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Biomedical subjects

P Parronchi

Publications and source records attributed to P Parronchi.

At least 19 recordsLinked to original sources
PubMed2001

Reversal of human allergen-specific CRTH2+ T(H)2 cells by IL-12 or the PS-DSP30 oligodeoxynucleotide.

BACKGROUND: The chemoattractant receptor homologous molecule expressed on T(H)2 cells (CRTH2) is a receptor for prostaglandin D(2), which among human T cells is selectively expressed by T(H)2 and type 2 cytotoxic effectors. OBJECTIVE: Our purpose was to assess whether the cytokine production profile of T(H)2 effectors could be reversed by exploiting their selective expression of CRTH2. METHODS: CRTH2(+) T cells were purified from the blood of allergic subjects, stimulated with the specific allergen in the absence or presence of IL-12, and assessed by flow cytometry at the single-cell level for their ability to produce IL-4 and/or IFN-gamma after antigen or polyclonal stimulation. RESULTS: Both IL-12 and the PS-DSP30 oligodeoxynucleotide enabled CRTH2(+) allergen-stimulated T(H)2 cells to produce IFN-gamma. This change in the profile of cytokine production by T(H)2 cells from allergic subjects was related to the upregulation of IL-12 receptor beta2 chain and was associated with the loss of CRTH2. CONCLUSIONS: These data demonstrate that the cytokine production pattern of fully differentiated T(H)2 effectors can be changed to a less polarized profile, thus providing the physiologic basis for new immunotherapeutic strategies in allergic disorders.

Allergens↗
PubMed2000

Genetic and environmental factors contributing to the onset of allergic disorders.

Evidence has been accumulated to suggest that allergen-reactive Th2 cells play a triggering role in the activation and/or recruitment of IgE antibody-producing B cells, mast cells and eosinophils, the cellular triad involved in allergic inflammation. Recently, chemokines and chemokine receptors involved in such Th2-type response have been also defined. Th2 cells represent the polarized arm of the effector-specific responses that contribute to the protection against gastrointestinal nematodes and act as regulatory cells for chronic and/or excessive Th1-mediated responses. Th2 cells are generated from precursor naive Th cells when they encounter the specific antigen in an IL-4-containing microenvironment. The question of how these Th2 cells are selected in atopic patients is also unclear. Both the nature of the T cell receptor signalling provided by the allergen peptide ligand and a disregulation of IL-4 production likely concur to determine the Th2 profile of allergen-specific Th cells, but the genetic unbalanced IL-4 production is certainly overwhelming. Some gene products selectively expressed in Th2 cells or selectively controlling the expression of IL-4 have recently been described. These findings allow to suggest that the upregulation of genes controlling IL-4 expression and/or abnormalities of regulatory mechanisms of Th2 development and/or function may be responsible for Th2 responses against allergens in atopic people. The increasing prevalence of allergy in developed countries suggests that environmental factors acting either before or after birth also contribute to regulate the development of Th2 cells and/or their function. The reduction of infectious diseases in early life due to increasing vaccinations, antimicrobial treatments as well as changed lifestyle are certainly important in influencing the individual outcome in the Th response to ubiquitous allergens. Moreover, the recent evidence that bacterial DNA or oligodeoxynucleotides containing unmethylated 'CpG motifs' promote the development of Th1 cells via the production of immunomodulatory cytokines (namely IL-12, IL-18 and IFNs) by professional antigen-presenting cells confirms previous epidemiological data. The new insight into the pathophysiology of T cell responses in atopic diseases provides exciting opportunities for the development of novel immunotherapeutic strategies.

Adjuvants, Immunologic↗
PubMed1999

Phosphorothioate oligodeoxynucleotides promote the in vitro development of human allergen-specific CD4+ T cells into Th1 effectors.

