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D C Wraith

Publications and source records attributed to D C Wraith.

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

Prolongation of murine vascularized heart allograft survival by recipient-specific anti-major histocompatibility complex class II antibody.

BACKGROUND: Antibodies targeting recipient major histocompatibility complex (MHC) class II molecules have been demonstrated to be effective at prolonging allograft survival. However, antigen-presenting cell depletion would explain this effect and has not been definitively excluded as the mechanism of action of such antibodies. We have studied an anti-MHC class II antibody (OX6) proven to be noncytotoxic in the recipient strain used. METHODS: Antibody was administered the day before, 2 hr before, and the day after grafting. RESULTS: Antibody administration on the day before, 2 hr before, and the day after grafting significantly prolonged vascularized cardiac allograft survival. Importantly, treatment recognizing recipient MHC was effective, whereas a similar regimen recognizing donor MHC was not. CONCLUSIONS: Noncytotoxic recipient MHC class II-specific antibodies modify allograft rejection. Possible mechanisms for this therapeutic effect are discussed.

Animals↗
PubMed1996

Encephalitogenic epitopes of myelin basic protein, proteolipid protein, myelin oligodendrocyte glycoprotein for experimental allergic encephalomyelitis induction in Biozzi ABH (H-2Ag7) mice share an amino acid motif.

Myelin basic protein (MBP) and synthetic MBP peptides were screened for their ability to induce experimental allergic encephalomyelitis in Biozzi ABH (H-2Ag7) mice. In contrast to the failure of native MBP to induce experimental allergic encephalomyelitis, the use of overlapping MBP peptides revealed epitopes within MBP 12-26 and MBP 21-35, which induced mild disease. In comparison with disease induced by spinal cord homogenate or peptides of myelin oligodendrocyte glycoprotein (MOG) or proteolipid protein (PLP), the low incidence indicates that, at least in ABH mice, MBP is a minor encephalitogen. However, the data suggest the presence of a peptide core between MBP 21-26 (HARHGF), which contains similar elements to the previously defined encephalitogenic MOG 1-22 and PLP 56-70 peptides. The fine specificity of these epitopes was further investigated using frame-shifted peptides, which indicated cores between MOG 9-15 (GYPIRAL) and PLP 62-68 (NVIHAFQ). Based on these pathogenic peptides, a putative H-2Ag7 binding motif is suggested that contains a series of hydrophobic, basic, small, and large hydrophobic residues within a 6 to 7 amino acid core. The core and particular importance of these four residues in PLP 56-70 was confirmed in vitro using amino acid substitution studies. These findings support many of the predictions made by computer modeling of peptide:H-2Ag7 interactions. This may have relevance in the design of strategies in the treatment of experimental autoimmune diseases in animals that express this haplotype.

Amino Acid Sequence↗
PubMed1996

Mucosal tolerance in a murine model of experimental autoimmune encephalomyelitis.

Attempts to induce oral tolerance in a murine model of EAE with either the dominant T-cell epitope or whole protein have failed. These results may, in part, be due to the extraordinarily low affinity for class II MHC displayed by the dominant T-cell epitope. This belief is supported by experiments using a high-affinity analogue of the peptide that was capable of inducing tolerance at a high dose. By contrast, peptide inhalation has proven an effective route for induction of mucosal tolerance in this model. Most importantly, the inhalation of a single peptide could inhibit disease induced by the complex mixture of antigens found in whole myelin. Peptide inhalation was effective both before and after disease induction, and there was a positive correlation between affinity of class II binding and tolerogenicity of a panel of analogues of the N-terminal peptide of myelin basic protein.

Administration, Inhalation↗
PubMed1996

Treatment of experimental encephalomyelitis with a peptide analogue of myelin basic protein.

Following induction of experimental encephalomyelitis with a T-cell clone, L10C1, that is specific for the myelin basic protein epitope p87-99, the inflammatory infiltrate in the central nervous system contains a diverse collection of T cells with heterogeneous receptors. We show here that when clone L10C1 is tolerized in vivo with an analogue of p87-99, established paralysis is reversed, inflammatory infiltrates regress, and the heterogeneous T-cell infiltrate disappears from the brain, with only the T-cell clones that incited disease remaining in the original lesions. We found that antibody raised against interleukin-4 reversed the tolerance induced by the altered peptide ligand. Treatment with this altered peptide ligand selectively silences pathogenic T cells and actively signals for the efflux of other T cells recruited to the site of disease as a result of the production of interleukin-4 and the reduction of tumour-necrosis factor-alpha in the lesion.

Amino Acid Sequence↗
PubMed1996

Lowering the tone: mechanisms of immunodominance among epitopes with low affinity for MHC.

Past studies of immunodominance among T-cell epitopes have focused on peptides with high affinity for their restriction element, assuming epitopes of low affinity to be immunologically irrelevant. Here, Paul Fairchild and David Wraith challenge this assumption by reviewing evidence that such peptides may contribute to T-cell repertoire selection and autoimmune disease, and suggest approaches to immunotherapy based on exploitation of these peptides.

Animals↗
PubMed1996

The nature of cryptic epitopes within the self-antigen myelin basic protein.

