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Biomedical subjects

H O McDevitt

Publications and source records attributed to H O McDevitt.

At least 37 records · Page 2Linked to original sources
PubMed1997

Reduction in diabetes incidence in an I-Ag7 transgenic nonobese diabetic mouse line.

Susceptibility to IDDM is strongly associated with major histocompatibility complex (MHC) class II genotypes. Nonobese diabetic (NOD) mice develop a similar autoimmune diabetes and have a unique MHC class II I-A allele that is required for the development of diabetes. A number of groups have shown that the introduction of resistant MHC class II alleles as transgenes into the NOD mouse protects from diabetes. We made control transgenic NOD mice, expressing their own I-Abetag7 molecule as a transgene. One of two lines of these mice showed a reduced incidence of diabetes, without any change in T-cell proliferative response to a number of diabetes autoantigens or any change in insulitis severity. This line developed a subtle decrease in the percentage of splenic B-cells that progressed with age. This defect was not associated with any other phenotypic abnormalities. Our findings suggest that assessment of splenic B-cell number is necessary in interpretation of the effects of MHC class II transgenes on the development of diabetes in the NOD mouse.

Alleles↗
PubMed1997

Involvement of beta 7 integrin and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) in the development of diabetes in obese diabetic mice.

Nonobese diabetic (NOD) mice develop autoimmune-mediated lymphocytic inflammation of pancreatic islets (insulitis) that leads to beta-cell destruction and development of diabetes. Inflamed islets show expression of lymphocyte alpha 4 beta 7 integrin and endothelial mucosal addressin cell adhesion molecule-1 (MAdCAM-1), adhesion molecules involved in tissue-selective migration of lymphocytes to mucosal lymphoid tissues. To elucidate the roles of the mucosal lymphocyte/endothelial adhesion system in the development of diabetes, we treated NOD mice with monoclonal antibody against beta 7 integrin or MAdCAM-1. Treatment of mice from age 7 to 28 days or 8 to 12 weeks with either antibody led to significant and long-standing protection against the spontaneous development of diabetes and insulitis. In contrast, neither treatment prevented the development of salivary gland inflammation (sialadenitis), indicating that the effect was tissue-selective. Monoclonal antibody treatment had no demonstrable effect on numbers or phenotypes of peripheral lymphocytes or on the immune response to pancreatic islet or exogenous antigens. These data indicate that lymphocyte and endothelial adhesion molecules involved in the migration of lymphocytes into mucosal lymphoid tissues play a role in the development of diabetes in NOD mice. Moreover, the results suggest that treatment of humans with antibodies against tissue-selective lymphocyte or endothelial adhesion molecules may selectively inhibit the development of autoimmune diseases such as diabetes.

Animals↗
PubMed1996

Disrupted splenic architecture, but normal lymph node development in mice expressing a soluble lymphotoxin-beta receptor-IgG1 fusion protein.

Early in ontogeny, the secondary lymphoid organs become populated with numerous cells of mesodermal origin which forms both the lymphoid and stromal elements. The critical receptor/ligand interactions necessary for lymphoid organogenesis to occur are for the most part unknown. Although lymphotoxin-alpha (LT alpha) has been shown to be required for normal lymph node, Peyer's patch, and splenic development, it is unclear if soluble LT alpha 3, and/or cell-bound lymphotoxin-alpha beta (LT alpha beta) mediate these developmental events. Here we report that blocking LT alpha beta/lymphotoxin-beta receptor (LT beta R) interaction in vivo by generating mice which express a soluble LT beta R-Fc fusion protein driven by the human cytomegalovirus promoter results in an array of anatomic abnormalities affecting both the spleen and Peyer's patches, but not the lymph nodes. These results demonstrate that surface LT alpha beta ligand plays a critical role in normal lymphoid organ development.

Aging↗
PubMed1996

CD8(+) T cell-mediated spontaneous diabetes in neonatal mice.

Transgenic mice that express the influenza virus hemagglutinin (HA) on pancreatic islet beta cells (ins-HA) demonstrate tolerance of HA even after immunization with influenza virus. Surprisingly, when Ins-HA mice were mated with a transgenic mouse expressing a TCR specific for an epitope of HA that is restricted by MHC class I H-2Kd (Clone-4 TCR), the resulting double transgenic (Ins-HA x Clone-4 TCR)F1 neonates developed spontaneous autoimmune diabetes immediately after birth and died within 10 days. This represents a unique situation in which all safeguards within the immune system that normally maintain tolerance of self-antigens in the neonate are insufficient.