DNA vaccination is an effective approach in inducing the switch of murine immune responses from a Th2 to a Th1 profile of cytokine production that has been related to the activity of unmethylated CpG motifs present in bacterial, but not mammalian, DNA. We report here that some synthetic phosphorothioate, but not phosphodiester, oligodeoxynucleotides (ODNs) were able to induce B cell proliferation and to shift the in vitro differentiation of Dermatophagoides pteronyssinus group 1-specific human CD4+ T cells from atopic donors into Th cell effectors showing a prevalent Th1, instead of Th2, cytokine profile. This latter effect was completely blocked by the neutralization of IL-12 and IFN (alpha and gamma) in bulk culture, suggesting that the Th1-inducing activity of phosphorothioate ODNs was mediated by their ability to stimulate the production of these cytokines by monocytes, dendritic, and NK cells. Cytosine methylation abolished the Th1-inducing activity of ODNs; however, CpG dinucleotide-containing ODNs exhibited the Th1-shifting effect independently of the presence or the absence of CpG motifs (5'-pur-pur-CpG-pyr-pyr-3'). Moreover, the inversion of CpG to GpC resulted only in a partial reduction of this activity, suggesting that the motif responsible for the Th1-skewing effect in humans is at least partially different from that previously defined in mice. These results support the concept that the injection of allergens mixed to, or conjugated with, appropriate ODNs may provide a novel allergen-specific immunotherapeutic regimen for the treatment of allergic disorders.

Adult↗
PubMed1999

Highly Th2-skewed cytokine profile of beta-lactam-specific T cells from nonatopic subjects with adverse drug reactions.

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.

Allergens↗
PubMed1998

Influence of both TCR repertoire and severity of the atopic status on the cytokine secretion profile of Parietaria officinalis-specific T cells.

Peripheral blood mononuclear cells (PBMC) from both nonatopic and Parietaria officinalis-sensitive donors proliferated in response to the allergen Par o 1 and developed into Par o 1-specific T cell lines and clones, which also showed reactivity for Par o 1-derived peptides. Virtually all Par o 1-specific T cell lines and large numbers of Par o 1-specific T cell clones proliferated in response to two Par o 1 nonapeptides (p92 and p96), which probably contain immunodominant epitopes of the Par o 1 allergen. Both p92- and p96-specific T cell clones showed the ability to produce IFN-gamma, but p92-specific T cell clones produced significantly lower amounts of IL-4 and IL-5 than p96-specific T cell clones, indicating that distinct epitopes, able to elicit functionally different T helper cell responses, may coexist in Par o 1. However, p92-specific T cell clones derived from atopic subjects with high IgE serum levels (high IgE producers) secreted significantly higher amounts of IL-4 and IL-5 than corresponding T cell clones generated from nonatopic subjects or patients with low IgE serum levels (low IgE producers), whereas p96-specific T cell clones secreted high IL-4 and IL-5 concentrations irrespective of whether they derived from high or low IgE producers. The addition of IL-4 and anti-IL-12 mAb to bulk culture significantly up-regulated the development of p92-specific T cells into IL-4-producing cells, whereas the addition of IL-12 and anti-IL-4 mAb shifted the differentiation of p96-specific T cells towards IFN-gamma-producing cells. Taken together, these results suggest that the cytokine profile of allergen-specific T cells is influenced by both the T cell receptor repertoire and the severity of atopic status and can be modulated, at least in vitro, by stimulation with the specific peptide in the presence, or after removal, of appropriate cytokines.

Allergens↗
PubMed1997

T cells and cytokines in Crohn's disease.

Recent findings indicate that activated T lymphocytes, showing restricted T-cell receptor repertoire and a Th1-like profile of cytokine production, are responsible for macrophage activation and release of inflammatory cytokines, toxic oxygen metabolites and nitric oxide, which initiate and maintain the transmural intestinal inflammation in Crohn's disease. A critical event in the promotion of Th1-type response at gut level may involve up-regulation of IL-12 production and the breakdown of tolerance against the intestinal flora.

Crohn Disease↗
PubMed1997

Type 1 T-helper cell predominance and interleukin-12 expression in the gut of patients with Crohn's disease.

