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Biomedical subjects

L Adorini

Publications and source records attributed to L Adorini.

At least 37 records · Page 2Linked to original sources
PubMed2001

Interleukin 12 and autoimmune diabetes.

Interleukin 12 (IL-12) has been implicated in the pathogenesis of type 1 diabetes in the non-obese diabetic (NOD) mouse. Following this lead, a new locus associated with human type 1 diabetes, IDDM18, has been identified near the gene encoding the p40 subunit of interleukin 12 (IL12B). This finding has potential implications for the prediction of at-risk individuals and, perhaps, for the implementation of prevention strategies relevant to several autoimmune diseases.

Animals↗
PubMed2001

Central nervous system gene therapy with interleukin-4 inhibits progression of ongoing relapsing-remitting autoimmune encephalomyelitis in Biozzi AB/H mice.

Multiple sclerosis (MS) is an immune-mediated inflammatory disease of the central nervous system (CNS) that might benefit from anti-inflammatory therapies. However, systemic delivery of anti-inflammatory drugs in MS patients has so far been disappointing, mostly due to the limited capacity of these molecules to enter the CNS. We injected into the cisterna magna (i.c.) of Biozzi AB/H mice affected by a relapsing-remitting form of experimental autoimmune encephalomyelitis (EAE), the animal model of MS, a non-replicative herpes simplex virus (HSV) type-1-derived vector containing the interleukin (IL)-4 gene (d120:LacZ:IL-4). CNS delivery of the d120:LacZ:IL-4 vector, after EAE onset, induced the in situ production of IL-4 by CNS-resident cells facing the cerebrospinal fluid (CSF) spaces and reduced by 47% (P < 0.02) the disease-related deaths. Compared with mice treated with the control d120:lacZ vector, IL-4-treated mice also showed a shorter duration of the first EAE attack, a longer inter-relapse period, and a reduction in the severity and duration of the first relapse. Protection from EAE progression in IL-4-treated mice was associated with activation of microglia in spinal cord areas where mRNA content of the pro-inflammatory chemokines, macrophage chemoattractant protein-1 (MCP-1) and Rantes, was reduced and that of the anti-inflammatory cytokine IL-4 was increased. Finally, CNS-infiltrating mononuclear cells from IL-4-treated mice produced lower levels of MCP-1 mRNA compared with control mice. Our results, showing that IL-4 gene delivery using HSV-1 vectors induces protection from EAE by in situ modulating the cytokine/chemokine-mediated circuits sustaining effector cell functions, indicate that the intrathecal 'therapeutic' use of nonreplicative HSV-1-derived vectors containing anti-inflammatory molecules might represent an alternative strategy in inflammatory diseases of the CNS.

Animals↗
PubMed2001

Selective immunointervention in autoimmune diseases: lessons from multiple sclerosis.

Activation of peripheral T cells by foreign and self antigens is under stringent control by different mechanisms, both thymic and peripheral. Control of T cell reactivity is accomplished by three major types of mechanisms: 1) deletion, the physical elimination of T cells specific for a given antigen, 2) anergy, the functional incapacity of T cells to respond to antigen, 3) suppression, the inhibition of T cell function by a regulatory (suppressor) cell. Their failure may lead to autoimmune diseases. The progress in understanding T cell activation, inactivation and modulation is being translated into strategies able to induce selective immunosuppression to treat different pathological situations, notably autoimmune diseases, allergies, and allograft rejection. The medical need for selective immunosuppression is very high, as the available immunosuppressive drugs are substantially inadequate because of limited efficacy, modest selectivity, and considerable toxicity. Key attack points for selective immunointervention have been identified: modulation of antigen recognition, co-stimulation blockade, induction of regulatory cells, deviation to non-pathogenic or protective responses, neutralization of proinflammatory cytokines, induction or administration of anti-inflammatory cytokines, and modulation of leukocyte trafficking. All these forms of immunointervention have been successfully used to prevent and sometimes treat experimental autoimmune diseases. Based on these results, expectations have been raised for exploiting the same strategies to inhibit the activation of human autoreactive T cells. In this overview, we will examine recent advances towards immunointervention in multiple sclerosis (MS) as a paradigm for successes and failures of current immunotherapeutic approaches in human autoimmune diseases.

