EC:3.4.22.65 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.22.65 (Der p 1)
346 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The induction of anergy in T cells is believed to be the result of triggering of the TCR in the absence of adequate costimulation mediated through the interaction of CD28 and its ligands, CD80 and CD86. Here, we demonstrate that stimulation of human group I allergen in Dermatophagoides pteronyssinus extract (Der p 1)-specific CD4+ Th2-like T cell clones with Der p 1-derived peptides in the absence of professional APC results in a state of nonresponsiveness. The induction of anergy occurred despite the expression of high levels of CD28, CD80, and CD86 on the surface of the T cell clones and was not prevented by the addition of anti-CD28 mAb. The anergic, Der p 1-specific, Th2 cells failed to mobilize calcium from intracellular stores, to proliferate, and to produce IL-2, IL-4, IL-13, GM-CSF, and TNF-alpha following optimal stimulation with Der p 1-derived peptide and autologous APC. However, they mobilized intracellular calcium following stimulation with Ca(2+)-ionophore and produced all of the above cytokines, including IFN-gamma, when stimulated with phorbol ester and Ca2+ ionophore. These results indicate that the anergic T cell clones are capable of responding to signals circumventing the TCR/CD3 complex activation pathway. In contrast to T cell clones optimally activated with peptide and APC, anergic T cells failed to induce IgG4 and IgE synthesis when cocultured with B cells, even in the presence of exogenous IL-4 or IL-13. Anergic T cells expressed normal levels of CD40L, suggesting that their inability to help in Ig production by B cells is due to conditions other than a lack of expression of this molecule. Finally, exogenous IL-2 restored the helper function of anergic Th2 T cells for IgE production by B cells, which was greatly enhanced by the addition of IL-4 or IL-13. These data suggest that induction of anergy in allergen-specific Th2 T cells by allergen-derived peptides may play an important role in the successful desensitization of allergic patients.
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PMID:Peptide-induced anergy in allergen-specific human Th2 cells results in lack of cytokine production and B cell help for IgE synthesis. Reversal by IL-2, not by IL-4 or IL-13. 759 75

Allergens from the house dust mite Dermatophagoides pteronyssinus are a major cause of human respiratory diseases, including asthma. In order to help in understanding the early events in allergen sensitization, a murine model of allergic respiratory disease was developed. Mice were immunized by intranasal inoculation of Der p 1 or Der p 2 on days 0, 3, 7, 10, 14, 17, 21 and 29. T cell reactivity was determined using in vitro assays of allergen-specific cytokine production by cells from the spleen, the draining superficial cervical lymph nodes (SCLN) and the non-draining brachial and inguinal nodes. The cytokines assayed in supernatants were IL-4, as a measure of Th2 activation, IL-2 as a measure of Th 1 activation, and IL-3/GM-CSF as an overall marker of T cell stimulation. There was evidence of local and systemic T cell activation by day 7, with the release of IL-2 and of IL-3/GM-CSF by SCLN and spleen cells, respectively. IL-4 production by SCLN and spleen cells was not evident until day 21. T cell sensitization in non-draining node groups was not detected. Intradermal skin tests were performed at the above specified times and positive wheal responses indicated that specific IgE was present from day 3. The above data suggest that respiratory immunization to allergen is rapid and is associated with early systemic sensitization. In this model both Th1 and Th2 responses were evident, with the Th1 response occurring early and the Th2 following after repeated immunizations.
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PMID:Immunologic responses following respiratory sensitization to house dust mite allergens in mice. 872 6

