Matteo G Levisetti

Washington University in St. Louis, San Luis, Missouri, United States

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Publications (16)108.16 Total impact

  • Anish Suri, Matteo Levisetti
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    ABSTRACT: The incidence of autoimmune diabetes has been steadily increasing in the developed world. A complex interplay between genetic factors and dysregulated immune cells ultimately results in breakdown of self-tolerance against islet beta cell antigens and loss of beta cell mass, which leads to insulin deficiency and persistent hyperglycemia. Much progress in our understanding of immunological mechanisms that underlie autoimmune diabetes has been made in recent years. A significant portion of the experimental investigations have been performed in rodent models of autoimmune diabetes that are reviewed in this chapter. In addition, an understanding of the biochemical characteristics of class II MHC molecules that predispose to autoimmune diabetes and their relationship to selection of the autoimmune T-cell repertoire are discussed. Finally, data supporting insulin as a dominant autoantigen are reviewed along with various effector pathways and cell types that induce islet beta cell death.
    01/2012: pages 303-318;
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    ABSTRACT: In addition to the genetic framework, there are two other critical requirements for the development of tissue-specific autoimmune disease. First, autoreactive T cells need to escape thymic negative selection. Second, they need to find suitable conditions for autoantigen presentation and activation in the target tissue. We show here that these two conditions are fulfilled in diabetic mice of the nonobese diabetic (NOD) strain. A set of autoreactive CD4(+) T cells specific for an insulin peptide, with the noteworthy feature of not recognizing the insulin protein when processed by antigen-presenting cells (APCs), escaped thymic control, participated in diabetes and caused disease. Moreover, APCs in close contact with beta cells in the islets of Langerhans bore vesicles with the antigenic insulin peptides and activated peptide-specific T cells. Our findings may be relevant for other cases of endocrine autoimmunity.
    Nature Immunology 02/2010; 11(4):350-4. DOI:10.1038/ni.1850 · 24.97 Impact Factor
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    Matteo G Levisetti, Danna M Lewis, Anish Suri, Emil R Unanue
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    ABSTRACT: Weak major histocompatibility complex (MHC) binding of self-peptides has been proposed as a mechanism that may contribute to autoimmunity by allowing for escape of autoreactive T-cells from the thymus. We examined the relationship between the MHC-binding characteristics of a beta-cell antigen epitope and T-cell autoreactivity in a model of autoimmune diabetes. The binding of a proinsulin epitope, proinsulin-1(47-64) (PI-1[47-64]), to the MHC class II molecules I-A(g7) and I-A(k) was measured using purified class II molecules. T-cell reactivity to the proinsulin epitope was examined in I-A(g7+) and I-A(k+) mice. C-peptide epitopes bound very weakly to I-A(g7) molecules. However, C-peptide-reactive T-cells were induced after immunization in I-A(g7)-bearing mice (NOD and B6.g7) but not in I-A(k)-bearing mice (B10.BR and NOD.h4). T-cells reactive with the PI-1(47-64) peptide were found spontaneously in the peripancreatic lymph nodes of pre-diabetic NOD mice. These T-cells were activated by freshly isolated beta-cells in the presence of antigen-presenting cells and caused diabetes when transferred into NOD.scid mice. These data demonstrate an inverse relationship between self-peptide-MHC binding and T-cell autoreactivity for the PI-1(47-64) epitope in autoimmune diabetes.
    Diabetes 08/2008; 57(7):1852-60. DOI:10.2337/db08-0068 · 8.47 Impact Factor
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    Anish Suri, Matteo G Levisetti, Emil R Unanue
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    ABSTRACT: One seminal aspect in autoimmune diabetes is antigen presentation of beta cell antigens by the diabetes-propensity class II histocompatibility molecules. The binding properties of I-Ag7 molecules are reviewed here and an emphasis is placed on their selection of peptides with a highly specific sequence motif, in which one or more acidic amino acids are found at the carboxy end interacting at the P9 anchoring site of I-Ag7. The reasons for the central role of I-Ag7 in the autoimmune response are analyzed. The insulin B chain segment 9-23 is a hot spot for T cell selection and a striking example of a weak MHC binding peptide that triggers autoreactivity.
    Current Opinion in Immunology 03/2008; 20(1):105-10. DOI:10.1016/j.coi.2007.10.007 · 7.87 Impact Factor