Animals↗
PubMed1996

High copy number I-Ab transgenes induce production of IgE through an interluekin 4-dependent mechanism.

To better understand the role of class II major histocompatibility complex molecules in both normal and autoimmune responses, we have produced a series of I-Ab transgenic mice. One of these transgenic constructs, designated NOD.PD, has the sequence of the NOD beta chain (Abeta(g7)) except at positions 56 and 57, where Pro-Asp replaces His-Ser. Several NOD.PD transgenic lines have been produced. One line of these mice carried a very high number of copies (>50) of the NOD.PD transgene. As has been described in other mice carrying high copy numbers of I-Ab transgenes, B-cell development was abnormal. The steady state numbers of mature B cells (IgM+/IgD(hi)) in the periphery were greatly reduced in transgenic mice compared to nontransgenic littermates. Surprisingly, rather than being accompanied by a generalized hypogammaglobulinemia, this B-cell deficiency was accompanied by elevated concentrations of IgG1 and IgE in the serum. Conversely, the levels of IgG2a were reduced in transgenic mice compared to nontransgenic littermates. Because this isotype pattern was characteristic of interleukin (IL)-4-induced class-switching, we then investigated the role of IL-4 in causing the observed phenotype. We crossed the high copy number transgenic mice with an IL-4-deficient strain of mice. As expected, the elevated levels of IgE in high copy number transgenic mice were eliminated when the IL-4 gene was inactivated. However, the reduction in the number of B cells was not ameliorated. These data indicate that the primary defect caused by the transgene was to reduce the number of B cells in these mice. This reduction was accompanied by a secondary increase in IL-4 production, which drove the remaining B cells toward the production of IgGl and IgE.

Animals↗
PubMed1996

Intravenous injection of soluble antigen induces thymic and peripheral T-cells apoptosis.

The mechanism by which tolerance is induced via systemic administration of high doses of aqueous antigen has been analyzed by using mice transgenic for a T-cell receptor specific for the influenza virus hemagglutinin (HA) peptide comprising amino acids 126-138. After intravenous injection of 750 (but not 75) micrograms of HA peptide, a state of hyporesponsiveness was rapidly induced. In the thymus, in situ apoptosis in the cortex and at the corticomedullary junction was responsible for a synchronous and massive deletion of CD4+ CD8+ thymocytes. In secondary lymphoid organs, HA-reactive T cells were initially activated but were hyporesponsive at the single cell level. After 3 days, however, those cells were rapidly deleted, at least partially, through an apoptotic process. Therefore, both thymic and peripheral apoptosis, in addition to T-cell receptor desensitization, contribute to high-dose tolerance.

Amino Acid Sequence↗
PubMed1996

The roles of Fas/APO-1 (CD95) and TNF in antigen-induced programmed cell death in T cell receptor transgenic mice.

The possible involvement of Fas/APO-1 (CD95) and TNF in antigen-specific AICD of thymocytes and mature T cells has been investigated. Antigenic stimulation in vivo of influenza hemagglutinin (HA)-specific TCRtg mice was used to demonstrate that the kinetics of thymocyte and peripheral CD4+ T cell deletion are similar in mice with normal (+/+) or defective Fas (lpr/lpr) background, indicating that a Fas-independent pathway(s) is responsible for the deletion of activated T cells. TCRtg-+/+ or TCRtg-lpr/lpr mice injected with murine TNF-blocking MAb (TN3) showed rapid apoptosis of thymocytes after HA stimulation, indicating that death signaling through Fas and TNF receptors is not essential for HA-induced thymocyte deletion. CDC peripheral T cells in TCRtg-lpr/lpr mice did not undergo apoptosis following injection with HA and TN3, indicating that TNF-mediated apoptosis is involved in the deletion of mature T cells after antigenic stimulation. However, apoptosis still occurred in TCRtg-+/+ mice injected with TN3, indicating that both Fas- and TNF-mediated cell death can contribute to the deletion of activated peripheral T cells.

Amino Acid Sequence↗
PubMed1996

No linkage or association of telomeric and centromeric T-cell receptor beta-chain markers with susceptibility to type 1 insulin-dependent diabetes in HLA-DR4 multiplex families.