Allergic inflammatory responses are regulated by cytokines [interleukin (IL)-4, IL-5, IL-10, and IL-13] produced by CD4+ helper (Th0 and Th2) cells. The activation of these T cells follows engagement of T-cell antigen receptors (TCR) by antigenic peptides complexed with major histocompatibility complex (MHC) class II molecules. Under defined conditions presentation of T-cell epitopes as peptides can downregulate immune responses, and here we discuss the potential of peptide-mediated immunotherapy in the regulation of responses to the house dust mite (HDM). Cloning the major allergens of HDM has allowed detailed analysis of the HDM-reactive T-cell repertoire and has revealed that MHC class II restriction is heterogeneous, involving HLA-DP,-DQ, and -DR molecules, and that multiple T-cell epitopes are recognized. There is, however, evidence for a bias in TCR gene usage, which has prompted the analysis of peptide-mediated densitization of human T cells in vitro. CD4+ T cells exposed to high concentrations of HDM peptides become refractory to restimulation and fail to provide B-cell help. This is accompanied by complex changes in the surface phenotype, including the downregulation of TCR and CD28. During the induction of anergy cytokine-specific mRNA levels are enhanced, but when the anergic T cells are restimulated they fail to secrete IL-4 and IL-5, although interferon (IFN)-gamma production may remain unaltered. The ability of peptides to modulate the function of HDM-specific T cells in vivo has been investigated in mice. Following inhalation of peptide containing a major T-cell epitope of Der p 1 (residues 111-139) transient T-cell activation was observed prior to the inhibition of responses in naive and sensitized mice. T cells from the tolerant mice restimulated in vitro produced low levels of cytokines and failed to provide help for B cells.
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PMID:From epitopes to peptides to immunotherapy. 881 Oct 60

A common property of allergens is their potential to generate type 2 cytokine responses. To understand the mechanisms involved in this phenomenon, we have evaluated the polarizing potential of a major allergen, Dermatophagoides pteronyssinus 1 (Der p 1), in an heterologous immunization system using the glutathione S-transferase of the parasite Schistosoma mansoni (Sm28-GST) as immunogen. In previous studies, we showed that immunization with the Sm28-GST emulsified in CFA induced a nonpolarized immune response. In contrast, when alum was used as adjuvant, a type 2 immune response was induced against Sm28-GST. Using this experimental model, we examined whether the administration of Der p 1 together with Sm28-GST influenced the nonpolarized and/or the Th2 profiles induced by the CFA or the alum immunization, respectively. Our results showed that the introduction of Der p 1 in the CFA immunization protocol was associated with diminished anti-Sm28-GST IgG2a Ab titers, reduced IFN-gamma mRNA expression, and frequency of IFN-gamma-producing cells. In contrast, the introduction of Der p 1 in the alum protocol did not affect IL-4 or Ig isotype responses. The effect of Der p 1 was specific, since coimmunization with tetanus toxin fragment C did not affect the profile of the response against Sm28-GST. Furthermore, inactivation of Der p 1 reduced its ability to modify the immune response profile, suggesting that its protease activity played an important role in deviating the immune response. Our results suggest that the Der p 1 has the ability to modify the profile of an immune response by modulating the balance between the polarizing cytokines IL-4 and IFN-gamma.
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PMID:The house dust mite allergen, Dermatophagoides pteronyssinus, promotes type 2 responses by modulating the balance between IL-4 and IFN-gamma. 949 90

A positive lymphocyte transformation test to beta-lactams (beta-L) was found in 12 of 29 subjects with adverse drug reaction (ADR) to beta-L, irrespective of either the type of clinical manifestation or the presence of specific serum IgE. Short-term T cell lines specific for penicillin G, amoxicillin, and ampicillin could be generated only from subjects with ADR (eight with positive and one with negative lymphocyte transformation test), while streptokinase and Dermatophagoides pteronyssinus group 1 (Der p 1)-specific T cells were obtained from all these subjects, from 7 atopic Der p-sensitive donors without history of ADR and 17 healthy nonatopic donors. Streptokinase-specific T cells from all subjects showed intracellular expression of IFN-gamma with poor or no IL-4, whereas Der p 1-specific T cells exhibited IFN-gamma but low or no IL-4 expression in nonatopics, and remarkable IL-4 expression in atopic donors. By contrast, all penicillin G-, ampicillin-, and amoxicillin-specific short-term T cell lines showed high intracellular expression of IL-4, IL-5, and IL-13, but poor or no expression of IFN-gamma, thus exhibiting a clear-cut Th2 profile. Accordingly, most penicillin G-specific T cell clones derived from two subjects with ADR released high concentrations of IL-4 alone or IL-4 and IFN-gamma. These data suggest that cytokines produced by Th2 cells play an important role in all beta-L-induced ADR, even when late clinical manifestations occur and an IgE-mediated mechanism is apparently indemonstrable.
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PMID:Highly Th2-skewed cytokine profile of beta-lactam-specific T cells from nonatopic subjects with adverse drug reactions. 1039 4

