by overexpression and in response to IL-1. This artificial activation requires the IL1RAcP recruited via the extracellular portion (IL1R1) of the chimera. T1/ST2 is, however, able to activate the transcription factor activator protein-1 (AP-1), increase phosphorylation of c-Jun, and activate the MAP kinases c-Jun N-terminal kinase (JNK), p42/p44 and p38. Anti-T1/ST2 also induces the selective expression of IL-4 but not IFN-gamma in naive T cells. Importantly, this effect is blocked by prior treatment with the JNK inhibitor SP600125 confirming that JNK as a key effector in T1/ST2 signaling. The lack of effect on NF-kappaB when T1/ST2 is homodimerized identifies T1/ST2 as the first member of the IL-1 receptor superfamily so far studied that is apparently unable to activate NF-kappaB, consistent with evidence indicating the lack of a role for NF-kappaB in Th2 cell function.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Inhibition of type 1 cytokine-mediated inflammation by a soluble CD30 homologue encoded by ectromelia (mousepox) virus.

CD30 is up-regulated in several human diseases and viral infections but its role in immune regulation is poorly understood. Here, we report the expression of a functional soluble CD30 homologue, viral CD30 (vCD30), encoded by ectromelia (mousepox) virus, a poxvirus that causes a severe disease related to human smallpox. We show that vCD30 is a 12-kD secreted protein that not only binds CD30L with high affinity and prevents its interaction with CD30, but it also induces reverse signaling in cells expressing CD30L. vCD30 blocked the generation of interferon gamma-producing cells in vitro and was a potent inhibitor of T helper cell (Th)1- but not Th2-mediated inflammation in vivo. The finding of a CD30 homologue encoded by ectromelia virus suggests a role for CD30 in antiviral defense. Characterization of the immunological properties of vCD30 has uncovered a role of CD30-CD30L interactions in the generation of inflammatory responses.

Amino Acid Sequence↗
PubMed2002

Th2 activities induced during virgin T cell priming in the absence of IL-4, IL-13, and B cells.

Virgin T cells being primed to Th2-inducing or Th1-inducing Ags, respectively, start to synthesize IL-4 or IFN-gamma as they begin to proliferate. Parallel respective induction of B cells to produce gamma1 or gamma2a switch transcripts provides additional evidence of early divergent Th activity. This report concerns the roles of IL-4, IL-13, and B cells in these early events in vivo. Th2 responses were induced in lymph nodes against hapten-protein given s.c. with killed Bordetella pertussis adjuvant. In T cell proliferation in wild-type mice, IL-4 message up-regulation and gamma1 and epsilon switch transcript production were underway 48-72 h after immunization. The absence of IL-4, IL-13, or B cells did not alter the early T cell proliferative response. The gamma1 and epsilon switch transcript production was still induced in the absence of IL-4, IL-13, or both, but at a reduced level, while the dominance of switching to IgG1 in the extrafollicular hapten-specific plasma cell response was retained. The up-regulation of IL-4 message was not reduced or delayed in the absence of B cells and was only marginally reduced by the absence of IL-13. It is concluded that signals delivered by dendritic cells, which are not dependent on the presence of IL-4, IL-13, or B cells, can prime virgin T cells and induce the early Th2 activities studied. These early events that direct virgin T cells toward Th2 differentiation contrast with the critical later role of Th2 cytokines in selectively expanding Th2 clones and driving further IL-4 synthesis.

Animals↗
PubMed2002

Previous infection with the nematode Nippostrongylus brasiliensis alters the immune specific response against Chlamydophila abortus infection.

An experimental mouse model to analyze the interaction between the immune responses elicited following infection with Nippostrongylus brasiliensis and Chlamydophila abortus has been established. Mice infected with C. abortus 7 days after N. brasiliensis showed an increased bacterial multiplication in spleen and liver compared to bacteria-alone infected mice. However the morbidity of these mice, expressed as weight loss, was significantly lower. Analysis of the immune responses elicited showed that spleen from co-infected mice had reduced IFN-gamma production in response to C. abortus antigen. The bias towards a type 2 response in co-infected mice was confirmed by an increase in the production of IL-4 and in the lower ratio IgG2a/IgG1. In pregnant mice co-infection caused a delay in the time of abortion and an increased systemic susceptibility to C. abortus infection.

Animals↗