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Biomedical subjects

S Romagnani

Publications and source records attributed to S Romagnani.

At least 19 recordsLinked to original sources
PubMed2006

Sublingual immunotherapy with Dermatophagoides monomeric allergoid down-regulates allergen-specific immunoglobulin E and increases both interferon-gamma- and interleukin-10-production.

BACKGROUND: The clinical efficacy and safety of sublingual immunotherapy (SLIT) for aeroallergens has been demonstrated in several trials, whereas the immunological changes induced by this treatment, which may account for the clinical improvement, are still unclear. OBJECTIVE: To investigate the effects of a successful SLIT on the in vitro allergen-driven T cell response and cytokine secretion as well as on the serum levels of chemokines and of IgE, IgG1 and IgG4 antibodies (Abs). MATERIALS AND METHODS: Twenty-five Dermatophagoides pteronyssinus (Dp)-sensitive patients with perennial rhinitic and/or rhinitic and asthmatic symptoms were randomized into two groups (13 untreated (UT) and 12 SLIT-treated) for a 1 year and half study. The proliferative response of peripheral blood mononuclear cell (PBMC) to purified Der p1 allergen, their cytokines (IFN-gamma, IL-4, IL-10 and TGF-beta) production and serum levels of chemokines associated with T helper type 1 (Th1) (CXCL10) or T helper type 2 (Th2) (CCL22) responses and of Dp-specific IgE, IgG1 and IgG4 Abs were evaluated before and after 6 months of treatment. RESULTS: SLIT induced a significant reduction of symptom medication scores after 6, 12 and 18 months of treatment in comparison with UT patients. SLIT-treated patients showed a significant decrease in serum levels of DP-specific IgE Abs, whereas total IgE, and specific IgG1 and IgG4 Abs remained unchanged. The proliferative response of allergen-specific T cells to Der p1 in vitro after 6 months of treatment was reduced, while no effect was observed on T cell proliferation to recall antigen (streptokinase). Moreover, Der p1-driven IFN-gamma and IL-10 were significantly increased in culture supernatants of PBMC from 6 month-treated patients in comparison with those detected at the beginning of therapy. CONCLUSIONS: These data suggest that the allergen-driven enhancement of IL-10- and IFN-gamma-producing T cells precedes and associates with SLIT-induced down-regulation of specific IgE, thus providing a rationale to explain the clinical benefit of SLIT in allergic patients.

Administration, Sublingual↗
PubMed2006

Regulation of the T cell response.

The T cell branch of the immune system can respond to a virtually infinite variety of exogenous antigens, thus including the possibility of self-antigen recognition and dangerous autoimmune reactions. Therefore, regulatory mechanisms operate both during ontogeny within the thymus and after birth in the periphery. The control of self-reactive T cells occurs through a process of negative selection that results in apoptosis of T cells showing high affinity for self-peptides expressed at the thymic level by means of promiscuous gene expression. Self-reactive T cells escaped to negative selection are controlled in the periphery by other regulatory mechanisms, the most important being natural Foxp3+ T regulatory (Treg) cells. Regulation is also required to control excessive effector T cell responses against exogenous antigens, when they become dangerous for the body. Three types of effector T cells have been recognized: T helper 1 (Th1) cells, which are protective against intracellular bacteria; Th2 cells, which play some role in the protection against nematodes, but are responsible for allergic reactions; Th17 cells, which are probably effective in the protection against extracellular bacteria, but also play a role in the amplification of autoimmune disorders. Abnormal or excessive Th effector responses are regulated by different mechanisms. Redirection or immune deviation of Th1- or Th2-dominated responses is provided by cytokines [interferon-gamma (IFN-gamma) vs. interleukin-4 (IL-4)] produced by the same cell types and by the CXCR3-binding chemokines CXCL4 and CXCL10. Moreover, both Th1 and Th2 responses can be suppressed by adaptive Treg cells through contact-dependent mechanisms and/or the production of IL-10 and transforming growth factor-beta (TGF-beta). Finally, TGF-beta1 can promote the development of both Th17 effector and adaptive Treg cells, while the contemporaneous production of IL-6 contributes to the development of Th17 cells, but inhibits Treg cells. The development of Th17 cells is also down-regulated by IL-4 produced by Th2 cells and by IFN-gamma produced by Th1 cells.