The T-cell receptor beta locus (TCRB) on chromosome 7q35 was studied as a candidate region for genetic susceptibility to type 1 insulin-dependent diabetes (IDDM). A highly polymorphic microsatellite marker mapping to the TCRBV6.7 gene and a TCRB C-region RFLP were used to genotype the members of a total of 21 multiplex IDDM families from two different geographical areas. There was no evidence to support linkage to either of these markers with IDDM, and conventional two-point analysis excluded linkage to the telomeric end of the TCRB complex, in the region of the highly informative TCRBV6.7 marker. There was significant linkage of IDDM to the class II HLA-D locus with significant lod scores > 3.0 obtained for the HLA-DRB1 and HLA-DQB1 genes. Affected sib-pair (ASP) and transmission disequilibrium (TDT) association tests confirmed these findings.

Adolescent↗
PubMed1996

The role of cell adhesion molecules in the development of IDDM: implications for pathogenesis and therapy.

IDDM is a chronic inflammatory disease in which there is autoimmune-mediated organ-specific destruction of the insulin-producing beta-cells in the pancreatic islets of Langerhans. The migration of autoreactive lymphocytes and other leukocytes from the bloodstream into the target organ is of clear importance in the etiology of many organ-specific autoimmune/inflammatory disorders, including IDDM. In IDDM, this migration results in lymphocytic invasion of the islets (formation of insulitis) and subsequent destruction of beta-cells. Migration of lymphocytes from the bloodstream into tissues is a complex process involving sequential adhesion and activation events. This migration is controlled in part by selective expression and functional regulation of cell adhesion molecules (CAMs) on the surface of lymphocytes and vascular endothelial cells or in the extracellular matrix. Understanding the mechanisms that regulate lymphocyte migration to the pancreatic islets will lead to further understanding of the pathogenesis of IDDM. In this article, we summarize the recent advances regarding the function of CAMs in the development of IDDM in animal models and in humans and discuss the potential for developing CAM-based therapies for IDDM.

Animals↗
PubMed1996

Quantitative analysis of peptides from myelin basic protein binding to the MHC class II protein, I-Au, which confers susceptibility to experimental allergic encephalomyelitis.

BACKGROUND: An important issue in autoimmune diseases mediated by T cells, such as experimental allergic encephalomyelitis (EAE), is the affinity of the disease-inducing determinants for MHC class II proteins. Tolerance, either due to clonal deletion or anergy induction, is thought to require high-affinity interactions between peptides and MHC molecules. Low-affinity binding is compatible with the hypothesis that breaking tolerance to self proteins does not have to occur for onset of disease. In contrast, a high-affinity interaction implies that an event leading to a breakdown of tolerance is central to the autoimmune process. MATERIALS AND METHODS: Detergent-solubilized and affinity-purified I-Au was incubated with varying concentrations of a set of peptides from myelin basic protein and a biotinylated peptide agonist. The specific complexes were separated from excess peptide by capture on antibody-coated plates, and the affinity of the peptides was measured by adding europium-labeled streptavidin and measuring the resultant fluorescence. RESULTS: The immunodominant and encephalitogenic determinant, Ac 1-11, was shown to bind to I-Au relatively poorly (IC50 = 100 microM), demonstrating that in this protein, immunodominance did not correlate with high-affinity binding. In contrast with the natural sequence, the ability of shorter analogs to induce EAE did correlate with their apparent affinity. CONCLUSIONS: The dominance of the natural determinant does not arise from a high-affinity interaction with the MHC class II molecule. This suggests that other mechanisms are operative and that the specific T cell for this peptide/MHC ligand is of high affinity.

Amino Acid Sequence↗
PubMed1995

Autoimmune diabetes and its antigenic triggers.

Susceptibility to insulin-dependent disease is largely determined by alterations in an HLA gene. In addition to insulin, several other antigenic triggers have been identified. One of these, glutamic acid decarboxylase-65, appears to be a primary trigger and may be a key to future treatment. Experimentally, intrathymic or intravenous injection of GAD-65 dampens the autoimmune response and delays disease.

Animals↗
PubMed1995

Binding of an invariant-chain peptide, CLIP, to I-A major histocompatibility complex class II molecules.