Administration, Oral↗
PubMed2000

Early Th1 response in unprimed nonobese diabetic mice to the tyrosine phosphatase-like insulinoma-associated protein 2, an autoantigen in type 1 diabetes.

The insulinoma-associated protein 2 (IA-2) is a phosphatase-like autoantigen inducing T and B cell responses associated with human insulin-dependent diabetes mellitus (IDDM). We now report that T cell responses to IA-2 can also be detected in the nonobese diabetic (NOD) mouse, a model of human IDDM. Cytokine secretion in response to purified mouse rIA-2, characterized by high IFN-gamma and relatively low IL-10 and IL-6 secretion, was elicited in spleen cells from unprimed NOD mice. Conversely, no response to IA-2 was induced in spleen cells from BALB/c, C57BL/6, or Biozzi AB/H mice that express, like NOD, the I-A(g7) class II molecule, but are not susceptible to spontaneous IDDM. The IA-2-induced IFN-gamma response in NOD spleen cells could already be detected at 3 wk and peaked at 8 wk of age, whereas the IL-10 secretion was maximal at 4 wk of age and then waned. IA-2-dependent IFN-gamma secretion was induced in CD4(+) cells from spleen as well as pancreatic and mesenteric lymph nodes. It required Ag presentation by I-A(g7) molecules and engagement of the CD4 coreceptor. Interestingly, cytokines were produced in the absence of cell proliferation and IL-2 secretion. The biological relevance of the response to IA-2 is indicated by the enhanced IDDM following a single injection of the recombinant protein emulsified in IFA into 18-day-old NOD mice. In addition, IFN-gamma production in response to IA-2 and IDDM acceleration could be induced by IL-12 administration to 12-day-old NOD mice. These results identify IA-2 as an early T cell-inducing autoantigen in the NOD mouse and indicate a role for the IA-2-induced Th1 cell response in IDDM pathogenesis.

Aging↗
PubMed2000

Glia-T cell dialogue.

Interactions of CD4(+) T helper (Th) cells with microglia and astrocytes are likely to play an important role in regulating immune responses as well as tissue damage and repair during infectious and autoimmune central nervous system (CNS) diseases. T cells secreting Th1-type cytokines provide inducing signals for microglia to mature into functional antigen presenting cells (APC). The ability of microglia to act as efficient APC for the restimulation of Th1 cells suggests a role for these cells in the local amplification of pro-inflammatory immune responses. Conversely, the Th2-inducing capacity of microglia and astrocytes together with their ability to produce anti-inflammatory mediators could play a role in providing counter-regulatory signals limiting CNS inflammation. In this article, we review recent studies addressing the functional significance of T cell-CNS glia interactions and present new data on the expression of cyclooxygenase-2, the inducible enzyme involved in prostanoid biosynthesis, in microglia and astrocytes during the course of experimental allergic encephalomyelitis.

Astrocytes↗
PubMed2000

Cytokine therapy in immune-mediated demyelinating diseases of the central nervous system: a novel gene therapy approach.

Pro-inflammatory cytokines play a crucial role in the regulatory and effector phase of the immune-mediated mechanism sustaining multiple sclerosis pathogenesis (MS) thus supporting the use of anti-inflammatory cytokines as a therapeutic option. Systemic administration of cytokines shows, however, limited therapeutic efficacy and undesirable/unpredictable side-effects. We have developed a non-toxic system to deliver cytokines within the central nervous system (CNS) based on the intrathecal (i.c.) administration of non-replicative herpes simplex (HSV) type-1-derived viral vectors engineered with heterologous cytokine genes. Compared to controls, mice affected by experimental autoimmune encephalomyelitis (EAE) and i.c. injected with an HSV-1-derived vector containing the gene of the anti-inflammatory cytokine IL-4 showed a significant amelioration of clinical and pathological EAE signs. A decreased mRNA expression of the monocyte chemoattractant protein-1 (MCP-1) by mononuclear CNS-infiltrating cells was also observed. Peripheral T cells from IL-4-treated mice were not affected both in their antigen-specific proliferative response and in the cytokine secretion pattern. Our results indicate that CNS cytokine delivery with HSV-1-derived vectors is a feasible therapeutic strategy and might represent an alternative approach for the treatment of immune-mediated demyelinating diseases. Advantages of this approach over systemic cytokine administration are the high cytokine level reached within the CNS and the absence of side-effects on the peripheral immune system. The short-lasting cytokine production in the CNS after a single vector administration (4 weeks) is the limiting factor of this novel technology which, although promising, has to be improved.