The house dust mite Dermatophagoides pteronyssinus allergen Der p 1 elicits IgE antibody responses in a significant proportion of patients suffering from dust mite allergy. We have recently shown that Der p 1 proteolytically cleaves a cell surface molecule involved in the homeostatic control of human IgE synthesis, namely the IL-2 receptor (CD25) on T cells. As a result, these T cells show markedly diminished proliferation and IFN-gamma secretion in response to stimulation by anti-CD3 antibody. However, these observations still leave open the important issue of whether CD25 cleavage, and the consequent suppression of IFN-gamma secretion, leads to enhanced IL-4 secretion, and whether such cytokine changes would be exhibited by both CD4 and CD8 T cells. Here we demonstrate for the first time that the proteolytic activity of Der p 1 biases human CD4 and CD8 T cells towards a type 2 cytokine profile. Our data provide compelling evidence for the role of the proteolytic activity of Der p 1 in creating a microenvironment conducive for IgE synthesis.
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PMID:Human T cell subset commitment determined by the intrinsic property of antigen: the proteolytic activity of the major mite allergen Der p 1 conditions T cells to produce more IL-4 and less IFN-gamma. 1129 46

The polarization of the immune response toward a Th2 or a Th1 profile can be mediated by dendritic cells (DCs) following antigen presentation and interaction with T cells. Costimulatory molecules such as CD80 and CD86 expressed by DCs, the polarizing cytokine environment during DC--T-cell interaction, and also the nature of the antigen are critical in the orientation of the immune response. In this study, the effect of the cysteine protease Der p 1, one of the major allergens of the house dust mite Dermatophagoides pteronyssinus, on these different parameters was evaluated comparatively on monocyte-derived DCs obtained from healthy donors, from pollen-sensitive patients, or from patients sensitive to Dermatophagoides pteronyssinus. Results showed that Der p 1 induced an increase in CD86 expression only on DCs from house dust mite--sensitive patients. This was also associated with a higher capacity to induce T-cell proliferation, a rapid increase in the production of proinflammatory cytokines, tumor necrosis factor--alpha and interleukin (IL)-1 beta, and the type 2 cytokine IL-10. No changes in the release of IL-12 p70 were induced by Der p 1. Finally, purified T cells from house dust mite-sensitive patients stimulated by autologous Der p 1--pulsed DCs preferentially produced IL-4 rather than interferon-gamma. These effects were abolished in the presence of the inactive precursor of Der p 1 (ProDer p 1). Taken together, these data suggest that DCs from house dust mite--sensitive patients, in contrast to DCs from healthy donors and from pollen-sensitive patients, exposed to Der p 1 play a pivotal role in the enhancement of the Th2 response associated with the allergic reaction developed in response to house dust mite exposure. (Blood. 2001;98:1135-1141)
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PMID:Th2 polarization by Der p 1--pulsed monocyte-derived dendritic cells is due to the allergic status of the donors. 1149 62

Although the intranasal administration of peptides containing T cell epitopes has been shown to be a potent method of inhibiting responses to the allergen Der p 1, the experiments to date have concentrated on their ability to regulate immune responses to the injection of antigen in a T(h)1-type adjuvant. Their ability to regulate responses to a T(h)2-type immunization and to sensitization via the respiratory mucosa has not been examined. Here it is shown that peptide used in doses required to block delayed-type hypersensitivity can also readily inhibit IgE responses to Der p 1 injected in alum. To examine responses induced in the respiratory mucosa, mice pretreated with intranasal peptide were sensitized with an intranasal dose of Der p 1 in conjunction with a mutated enterotoxin adjuvant. Intranasal peptide even in very high doses did not reduce IgE titers, but the ability of cells from the draining lymph nodes to release IL-4 and IL-13 but not IL-2, IL-5, IL-10 or IFN-gamma was reduced. These are the first reports on the effect of intranasal peptides containing T cell epitopes on IgE in T(h)2 immunization and on responses to respiratory immunization. Thus the effect of the peptide-induced mucosal tolerance differs depending on the type of immunization used for sensitization, but the potential to inhibit T(h)2 responses and responses to respiratory sensitization as well as T(h)1 responses has been demonstrated.
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PMID:Inhibition of mucosal and systemic T(h)2-type immune responses by intranasal peptides containing a dominant T cell epitope of the allergen Der p 1. 1158 Nov 67