Allergens↗
PubMed2006

Regulatory T cells: which role in the pathogenesis and treatment of allergic disorders?

Several recent data suggest the importance of different types of cells in the regulation of T-cell effector-mediated immune responses. However, a unique specific marker for these cells has not yet been identified. Moreover, in addition to a dedicated functional lineage, even a 'plastic' phenotype of regulatory T cells seems to exist. The lack of a unique specific marker for regulatory T cells, as well as their heterogeneity, make it difficult to determine whether a defect of regulatory T cells plays a role in the pathogenesis of common allergic disorders. Novel therapeutic strategies based on the induction or potentiation of regulatory T cells able to hamper allergic inflammatory reactions are desirable, but their possible efficacy and safety are not yet known. At present, therapeutic strategies able to induce an immune deviation of allergen-specific type 2 T-helper responses to a less polarized phenotype rather than a general immune suppression appear more realistic.

Animals↗
PubMed2005

CXCR3 and alphaEbeta7 integrin identify a subset of CD8+ mature thymocytes that share phenotypic and functional properties with CD8+ gut intraepithelial lymphocytes.

BACKGROUND: We previously demonstrated the existence of two distinct subsets of T cell receptor (TCR)alphabeta+CD8alphabeta+ single positive (SP) cells in human postnatal thymus which express the chemokine receptor CCR7 or CXCR3 and migrate in vitro in response to their specific ligands. AIM: To investigate whether these two CD8+ thymocyte subsets had distinct peripheral colonisation. METHODS: TCRalphabeta+CD8+ SP cells were obtained from normal postnatal thymus, mesenteric lymph node (LNs), small bowel, and peripheral blood (PB) specimens. Cells were then evaluated for expression of surface molecules, cytolytic potential, telomere length, and profile of cytokine production. RESULTS: CD8+CCR7+CXCR3- thymocytes exhibited CD62L, in common with those which localise to LNs. In contrast, CD8+CCR7-CXCR3+ thymocytes lacked CD62L but exhibited CD103, similar to intraepithelial lymphocytes (IELs) present in the gut mucosa where the CXCR3 ligand, CXCL10, and the CD103 ligand, E-cadherin, are highly and consistently expressed. In addition, thymocytes and gut CD8+CXCR3+CD103+ cells showed comparable telomere length, which was higher than that of PB CXCR3+CD8+ T cells. However, both of these populations contained perforin and granzyme A, and displayed the ability to produce interferon gamma and interleukin 2. Of note, CXCR3 deficient, in comparison with wild-type C57Black/6, mice showed decreased proportions of CD3+CD8alphabeta+ and increased proportions of CD3+CD8alphaalpha+ lymphocytes at gut level. Moreover, adoptive transfer of CD3+CD8alphabeta+ thymocytes from wild-type into CXCR3 deficient mice resulted in a significant increase in CD3+CD8alphabeta+ T cells in the gut mucosa but not in other tissues. CONCLUSIONS: The results of this study demonstrate the existence of a previously unrecognised subset of TCRalphabeta+CD8alphabeta+ SP CXCR3+CD103+ thymocytes which share phenotypic and functional features with CD8+ IELs, thus suggesting the possibility of their direct colonisation of the gut mucosa.

Adoptive Transfer↗
PubMed2002

Cytokines and chemoattractants in allergic inflammation.

It is now generally accepted type 2 T helper (Th2) cytokines and some chemoattractants play an essential role in the pathogenesis of the allergic inflammation. The effects of Th2 cytokines, such as interleukin (IL)-4, IL-5, IL-9, and IL-13, account for virtually all the pathophysiological manifestations of allergy and asthma. Moreover, both Th2 cells and the effector cells usually present in the areas of allergic inflammation (basophils, mast cells, and eosinophils) express chemoattractant receptors, such as CCR3, CCR4, CCR8 and CRTH2. Therefore, interactions of eotaxin(s), eotaxin/CCL11, RANTES/CCL5, and MCP-1/CCL2, MCP-2/CCL8, MCP-3/CCL7, MCP-4/CCL13 with CCR3 are responsible for the recruitment of basophils, eosinophils and mast cells, whereas interactions of CCR4 with MDC/CCL22 or TARC/CCL17, CCR8 with I-309/CCL1, and CRTH2 with prostaglandin D(2) play a critical role in the allergen-induced recruitment of Th2 cells in the target tissues of allergic inflammation. The demonstration that Th2-polarized responses against allergens represent the triggering event for the development of allergic diseases, together with the recognition that some chemoattractants are responsible for the recruitment of both Th2 cells and other effector cells of allergic inflammation, can provide the conceptual basis for the development of new therapeutic strategies in allergic conditions.