Crohn's disease (CD) is a chronic bowel inflammatory disorder in which the pathogenic role of immune alterations has been suggested, but the immunologic mechanisms responsible for the inflammatory reaction are still poorly understood. We investigated the profile of cytokine secretion by T-cell clones generated from gut tissue specimens of four patients with active CD, five patients with ulcerative colitis, and four patients with noninflammatory gut disorders (NIGDs). The great majority of CD4+ T-cell clones generated from the gut of patients with CD produced high levels of interferon-gamma (IFN-gamma) but low or undetectable amounts of interleukin-4 (IL-4), whereas substantial proportions of CD4+ T-cell clones derived from the gut of patients with either ulcerative colitis or NIGDs produced IL-4 in addition to IFN-gamma. The immunohistochemical analysis revealed high numbers of activated CD4+ T cells showing IFN-gamma but not IL-4 reactivity, as well as substantial proportions of IL-12-containing macrophages, in the intestinal lamina propria and muscularis propria of patients with CD, whereas these cells were very rare or undetectable in patients with NIGDs. Culturing T cells from gut biopsy specimens of a patient with CD in the presence of a neutralizing anti-IL-12 antibody down-regulated the development of IFN-gamma-producing CD4+ T cells. These findings suggest that a critical event in the initiation of bowel inflammatory lesions in CD may involve up-regulation of IL-12 production, resulting in conditions that maximally promote type 1 T-helper immune responses.

CD4-Positive T-Lymphocytes↗
PubMed1997

In vivo CD30 expression in human diseases with predominant activation of Th2-like T cells.

CD30 is a member of the tumor necrosis factor (TNF) receptor family, originally described as a marker for Hodgkin and Reed-Sternberg cells in Hodgkin's disease, which has been found to be preferentially expressed by T cells producing Th2-type cytokines. The presence of CD30 expression was assessed by both immunohistochemistry and reverse transcriptase-polymerase chain reaction in the target organs of patients with Th1- or Th2-dominated disorders. CD30 expression was found in neither the gut of patients with Crohn's disease nor in the gastric antrum of Helicobacter pylori-infected patients, where there was high interferon-gamma (IFN-gamma) expression. In contrast, high CD30 expression in the apparent absence of IFN-gamma expression was observed in the skin of patients with systemic sclerosis or chronic graft versus host disease (GVHD), which can be considered Th2-dominated disorders. Moreover, high levels of soluble CD30 were found in the serum of both systemic sclerosis and GVHD patients but not in the serum of patients suffering from multiple sclerosis, a Th1-dominated disorder. Thus, CD30 expression appears to be preferentially associated with Th2-type responses not only in vitro but also in vivo.

Crohn Disease↗
PubMed1996

Effects of interferon-alpha on cytokine profile, T cell receptor repertoire and peptide reactivity of human allergen-specific T cells.

A large panel of T cell clones (TCC) specific for the recombinant form of Poa pratensis allergen (rKBG7.2 or Poa p9) were established from the peripheral blood of grass pollen-sensitive donor in the absence or presence of recombinant interferon-alpha (IFN-alpha) in bulk culture and their pattern of cytokine secretion, peptide reactivity and TCR V beta repertoire was examined. The majority of allergen-specific TCC derived in absence of IFN-alpha produced high amounts of interleukin-4 (IL-4) and IL-5 but not IFN-gamma (Th2 cells), while most of TCC derived in presence of IFN-alpha produced IFN-gamma but not, or limited amounts of, IL-4 and IL-5 (Th1 or Th0 cells). Of 24 TCC established in the presence of IFN-alpha, 22 were able to recognize a single allergen peptide, p26, while none of the clones established in the absence of IFN-alpha showed a similar specificity. The majority of both clones expressed the V beta 2 element regardless of whether they were established in the presence of INF-alpha, but the presence of IFN-alpha favored the expansion of V beta 2+, V beta 17+ and V beta 22+ Poa p9-specific T cells, whereas in the absence of IFN-alpha, other TCR V beta-bearing T cells (V beta 5, and V beta 6.7, and V beta 14) were expanded in addition to V beta 2+ T cells. None of V beta 2+ clones established in the absence of IFN-alpha reacted with p26, whereas all the V beta 2+ clones established in its presence in the absence of interferon-alpha reacted with p26, whereas all the V beta 2+ clones established in its presence reacted to this peptide. IFN-alpha also shifted the TCR V beta repertoire of both Poa p9- and Lolium perenne group 1 (Lol p1)-specific T cell lines generated from the same patient and from a different grass-sensitive individual. These data demonstrate that IFN-alpha modulates the development of allergen-specific T cells in vitro, and suggest that IFN-alpha may represent a useful tool for novel immunotherapeutic approaches in allergic disorders.