Animals↗
PubMed2000

1 Alpha,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation.

1 Alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3), the active form of vitamin D3, is a potent immunomodulatory agent. Here we show that dendritic cells (DCs) are major targets of 1,25(OH)2D3-induced immunosuppressive activity. 1,25(OH)2D3 prevents the differentiation in immature DCs of human monocytes cultured with GM-CSF and IL-4. Addition of 1,25(OH)2D3 during LPS-induced maturation maintains the immature DC phenotype characterized by high mannose receptor and low CD83 expression and markedly inhibits up-regulation of the costimulatory molecules CD40, CD80, and CD86 and of class II MHC molecules. This is associated with a reduced capacity of DCs to activate alloreactive T cells, as determined by decreased proliferation and IFN-gamma secretion in mixed leukocyte cultures. 1, 25(OH)2D3 also affects maturing DCs, leading to inhibition of IL-12p75 and enhanced IL-10 secretion upon activation by CD40 ligation. In addition, 1,25(OH)2D3 promotes the spontaneous apoptosis of mature DCs. The modulation of phenotype and function of DCs matured in the presence of 1,25(OH)2D3 induces cocultured alloreactive CD4+ cells to secrete less IFN-gamma upon restimulation, up-regulate CD152, and down-regulate CD154 molecules. The inhibition of DC differentiation and maturation as well as modulation of their activation and survival leading to T cell hyporesponsiveness may explain the immunosuppressive activity of 1, 25(OH)2D3.

Abatacept↗
PubMed2000

Functional maturation of adult mouse resting microglia into an APC is promoted by granulocyte-macrophage colony-stimulating factor and interaction with Th1 cells.

A precise knowledge of the early events inducing maturation of resting microglia into a competent APC may help to understand the involvement of this cell type in the development of CNS immunopathology. To elucidate whether signals from preactivated T cells are sufficient to induce APC features in resting microglia, microglia from the adult BALB/c mouse CNS were cocultured with Th1 and Th2 lines from DO11.10 TCR transgenic mice to examine modulation of APC-related molecules and Ag-presenting capacity. Upon Ag-specific interaction with Th1, but not Th2, cells, microglia strongly up-regulated the surface expression of MHC class II, CD40, and CD54 molecules. Induction of CD86 on mouse microglia did not require T cell-derived signals. Acutely isolated adult microglia stimulated Th1 cells to secrete IFN-gamma and, to a lesser extent, IL-2, but were inefficient stimulators of IL-4 secretion by Th2 cells. Microglia exposed in vitro to IFN-gamma showed enhanced expression of MHC class II, CD40, and CD54 molecules and became able to restimulate Th2 cells. In addition to IFN-gamma, GM-CSF increased the ability of microglia to activate Th1, but not Th2, cells without up-regulating MHC class II, CD40, or CD54 molecules. These results suggest that interaction with Th1 cells and/or Th1-secreted soluble factors induces the functional maturation of adult mouse microglia into an APC able to sustain CD4+ T cell activation. Moreover, GM-CSF, a cytokine secreted by T cells as well as reactive astrocytes, could prime microglia for Th1-stimulating capacity, possibly by enhancing their responsiveness to Th1-derived signals.