Diesel exhausts and their associated organic compounds may be involved in the recent increase in the prevalence of allergic disorders, through their ability to favor a type 2 immune response. Type 2 T cells have been shown to be preferentially recruited by the chemokines eotaxin (CCL11), macrophage-derived chemokine (MDC, CCL22), and thymus activation-regulated chemokine (CCL17) through their interaction with CCR3 and CCR4, respectively, whereas type 1 T cells are mainly recruited by IFN-gamma-induced protein-10 (CXCL10) through CXCR3 binding. The aim of the study was to evaluate the effect of diesel exposure on the expression of chemokines involved in type 1 and 2 T cell recruitment. PBMC and alveolar macrophages from house dust mite allergic patients were incubated with combinations of diesel extracts and Der p 1 allergen, and chemokine production was analyzed. Diesel exposure alone decreased the constitutive IP-10 production, while it further augmented allergen-induced MDC production, resulting in a significantly increased capacity to chemoattract human Th2, but not Th1 clones. Inhibition experiments with anti-type 1 or type 2 cytokine Abs as well as cytokine mRNA kinetic evaluation showed that the chemokine variations were not dependent upon IL-4, IL-13, or IFN-gamma expression. In contrast, inhibition of the B7:CD28 pathway using a CTLA-4-Ig fusion protein completely inhibited diesel-dependent increase of allergen-induced MDC production. This inhibition was mainly dependent upon the CD86 pathway and to a lesser extent upon the CD80 pathway. These results suggest that the exposure to diesel exhausts and allergen may likely amplify a deleterious type 2 immune response via a differential regulation of chemokine production through the CD28 pathway.
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PMID:Diesel exposure favors Th2 cell recruitment by mononuclear cells and alveolar macrophages from allergic patients by differentially regulating macrophage-derived chemokine and IFN-gamma-induced protein-10 production. 1202 97

In rodents, airway dendritic cells (DCs) capture inhaled Ag, undergo maturation, and migrate to the draining mediastinal lymph nodes (MLN) to initiate the Ag-specific T cell response. However, the role of human DCs in the pathogenesis of the Th2 cell-mediated disease asthma remains to be clarified. Here, by using SCID mice engrafted with T cells from either house dust mite (HDM)-allergic patients or healthy donors, we show that DCs pulsed with Der p 1, one of the major allergens of HDM, and injected intratracheally into naive animals migrated into the MLN. In the MLN, Der p 1-pulsed DCs from allergic patients induced the proliferation of IL-4-producing CD4(+) T cells, whereas those from healthy donors induced IFN-gamma-secreting cells. In reconstituted human PBMC-reconstituted SCID mice primed with pulsed DCs from allergic patients, repeated exposure to aerosols of HDM induced 1) a strong pulmonary inflammatory reaction rich in T cells and eosinophils, 2) an increase in IL-4 and IL-5 production in the lung lavage fluid, and 3) increased IgE production compared with that in mice primed with unpulsed DCs. All these effects were reduced following in vivo neutralization of the CCR7 ligand secondary lymphoid tissue chemokine. These data in human PBMC-reconstituted SCID mice show that monocyte-derived DCs might play a key role in the pathogenesis of the pulmonary allergic response by inducing Th2 effector function following migration to the MLN.
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PMID:Monocyte-derived dendritic cells induce a house dust mite-specific Th2 allergic inflammation in the lung of humanized SCID mice: involvement of CCR7. 1213 80

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