Invariant chain (Ii) associates with major histocompatibility complex (MHC) class II molecules and is crucial for antigen presentation by class II molecules. The exact nature of Ii interaction with MHC class II molecules remains undefined. A nested set of Ii peptides, CLIPs (class II-associated Ii peptides), have been eluted from various MHC class II molecules, suggesting that CLIPs correspond, at least in part, to the Ii motif which blocks the conventional peptide binding site in MHC class II molecules. Here we report how CLIPs interact with class II MHC molecules, I-A. We have identified regions critical for binding of CLIPs and I-A class II molecules. In most cases, the binding of CLIPs to a number of I-A molecules is modulated by the steric bulk of methionine residues at positions 93 and 99. In addition, the binding of CLIPs to an I-A molecule, I-Au, is sensitive to substitutions at aspartic acid-59 in the alpha chain and threonine-86 in the beta chain, whereas the binding of an antigen-derived peptide is not. Taken together, these results provide an insight as to how CLIPs bind to MHC class II heterodimers.

Animals↗
PubMed1995

Th1 and Th2 CD4+ T cells in the pathogenesis of organ-specific autoimmune diseases.

CD4+ T cells play a key role in regulating immune system function. When these regulatory processes go awry, organ-specific autoimmune diseases may develop. Here, Roland Liblau, Steven Singer and Hugh McDevitt explore the thesis that a particular subset of CD4+ T cells, namely T helper 1 (Th1) cells, contributes to the pathogenesis of organ-specific autoimmune diseases, while another subset, Th2 cells, prevents them.

Animals↗
PubMed1994

A predominant role of integrin alpha 4 in the spontaneous development of autoimmune diabetes in nonobese diabetic mice.

To elucidate the role of cell adhesion molecules in the pathogenesis of insulin-dependent diabetes mellitus and to determine the predominant lymphocytic homing pathway(s) involved in the selective lymphocytic infiltration of pancreatic islets (insulitis), nonobese diabetic mice were treated with monoclonal antibodies specific for the L-selectin and integrin alpha 4 lymphocyte adhesion molecules. Treatment of neonatal mice with either anti-L-selectin or anti-integrin alpha 4 monoclonal antibodies for the first 4 weeks of life led to a significant and long-term protection against spontaneous occurrence of insulitis and diabetes. The same treatment failed to inhibit lymphocytic infiltration of the salivary glands (sialadenitis). This tissue-specific inhibition of inflammation may be attributed to differences between the pancreas and salivary gland in their expression of endothelial ligands for L-selectin (peripheral vascular addressin) and for integrin alpha 4 (mucosal addressin cell adhesion molecule 1 and vascular cell adhesion molecule 1). Mucosal addressin cell adhesion molecule 1 is highly expressed by vessels within the inflamed islets but was not detected in the salivary glands. In contrast, peripheral vascular addressin- and vascular cell adhesion molecule 1-expressing vessels can be found in almost every area of inflammation within the salivary glands but are seen in only 40-50% of inflamed islets. Anti-L-selectin and anti-integrin alpha 4 treatment had no demonstrable effect on anti-beta-cell autoimmunity or on the immune responses to foreign antigens. Therapeutic treatment with anti-L-selectin after the onset of insulitis from 10 to 14 weeks of age delayed the onset but failed to prevent spontaneous insulin-dependent diabetes mellitus, whereas anti-integrin alpha 4 treatment resulted in a significant and long-lasting suppression of the disease. These data strongly suggest that integrin alpha 4 plays a prominent role in the spontaneous development of insulitis and diabetes in nonobese diabetic mice.

Animals↗
PubMed1994

Prevention of graft-versus-host disease by peptides binding to class II major histocompatibility complex molecules.

Graft-versus-host disease across minor histocompatibility barriers was induced in two different models by transplanting allogeneic bone marrow and spleen cells into irradiated H-2-compatible recipient mice. In this report, we show that administration of peptides with high binding affinity for the respective class II major histocompatibility complex molecules after transplantation is capable of preventing the development of graft-versus-host disease in two different murine models. The peptides used were myelin basic protein residues 1 through 11 with alanine at position 4 (Ac 1-11[4A]) for I-Au (A alpha uA beta u), and the antigenic core sequence 323 through 339 of ovalbumin with lysine and methionine extension (KM core) for I-As (A alpha sA beta s). In both systems, the mechanism of prevention was found to be major histocompatibility complex-associated, because nonbinding control peptides did not have any effect. Engraftment of allogeneic bone marrow cells was shown by polymerase chain reaction analysis of DNA polymorphisms in a microsatellite region within the murine interleukin-5 gene.

Amino Acid Sequence↗