Adjuvants, Immunologic↗
PubMed2000

IL-12 receptor regulation in IL-12-deficient BALB/c and C57BL/6 mice.

Immunization with protein antigen in complete Freund's adjuvant (CFA) induces Th1 cells in BALB/c and C57BL/6 (B6) mice. Pretreatment with the same protein in soluble form induces Th2 cells in BALB/c but not in B6 mice and inhibits Th1 cell development in both. We have previously shown that inhibition of Th1 in BALB/c mice correlates with the down-regulation of transcripts encoding the IL-12 receptor beta2 (IL-12Rbeta2) chain, which is required for IL-12 signaling and Th1 cell development. We now demonstrate that IL-12-deficient BALB/c mice, when primed with antigen in CFA, mount a Th2 instead of the Th1 response which develops in wild-type mice. Conversely, IL-12-deficient B6 mice fail to develop Th2 cells. Thus, a default Th2 development is induced by antigen priming in IL-12-deficient BALB/c but not B6 mice. IL-12Rbeta2 transcripts are still expressed in antigen-restimulated CD4(+) T cells from IL-12-deficient BALB/c and B6 mice and they are similarly reduced by pretreatment with soluble antigen, suggesting that intrinsic strain differences in IL-12R regulation do not account for the differential polarization to the Th2 pathway. IL-4 is not required for down-regulation of IL-12Rbeta2 transcripts and inhibition of Th1 development in mice pretreated with soluble protein, as shown by their reduction in IL-4-deficient BALB/c mice.

Animals↗
PubMed2000

Inhibition of Th1 development and treatment of chronic-relapsing experimental allergic encephalomyelitis by a non-hypercalcemic analogue of 1,25-dihydroxyvitamin D(3).

1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] inhibits production of IL-12, a cytokine involved in the development of Th1 cells and in the pathogenesis of Th1-mediated autoimmune diseases. Here, we show that 1,25(OH)(2)D(3) and a non-hypercalcemic analogue are selective and potent inhibitors of Th1 development in vitro and in vivo without inducing a deviation to the Th2 phenotype. Administration of 1,25(OH)(2)D(3) or its analogue prevents chronic-relapsing experimental allergic encephalomyelitis (CR-EAE) induced by the myelin oligodendrocyte glycoprotein (MOG) peptide 35 - 55 (MOG(35 - 55)) in Biozzi AB / H mice. The inhibition of EAE induction is associated with a profound reduction of MOG(35 - 55)-specific proliferation and Th1 cell development. Importantly, the non-hypercalcemic analogue also provides long-term protection from EAE relapses induced by immunization with spinal cord homogenate when administered for a short time at symptom onset or even after the first peak of disease. Neuropathological analysis shows a reduction of inflammatory infiltrates, demyelinated areas and axonal loss in brains and spinal cords of treated mice. These resuls indicate that inhibition of IL-12-dependent Th1 cell development is associated with effective treatment of CR-EAE and suggest the feasibility of an approach based on low molecular weight inhibitors of IL-12 production in the treatment of multiple sclerosis.

Animals↗
PubMed2000

The control of T cell responses by dendritic cell subsets.

Dendritic cells are known as the most efficient antigen-presenting cell type to activate naïve T cells; however, they are able to do more than just efficiently present antigen to T cells. They are key modulators of the immune response that can influence Th cell differentiation by preferentially inducing Th type 1 or 2 cell responses, and the differential polarisation of CD4(+) T cells appears to be mediated by discrete dendritic cell subsets.

Animals↗
PubMed2000

The motif for peptide binding to the insulin-dependent diabetes mellitus-associated class II MHC molecule I-Ag7 validated by phage display library.