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    ABSTRACT: Several naturally occurring anti-insulin CD4 T cells were isolated from islet infiltrates of NOD mice. In accordance with the results of others, these T cells recognized the segment of the beta-chain from residues 9-23. Peptides encompassing the B:(9-23) sequence bound weakly to I-Ag7 in two main contiguous registers in which two residues at the carboxyl end, P20Gly and P21Glu, influenced binding and T cell reactivity. Naturally occurring insulin-reactive T cells exhibited differing reactivities with the carboxyl-terminal amino acids, although various single residue changes in either the flanks or the core segments affected T cell responses. The insulin peptides represent another example of a weak MHC-binding ligand that is highly immunogenic, giving rise to distinct populations of autoimmune T cells.
    The Journal of Immunology 06/2007; 178(10):6051-7. DOI:10.4049/jimmunol.178.10.6051 · 5.36 Impact Factor
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    ABSTRACT: This report details the biochemical features of natural peptides selected by the H-2Kd class I MHC molecule. In normal cell lines, the length of the naturally processed peptides ranged from 8 to 18 amino acids, although the majority were 9-mers (16% were longer than nine residues). The binding motif for the 9-mer peptides was dominated by the presence of a tyrosine at P2 and an isoleucine/leucine at the P9 position. The P2 residue contributed most towards binding; and the short peptides bound better and formed longer-lived cell surface complexes than the long peptides, which bound poorly and dissociated rapidly. The longer peptides did not exhibit this strictly defined motif. Trimming the long peptides to their shorter forms did not enhance binding and conversely, extending the 9-mer peptides did not decrease binding. The long peptides were present on the cell-surface bound to H-2Kd (Kd) and were not intermediate products of the class I MHC processing pathway. Finally, in two different TAP-deficient cells the long peptides were the dominant species, which suggested that TAP-independent pathways selected for long peptides by class I MHC molecules.
    European Journal of Immunology 04/2006; 36(3):544-57. DOI:10.1002/eji.200526235 · 4.52 Impact Factor
  • Matteo Levisetti, Anish Suri, Shirley Petzold, Emil Unanue
    Clinical Immunology 01/2006; 119. DOI:10.1016/j.clim.2006.04.459 · 3.99 Impact Factor
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    Matteo G Levisetti, Kenneth S Polonsky
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    ABSTRACT: A complex network of interacting transcription factors plays a critical role in normal pancreatic beta cell function, with mutations in certain transcription factor genes known to cause diabetes. In a recent issue of Cell, Gunton et al.(2005) demonstrate a role for the transcription factor ARNT/HIF1beta (hydrocarbon nuclear receptor translocator/hypoxia-inducible factor 1 beta) in normal beta cell function. ARNT expression is reduced in diabetic human islets and beta cell-specific ARNT knockout mice show the impaired glucose tolerance and abnormal insulin secretion that are characteristic of type 2 diabetes.
    Cell Metabolism 09/2005; 2(2):78-80. DOI:10.1016/j.cmet.2005.07.005 · 16.75 Impact Factor
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    ABSTRACT: We discuss three areas of antigen presentation and macrophage biology being investigated in the laboratory. Using hen egg-white lysozyme as a protein antigen, all the segments of the molecules selected by the class II histocompatibility molecule I-A(k) were identified and characterized. The display of each family of peptides was explained biochemically and quantitated. Conformational isomers of a peptide-major histocompatibility complex (MHC) complex were identified. The relationship between the amounts of peptide-MHC displayed by the antigen-presenting cells and two biologic responses, central thymic selection and T-cell responses after immunization in adjuvant, were examined. The class II MHC molecule of the nonobese diabetic I-Ag7 is being examined for its properties of peptide selection. The objective is to identify the diabetogenic peptides, as well as the repertoire of protein antigens from beta-cells that trigger autoantibodies. The I-Ag7 molecule selects peptides that show very distinctive sequence motifs: one or more acidic residues at the carboxy terminus that interact at the P9 pocket of the binding groove. Finally, the investigations in listeriosis examined the early events in immune induction. More important, we found that Listeria causes marked apoptosis of lymphocytes around infective foci resulting from the apoptogenic properties of the pore-forming molecule Listeriolysin O.
    Immunologic Research 02/2005; 32(1-3):267-92. DOI:10.1385/IR:32:1-3:267 · 3.53 Impact Factor
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    ABSTRACT: Pregnant nonobese diabetic (NOD) mice were treated with lymphotoxin-beta receptor immunoglobulin fusion protein (LTbetaR-Ig) or control human immunoglobulin on days embryonic day 11 (E11) and E14, and offspring were followed for the development of anti-beta-cell antibodies, islet pathology, and hyperglycemia. The development of anti-beta-cell surface antibodies was abrogated in treated mice compared with controls. Autopsy examination of the mice at 30 weeks of age revealed normal development of secondary lymphoid structures in the control animals; however, mice treated with LTbetaR-Ig had no axillary, inguinal, popliteal, or peripancreatic lymph nodes. Histological examination of the pancreata of the control mice revealed a severe and destructive mononuclear cellular infiltrate in the islets, whereas the islets of the LTbetaR-Ig-treated mice were devoid of any insulitis. None of the LTbetaR-Ig-treated mice (n = 22) developed diabetes; in contrast, 80% of the control mice (n = 46) developed diabetes at 1 year of age. The LTbetaR-Ig-treated mice did not contain diabetogenic T-cells. However, the treated mice developed diabetes upon inoculation with diabetogenic T-cells. In this model of spontaneous autoimmune diabetes, secondary lymphoid structures, most likely the peripancreatic lymph nodes, were essential for the development of pathologic anti-beta-cell autoimmunity.