Animals↗
PubMed2001

Interferon-inducible protein 10, monokine induced by interferon gamma, and interferon-inducible T-cell alpha chemoattractant are produced by thymic epithelial cells and attract T-cell receptor (TCR) alphabeta+ CD8+ single-positive T cells, TCRgammadelta+ T cells, and natural killer-type cells in human thymus.

Strong reactivity for interferon-inducible protein 10 (IP-10), monokine induced by interferon gamma (Mig), and interferon-inducible T-cell alpha chemoattractant (I-TAC) was found in epithelial cells mainly localized to the medulla of postnatal human thymus. The CXC chemokine receptor common to the 3 chemokines (CXCR3) was also preferentially expressed in medullary areas of the same thymuses and appeared to be a property of 4 distinct populations: CD3+ T-cell receptor (TCR) alphabeta+ CD8+ single-positive (SP) T cells, TCRgammadelta+ T cells, natural killer (NK)-type cells, and a small subset of CD3+(low) CD4+ CD8+ TCRalphabeta+ double-positive (DP) T cells. IP-10, Mig, and I-TAC showed chemoattractant activity for TCRalphabeta+ CD8+ SP T cells, TCRgammadelta+ T cells, and NK-type cells, suggesting their role in the migration of different subsets of mature thymocytes during human thymus lymphopoiesis.

CD8-Positive T-Lymphocytes↗
PubMed2001

Production of IL-4 and leukemia inhibitory factor by T cells of the cumulus oophorus: a favorable microenvironment for pre-implantation embryo development.

The nature and the functional activity of immunocytes present in the cumulus oophorus, a mass of cells surrounding the oocyte, were examined here for the first time. The cumuli oophorus were obtained from women who had taken part in an in vitro fertilization program and were suffering from blocked fallopian tubes. Both macrophages and CD4(+) T cells were detected in all cumuli. CD4(+) T cell clones, generated from T cells of these cumuli, showed higher potential to produce IL-4 and leukemia inhibitory factor (LIF) than CD4(+) T cell clones generated from peripheral blood or ovary specimens from the same women. More importantly, IL-4 and LIF, but not IFN-gamma mRNA was found to be constitutively expressed in vivo by cumulus oophorus cells. Progesterone is highly produced by the cumulus oophorus/oocyte complex. We recently showed that progesterone up-regulates the production of LIF by T cells and that the progesterone-induced LIF production is mediated by IL-4. Progesterone produced by cumulus granulosa cells may favor IL-4 production by T cells, which in turn can produce LIF. As the treatment with LIF enhances the in vitro growth and development of mammalian embryos, our data suggest that T cells present in the cumulus oophorus produce cytokines that may provide a microenvironment suitable for pre-implantation development of the mammalian embryo.

Adult↗
PubMed2001

Chemokines and lymphopoiesis in human thymus.

Distinct and redundant chemokines are responsible for organizing the extraordinarily diverse thymocyte populations into discrete microenvironments, from the arrival of immature precursors in the thymus to the migration of different mature cell types to the periphery. We propose that, by selectively mobilizing cells, chemokines can sort positively selected cells from negatively selected cells, and that chemokines make distinctions among CD8+ subpopulations that previously have not been recognized.

CD8-Positive T-Lymphocytes↗
PubMed2001

H(+),K(+)-atpase (proton pump) is the target autoantigen of Th1-type cytotoxic T cells in autoimmune gastritis.