The MHC class II molecule I-Ag7 is essential for the development of insulin-dependent diabetes mellitus (IDDM) in the non-obese diabetic (NOD) mouse but the requirements for peptide binding to I-Ag7 are still controversial. We have now isolated I-Ag7-binding phage from a large phage display library encoding random nonamer peptides. Ninety peptide-encoding regions of phage eluted from I-Ag7 were sequenced and >75% of the corresponding synthetic peptides bound to I-Ag7. Peptide alignment led to the identification of position-specific anchor residues. Hydrophobic (V and P) and positively charged (K) residues were highly enriched at P6 and positively charged (R and K), aromatic (Y) or hydrophobic (L) residues at P9. In addition, small amino acid residues (G and A) were enriched at P7 and G at P8. The primary anchors at P6 and P9 defining the phage-derived motif were present in most high-affinity I-Ag7-binding peptides from IDDM candidate antigens but only in < or =25% of peptides that were low-affinity binders or failed to bind to I-Ag7. A comparison of these results with the proposed motifs for peptide binding to I-Ag7 validates the one we have previously described.

Amino Acid Motifs↗
PubMed2000

New trends in clinical and experimental immunosuppression--fourth international conference. 17-20 February 2000, Geneva, Switzerland.

The meeting covered several aspects of currently used immunosuppressive drugs, but focused on tolerance induction strategies in the treatment of both allograft rejection and autoimmune diseases. Topics discussed included: clinical trials with anti-CD3 in recently-diagnosed insulin-dependent diabetes mellitus (IDDM) patients; Tr1 cells in bone-marrow transplantation; and, 1 alpha,25-dihydroxyvitamin D3-associated with mycophenolate mofetil and anti-CD25 in islet transplantation. In addition, malononitrilamides, an emerging class of novel immunosuppressants, were discussed in depth.

Journal Article↗
PubMed1999

Leukocyte recruitment in the cerebrospinal fluid of mice with experimental meningitis is inhibited by an antibody to junctional adhesion molecule (JAM).

The mechanisms that govern leukocyte transmigration through the endothelium are not yet fully defined. Junctional adhesion molecule (JAM) is a newly cloned member of the immunoglobulin superfamily which is selectively concentrated at tight junctions of endothelial and epithelial cells. A blocking monoclonal antibody (BV11 mAb) directed to JAM was able to inhibit monocyte transmigration through endothelial cells in in vitro and in vivo chemotaxis assays. In this study, we report that BV11 administration was able to attenuate cytokine-induced meningitis in mice. The intravenous injection of BV11 mAb significantly inhibited leukocyte accumulation in the cerebrospinal fluid and infiltration in the brain parenchyma. Blood-brain barrier permeability was also reduced by the mAb. We conclude that JAM may be a new target in limiting the inflammatory response that accompanies meningitis.

Animals↗
PubMed1999

Caspase-1 regulates the inflammatory process leading to autoimmune demyelination.

T cell-mediated inflammation is considered to play a key role in the pathogenic mechanisms sustaining multiple sclerosis (MS). Caspase-1, formerly designated IL-1beta-converting enzyme, is crucially involved in immune-mediated inflammation because of its pivotal role in regulating the cellular export of IL-1beta and IL-18. We studied the role of caspase-1 in experimental autoimmune encephalomyelitis (EAE), the animal model for MS. Caspase-1 is transcriptionally induced during EAE, and its levels correlate with the clinical course and transcription rate of proinflammatory cytokines such as TNF-alpha, IL-1beta, IFN-gamma, and IL-6. A reduction of EAE incidence and severity is observed in caspase-1-deficient mice, depending on the immunogenicity and on the amount of the encephalitogenic myelin oligodendrocyte glycoprotein (MOG) peptide used. In caspase-1-deficient mice, reduced EAE incidence correlates with defective development of anti-MOG IFN-gamma-producing Th1 cells. Finally, pharmacological blockade of caspase-1 in Biozzi AB/H mice, immunized with spinal cord homogenate or MOG35-55 peptide, by the caspase-1-inhibitor Z-Val-Ala-dl -Asp-fluoromethylketone, significantly reduces EAE incidence in a preventive but not in a therapeutic protocol. These results indicate that caspase-1 plays an important role in the early stage of the immune-mediated inflammatory process leading to EAE, thus representing a possible therapeutic target in the acute phase of relapsing remitting MS.

Amino Acid Chloromethyl Ketones↗