    Diabetes 01/2005; 53(12):3115-9. DOI:10.2337/diabetes.53.12.3115 · 8.47 Impact Factor
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    ABSTRACT: We determined that, over a biologic time interval, from 4 to 8 weeks of age, female non-obese diabetic (NOD) mice develop antibodies against pancreatic beta-cell-surface antigens depending upon the presence of both the MHC class II susceptibility allele, I-A(g7), and other NOD background genes. We generated a mAb from a pre-diabetic NOD mouse that binds to the surface of insulinoma cells and isolated mouse beta cells, and identified the target as a retroviral envelope glycoprotein expressed on pancreatic beta cells. The cloned and expressed sequence for this protein was recognized by the mAb. The antibody as well as sera from pre-diabetic NOD mice recognized the recombinant protein. Spontaneous T cell reactivity against a peptide from the cloned protein was found in NOD mice. In conclusion, a beta cell retroviral envelope protein is a target antigen that is selected by the NOD mouse immune system early in the pathogenesis of autoimmune diabetes.
    International Immunology 01/2004; 15(12):1473-83. · 3.18 Impact Factor
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    ABSTRACT: To address the pathogenesis of diabetic autonomic neuropathy, we have examined the sympathetic nervous system in non-obese diabetic (NOD) and streptozotocin (STZ)-induced diabetic mice, two models of type 1 diabetes, and the db/db mouse, a model of type 2 diabetes. After only 3 to 5 weeks of diabetes, NOD mice developed markedly swollen axons and dendrites ("neuritic dystrophy") in the prevertebral superior mesenteric and celiac ganglia (SMG-CG), similar to the pathology described in diabetic STZ- and BBW-rat and man. Comparable changes failed to develop in the superior cervical ganglia of the NOD mouse or in the SMG-CG of non-diabetic NOD siblings. STZ-induced diabetic mice develop identical changes, although at a much slower pace and to a lesser degree than NOD mice. NOD-SCID mice, which are genetically identical to NOD mice except for the absence of T and B cells, do not develop diabetes or neuropathology comparable to diabetic NOD mice. However, STZ-treated NOD-SCID mice develop severe neuritic dystrophy, evidence against an exclusively autoimmune pathogenesis for autonomic neuropathy in this model. Chronically diabetic type 2 db/db mice fail to develop neuritic dystrophy, suggesting that hyperglycemia alone may not be the critical and sufficient element. The NOD mouse appears to be a valuable model of diabetic sympathetic autonomic neuropathy with unambiguous, rapidly developing neuropathology which corresponds closely to the characteristic pathology of other rodent models and man.
    American Journal Of Pathology 11/2003; 163(5):2077-91. DOI:10.1016/S0002-9440(10)63565-1 · 4.60 Impact Factor
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    ABSTRACT: Background, Insulin-dependent diabetes mellitus (IDDM) is the second most prevalent chronic illness of children. Investigation of the treatment of IDDM is hindered by the lack of a reproducible and easily maintained non-human primate model of this disorder. Methods. We induced IDDM in 11 juvenile cynomolgus monkeys after a single (150 mg/kg) intravenous injection of streptozotocin (STZ), All diabetic monkeys were treated with insulin twice daily, based on a sliding scale. Subcutaneous vascular access ports were surgically placed in each monkey to facilitate serial blood sampling and drug administration. Allogeneic pancreatic islet cells from unrelated donors were subsequently transplanted into the mesenteric circulation of all STZ-treated monkeys. Results, Mild, transient nausea and vomiting occurred in all animals after STZ injection; however, no additional signs of toxicity occurred. Within 36 hr, all monkeys required twice daily administration of exogenous insulin to maintain a non-ketotic state. Serum C-peptide levels decreased from >1.2 ng/ml before STZ, to between 0.0 and 0.9 ng/ml after STZ, confirming islet cell destruction. Animals were maintained in an insulin-dependent state for up to 147 days without any observable clinical complications, Subcutaneous vascular access port patency was maintained up to 136 days with a single incidence of local infection. Islet cell transplantation resulted in normoglycemia within 24 hr, Serum C-peptide levels increased (range: 2-8 ng/ml) for 6-8 days in immune competent animals, and for 39-98 days after transplant in immunosuppressed monkeys. Conclusions. IDDM can be consistently induced and safely treated in juvenile cynomolgus monkeys. Chronic vascular access can be maintained with minimal supervision and complications. This model is appropriate for studies investigating potential treatments for IDDM including islet cell transplantation.