Mechanisms that allow potentially autoreactive T cells to escape central tolerance and persist in the peripheral lymphoid organs of healthy individuals are poorly defined. It has been proposed that such cells are specific for epitopes which normally are not well presented to the immune system or, in other words, are cryptic. We have used synthetic peptides to define potential T cell epitopes within the N-terminal portion of myelin basic protein (MBP). These were defined in terms of their relative affinity for the MHC-restriction element I-Au and their ability to activate T cells in mice of the H-2(u) haplotype. Three epitopes were identified, one of which corresponded to the known dominant N-terminal epitope (Ac1-9). The other two epitopes (9-20 and 5-20) bound to their MHC-restriction element with relatively high affinity but were cryptic, as defined by the poor response to these epitopes following immunization with intact MBP. Even the longer of these two epitopes did not induce autoimmune encephalomyelitis in H-2(u) mice. These results demonstrate that antigen processing can control both the induction of and effector function of autoreactive T cells, and is therefore a principal mechanism involved in limiting the autoreactive T cell repertoire.

Amino Acid Sequence↗
PubMed1995

Low avidity recognition of self-antigen by T cells permits escape from central tolerance.

The immunodominant epitope of myelin basic protein, Ac1-9, is encephalitogenic in H-2u mice. We have previously demonstrated that this epitope displays low affinity for I-Au and have suggested that the avidity of T cell recognition in the thymus may be compromised, enabling autoreactive T cells to escape self-tolerance. We have addressed this hypothesis directly by constructing transgenic mice expressing an encephalitogenic T cell receptor (TCR). Parenteral administration of Ac1-9 had no discernable impact on developing thymocytes. In contrast, peptide analogs displaying far higher affinity for I-Au, provoked deletion of CD4+ CD8+ cells and transient down-regulation of the TCR by mature CD4+ CD8- thymocytes. The use of analogs of intermediate affinity permitted a margin of error to be defined for the induction of tolerance and confirmed that the affinity of Ac1-9 lies well below the critical threshold.

Animals↗
PubMed1995

Affinity for class II MHC determines the extent to which soluble peptides tolerize autoreactive T cells in naive and primed adult mice--implications for autoimmunity.

The N-terminal peptide (Ac1-9) of myelin basic protein (MBP) is the immunodominant encephalitogenic epitope in H-2u mice. Previous studies have defined the role of amino acid residue 4 in binding to I-Au. Accordingly, substitutions at this residue have generated peptides spanning a wide range of affinities for the MHC. In the present study, we have tested the tolerogenicity of three of these peptides. Ac1-9, Ac1-9[4A] and Ac1-9[4Y], by administering these to mice i.p. in the absence of adjuvant. Significantly, mice treated with the high affinity analogues Ac1-9[4A] and Ac1-9[4Y] prior to immunization became less susceptible to Ac1-9-induced experimental autoimmune encephalomyelitis (EAE), whereas those given the low affinity peptide Ac1-9 were only moderately protected. T cell priming, as assessed by in vitro proliferative and lymphokine assays, demonstrated a direct correlation between the level of disease inhibition and T cell unresponsiveness. In treatment studies, Ac1-9 and Ac1-9[4Y] were also shown to be effective when given on the first day of disease onset. Priming of T cells, when measured by proliferation in vitro, however, became more resistant to inactivation when soluble peptides were administered close to the day of assay. Kinetic studies revealed that tolerance could be achieved in primed mice but that this takes time to develop.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1995

Induction of antigen-specific unresponsiveness with synthetic peptides: specific immunotherapy for treatment of allergic and autoimmune conditions.

Current drug-based therapies for autoimmune and allergic conditions are non-specific and often associated with severe side effects. Recent advances in our knowledge of how T cells see antigens points to an improved strategy. T lymphocytes recognise processed forms of antigen which can be mimicked by synthetic peptides designed and built in the laboratory. It is clear from recent work that these synthetic peptides, when given systemically in solution, induce a state of hyporesponsiveness in naive T cells thereby specifically preventing a subsequent immune response. Moreover systemic administration of soluble peptides can inhibit ongoing immune responses. Taken together this new information offers great promise for future development of antigen-based drugs for the treatment of autoimmune and allergic diseases.

Adult↗
PubMed1994

Anti-class II MHC antibodies prevent and treat EAE without APC depletion.

We have demonstrated that a murine IgG1 anti-class II major histocompatibility complex (MHC) antibody (OX6) is able both to prevent and treat experimental autoimmune encephalomyelitis (EAE) in the Biozzi AB/H mouse. We have confirmed that this antibody is poorly cytotoxic, allowing mechanisms of action other than depletion of antigen-presenting cells (APC) to be assessed. Despite its effect on disease, OX6 administration does not prevent priming of T cells in the draining lymph node, implying an alternative mechanism for regulation of the autoimmune disease process.

Acute Disease↗
PubMed1993

Inhibition of T cell and antibody responses to house dust mite allergen by inhalation of the dominant T cell epitope in naive and sensitized mice.

Antigen-specific CD4+ T cells play an important role in the allergic immune response to house dust mite (HDM) allergens in humans. The group 1 allergen of Dermatophagoides spp. is a major target antigen in both B and T cell recognition of HDM. In vitro studies have shown that the presentation of peptides to human T cells under appropriate conditions may lead to a state of specific nonresponsiveness. Therefore, to determine if peptides are able to modulate the function of allergen-reactive T cells in vivo, we have used a murine model of T cell recognition of the HDM allergen Der p 1. The results demonstrate that inhalation of low concentrations of peptide containing the major T cell epitope of Der p 1 (residues 111-139), induces tolerance in naive C57BL/6J mice such that they become profoundly unresponsive to an immunogenic challenge with the intact allergen. When restimulated in vitro with antigen, lymph node T cells isolated from tolerant mice secrete very low levels of interleukin 2, proliferative poorly, and are unable to provide cognate help to stimulate specific antibody production. Furthermore, intranasal peptide therapy was able to inhibit an ongoing immune response to the allergen in mice and this has potential implications in the development of allergen-based immunotherapy.

Administration, Inhalation↗