Allergens↗
PubMed1996

Immune mechanisms in the pathogenesis of inflammatory gastrointestinal disorders.

The cytokine secretion profile of T cells present in the gastric antrum of Helicobacter pylori-infected patients with peptic ulcer and in the gut of patients with Crohn's disease was investigated. A type 1 T helper (Th1)-dominated response was detected in the gastric antrum of Helicobacter pylori-infected subjects with peptic ulcer by both reverse transcriptase-PCR and immunohistochemistry. By using a T-cell cloning technique, it was shown that the majority of Th 1 cells were specific for Hp antigens. A Th1 predominance, which associated with high IL-12 expression, was also found, at both clonal and immunohistochemical level, in the gut of patients with Crohn's disease. These findings suggest that the Th1/Th2 paradigm may be useful to explain the inflammatory reactions involved in the pathogenesis of some gastrointestinal disorders.

Crohn Disease↗
PubMed1995

Progesterone favors the development of human T helper cells producing Th2-type cytokines and promotes both IL-4 production and membrane CD30 expression in established Th1 cell clones.

The effect of progesterone (P) on the cytokine production profile of Ag-specific human CD4+ T cell lines and clones was investigated. T cell lines specific for purified protein derivative or streptokinase (SK) derived in the presence of P exhibited significant increased ability to produce IL-5 in comparison with T cell lines derived in the absence of P. Moreover, IL-4 was significantly increased in SK-specific T cell lines derived in the presence of P in comparison with SK-specific T cell lines derived in the absence of this hormone. In addition, SK-specific T cell lines generated in the presence of P developed into T cell clones showing a Th0-, instead of Th1-like, cytokine profile. Furthermore, SK-specific T cell clones with an established Th1 profile of cytokine secretion did express mRNA for, and produced detectable amounts of, IL-4 when stimulated with P in combination with insoluble anti-CD3 mAb. Combined stimulation with P and insoluble anti-CD3 mAb also enabled Th1 clones to express CD30 on their surface membrane. These results indicate that P can favor the development of Th cells producing Th2-type cytokines and is an inducer of both transient IL-4 production and CD30 expression in established Th1 cells. Thus, P production at the placental level may be responsible, at least in part, for increased production of Th2-type cytokines which have been implied in fetal allograft survival and maintenance of successful pregnancy.

Antigens, Surface↗
PubMed1995

Polyinosinic acid: polycytidylic acid promotes T helper type 1-specific immune responses by stimulating macrophage production of interferon-alpha and interleukin-12.

The effects exerted on the development in vitro of Dermatophagoides pteronyssinus group I (Der p I)-specific T cell lines and T cell clones by addition of polyinosinic acid: polycytidylic acid (poly I:C) in lymphocyte bulk culture were examined. Der p I-specific T cell lines generated in presence of poly I:C exhibited reduced ability to produce interleukin (IL)-4 and IL-5 and developed into Der p I-specific CD4+ T cell clones showing a T helper (Th) type 0 or Th1, instead of Th0/Th2 cytokine profile. This effect was prevented by addition to lymphocyte bulk cultures of a mixture of antibodies specific for interferon (IFN)-alpha and IL-12, whereas the addition of anti-IFN-alpha or anti-IL-12 antibody alone was uneffective. Poly I:C also showed the ability to stimulate the production of noticeable amounts of both IFN-alpha and IL-12 by human monocytes. Taken together, these data suggest that poly I:C is a Th1-inducing agent whose activity is mediated by its ability to stimulate the production of IFN-alpha and IL-12 by monocytes.

Cells, Cultured↗