    Transplantation 08/1999; 68(3):331-337. DOI:10.1097/00007890-199908150-00003 · 3.78 Impact Factor
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    [Show abstract] [Hide abstract]
    ABSTRACT: Insulin-dependent diabetes mellitus (IDDM) is the second most prevalent chronic illness of children. Investigation of the treatment of IDDM is hindered by the lack of a reproducible and easily maintained non-human primate model of this disorder. We induced IDDM in 11 juvenile cynomolgus monkeys after a single (150 mg/kg) intravenous injection of streptozotocin (STZ). All diabetic monkeys were treated with insulin twice daily, based on a sliding scale. Subcutaneous vascular access ports were surgically placed in each monkey to facilitate serial blood sampling and drug administration. Allogeneic pancreatic islet cells from unrelated donors were subsequently transplanted into the mesenteric circulation of all STZ-treated monkeys. Mild, transient nausea and vomiting occurred in all animals after STZ injection; however, no additional signs of toxicity occurred. Within 36 hr, all monkeys required twice daily administration of exogenous insulin to maintain a non-ketotic state. Serum C-peptide levels decreased from >1.2 ng/ml before STZ, to between 0.0 and 0.9 ng/ml after STZ, confirming islet cell destruction. Animals were maintained in an insulin-dependent state for up to 147 days without any observable clinical complications. Subcutaneous vascular access port patency was maintained up to 136 days with a single incidence of local infection. Islet cell transplantation resulted in normoglycemia within 24 hr. Serum C-peptide levels increased (range: 2-8 ng/ml) for 6 - 8 days in immune competent animals, and for 39-98 days after transplant in immunosuppressed monkeys. IDDM can be consistently induced and safely treated in juvenile cynomolgus monkeys. Chronic vascular access can be maintained with minimal supervision and complications. This model is appropriate for studies investigating potential treatments for IDDM including islet cell transplantation.
    Transplantation 08/1999; 68(3):331-7. · 3.78 Impact Factor
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    [Show abstract] [Hide abstract]
    ABSTRACT: We discuss three areas of antigen presentation and macrophage biology being investigated in the laboratory. Using hen egg-white lysozyme as a protein antigen, all the segments of the molecules selected by the class II histocompatibility molecule I-Ak were identified and characterized. The display of each family of peptides was explained biochemically and quantitated. Conformational isomers of a peptide-major histocompatibility complex (MHC) complex were identified. The relationship between the amounts of peptide-MHC displayed by the antigen-presenting cells and two biologic responses, central thymic selection and T-cell responses after immunization in adjuvant, were examined. The class II MHC molecule of the nonobese diabetic I-Ag7 is being examined for its properties of peptide selection. The objective is to identify the diabetogenic peptides, as well as the repertoire of protein antigens from β-cells that trigger autoantibodies. The I-Ag7 molecule selects peptides that show very distinctive sequence motifs: one or more acidic residues at the carboxy terminus that interact at the P9 pocket of the binding groove. Finally, the investigations in listeriosis examined the early events in immune induction. More important, we found that Listeria causes marked apoptosis of lymphocytes around infective foci resulting from the apoptogenic properties of the poreforming molecule Listeriolysin O.
    Immunologic Research 12/1998; 32(1):267-292. · 3.53 Impact Factor
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    ABSTRACT: Ag-specific T cell activation requires a CD28-mediated costimulatory interaction. This observation has suggested novel approaches to suppress donor-specific immunity, including the use of soluble CD28 antagonists, such as CTLA4Ig, which suppresses transplant rejection in small animal models. In this study, CTLA4Ig therapy was examined in a non-human primate model of allogeneic pancreatic islet transplantation. Two of five CTLA4Ig-treated monkeys showed prolonged graft survival, which correlated with donor-specific hyporesponsiveness in vitro. Humoral responses to the transplanted tissue were suppressed in all treated animals. These results suggest that CTLA4Ig is effective in suppressing both humoral and cellular immune responses in a non-human primate model of allogeneic transplantation.
    The Journal of Immunology 12/1997; 159(11):5187-91. · 5.36 Impact Factor

Publication Stats

531 Citations
108.16 Total Impact Points

Institutions

  • 1998–2010
    • Washington University in St. Louis
      • • Department of Pathology and Immunology
      • • Department of Medicine
      San Luis, Missouri, United States
  • 1999
    • University of Chicago
      Chicago, Illinois, United States