BACKGROUND & AIMS: The proton pump H(+),K(+)-adenosine triphosphatase (H(+),K(+)-ATPase) of parietal cells is the major humoral autoantigen in both human and experimental autoimmune gastritis (AIG) characterized by an inflammatory infiltrate in the gastric mucosa and loss of parietal cells. The aim of this study was to detect H(+),K(+)-ATPase-specific T cells in the gastric mucosa of patients with AIG and to define their functional properties. METHODS: In vivo-activated T cells from the infiltrates of the gastric mucosa of 5 patients with AIG were isolated and cloned. The ability of gastric T-cell clones to proliferate and to produce cytokines in response to H(+),K(+)-ATPase, as well as their expression of B-cell help, perforin-mediated cytotoxicity, and Fas-Fas ligand-mediated apoptosis in target cells, were assessed. RESULTS: A proportion (25%) of the CD4(+) clones from the gastric corpus of AIG patients proliferated in response to porcine H(+),K(+)-ATPase. Most of these clones (88%) showed a Th1 profile, whereas a few secreted both Th1 and Th2 cytokines. Virtually all of the H(+),K(+)-ATPase-specific clones produced tumor necrosis factor alpha and provided substantial help for B-cell immunoglobulin production, and most of them expressed perforin-mediated cytotoxicity against antigen-presenting cells and induced Fas-Fas ligand-mediated apoptosis in target cells. CONCLUSIONS: Activation of proton pump-specific Th1 cytotoxic/proapoptotic T cells in the gastric mucosa can represent an effector mechanism for the target cell destruction in AIG.

Adult↗
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↗
PubMed2001

T-cell responses in allergy and asthma.

T-helper-2-type cytokines and some chemokines play an essential role in the pathogenesis of both allergy and asthma. A change in the T-helper 1/T-helper 2 balance, caused by the dramatic change in the microbial environment of children, may account for the increasing prevalence of these conditions, but can also provide a conceptual basis for the development of new therapeutic strategies.

Animals↗
PubMed2001

Microchimerism and systemic sclerosis.

Systemic sclerosis (SSc) is a connective tissue disease characterized by progressive fibrosis of the skin and internal organs. SSc is an immunologically mediated disease. A prominent immunological abnormality in SSc patients is the presence of circulating autoantibodies against a variety of nuclear proteins. Furthermore, SSc is characterized by the presence of increased numbers of activated T cells, with the prevalence of CD4+ cells, present in the periphery of skin lesions as well as in other organs in the early stages of the disease. We have recently shown the existence of a predominant activation of IL-4-producing Th2-like T cells in patients with SSc, which may account for the major alterations which occur in this disease. SSc has clinical and serological similarities to chronic graft versus host disease (cGVHD), although there are some important differences. T cells, which orchestrate the tissue damage, are present in great amounts in the inflammatory infiltrates in SSc- and cGVHD-affected tissues. More importantly, T cells from cGVHD tissues produce Th2-like cytokines, thus showing a pathogenetic similarity with SSc. SSc has been postulated as a type of cGVHD resulting from the transplacental transfer of cells between mother and fetus. Very recently, we have shown that in SSc, the microchimeric T cells react with the maternal MHC antigens and are able to produce Th2-type cytokines. Both features are characteristics of cGVHD, supporting the hypothesis that SSc is a disease similar to cGVHD.

Chimera↗
PubMed2001

Chemoattractant receptors expressed on type 2 T cells and their role in disease.

The existence of two functionally distinguished populations among T cells has been established in both mice and humans. Type 1 T helper (Th1) cells are involved in the defense against intracellular bacteria and many viruses, while type 2 Th cells (Th2) are the major actors in the response against parasites and play a central role in allergic inflammation. More recently, several data have suggested that some chemokine receptors are tightly regulated on T cells, and in accordance with this selective expression, Th1 and Th2 cells can be differentially recruited by specific chemokines to the inflammatory sites. Among Th2-associated chemokine receptors, CCR3, CCR4 and CCR8 have been described to play a central role in allergic inflammation. However, CCR3 is mainly expressed on basophils, eosinophils and mast cells, but it is poorly expressed by Th2 cells, and CCR4 is also expressed by Th subsets different from Th2 cells. So far, the chemoattractant receptors which among T cells appear to be selectively expressed by Th2 cells or their subsets are CCR8 and CRTH2. The ligand for CRTH2 is not a chemokine, but is prostaglandin (PG)D2, which is able to attract basophils, eosinophils, Th2 cells and type 2 cytotoxic (Tc2) CD8+ T lymphocytes. The selective expression of CRTH2 on Th2 and Tc2 cells may be useful to develop new therapeutic strategies against allergic diseases and against other immune disorders. Additional studies, however, are required to understand its effective importance in the induction and maintenance of Th2- or Tc2-mediated response and inflammation.

Animals↗