Biomedical subjects

Claire H Sweenie

Publications and source records attributed to Claire H Sweenie.

5 recordsLinked to original sources

PubMed2006

Distinct T cell recognition of naturally processed and cryptic epitopes within the immunodominant 35-55 region of myelin oligodendrocyte glycoprotein.

We have assessed the complexity in T cell recognition of the immunodominant 35-55 region of myelin oligodendrocyte glycoprotein (MOG) in C57BL/6 mice. Immunization with the p35-55 peptide generated two types of T cell, recognizing either a cryptic, or a naturally-processed epitope. Clear differences in the recognition of residues within a core sequence of 40-48 were observed. The majority of the p35-55-reactive repertoire in vivo appeared responsive to the intact autoantigen, supporting the notion of a failure of central tolerance to this region of MOG. Our data also provide a basis for exploring the requirements for antigen processing of MOG.

Amino Acid Sequence↗

PubMed2006

Persistence of autoreactive myelin oligodendrocyte glycoprotein (MOG)-specific T cell repertoires in MOG-expressing mice.

Experimental autoimmune encephalomyelitis, an experimental murine model for multiple sclerosis, is induced by stimulation of myelin-specific T lymphocytes. Myelin oligodendrocyte glycoprotein (MOG), a minor component of myelin proteins, is a potent autoantigen which contributes extensively to the anti-myelin response. In the present work, immunoscope analyses and sequencing of the oligoclonal expansions revealed anti-MOG Valpha and Vbeta public repertoires in lymphocytes infiltrating the CNS of wild-type (WT) mice. Moreover, a subset of CNS-infiltrating CD4+ T lymphocytes bearing the public Vbeta8.2 segment have an inflammatory phenotype strongly suggesting that it is encephalitogenic. We then observed that, in lymph node cells of MOG-deficient and WT animals, the Valpha and Vbeta public repertoires expressed by MOG-specific T cells are identical in both strains of mice and correspond to those found in the CNS of WT animals. These findings indicate that the MOG immunodominant determinant is unable to induce tolerance by deletion, and public anti-MOG T cell repertoires are selected for, regardless of the presence of MOG in the thymus and peripheral organs.

Animals↗

PubMed2006

Circumventing tolerance at the T cell or the antigen-presenting cell surface: antibodies that ligate CD40 and OX40 have different effects.

An adjuvant can be defined as an agent that non-specifically promotes the immune response to an accompanying antigen. Ligation of CD40 on the surface of the antigen-presenting cell leads to upregulation of OX40 ligand which, in turn, ligates OX40 on the activated T cell resulting in prolonged T cell proliferation/survival, boosting the immune response. Thus agonistic anti-CD40 and anti-OX40 might be viewed as "adjuvant antibodies" and have been shown in diverse experimental systems to either boost immune responses or prevent the establishment of immunological tolerance. Here we describe that both these antibodies are able to prevent the induction of tolerance induced using soluble peptide antigen. However, unlike lipopolysaccharide, they are not sufficient to convert tolerance to immunity (i.e. they are not true adjuvants in this system). Using mice that are prone to either Th1 or Th2 immunity under identical immunization conditions, we show that the effects of anti-OX40 are quantitative -- boosting whichever response is dominant. In contrast, anti-CD40 boosts Th1 immunity and converts a Th2 response to Th1. We conclude that, although these two antibodies seem to impact on the same molecular pathway of costimulation to prevent tolerance, their effects are qualitatively distinct and their use cannot be viewed as interchangeable.

Adjuvants, Immunologic↗

PubMed2006

Immunological tolerance using synthetic peptides--basic mechanisms and clinical application.

Dysregulation of T lymphocyte function underpins the development of autoimmune and allergic diseases. These autoantigen-, or allergen-reactive pathogenic T cells are rare within the entire immune repertoire and it is therefore desirable to develop more specific therapies than are currently in use to directly target these cells and avoid adverse side effects. The obvious approach is to use the antigens that are recognized to impose a state of T cell tolerance. T cells recognize antigens as peptide fragments and we can therefore produce the relevant antigens as synthetic peptides. It has been known for many years that the decision of the T cell to mount a productive response (immunity) or to remain silent (tolerance) is controlled by the form in which the antigen is administered. Antigen with adjuvant leads to immunity, whereas soluble antigen without adjuvant leads to tolerance. This paradigm has been used successfully to induce tolerance with soluble peptides, preventing several animal models of autoimmune and allergic disease. These findings obviously have exciting potential for translation to human diseases. However, the basic immune mechanisms that lead to tolerance versus immunity are only beginning to be unravelled. The "effector" phase of tolerance also remains controversial with evidence for T cell death, anergy and the development of immunoregulatory function. This latter possibility of specifically generating autoantigen- or allergen-reactive regulatory T cells is particularly attractive. Here we review recent advances in our understanding of the requirements for tolerance induction and the potential for establishing dominant immune-regulation with peptide therapy.

Animals↗

PubMed2002

B cells regulate autoimmunity by provision of IL-10.

To assess the importance of B cell control of T cell differentiation, we analyzed the course of the T helper type 1 (T(H)1)-driven disease experimental autoimmune encephalomyelitis in mice with an altered B cell compartment. We found that recovery was dependent on the presence of autoantigen-reactive B cells. B cells from recovered mice produced interleukin 10 (IL-10) in response to autoantigen. With a bone marrow chimeric system, we generated mice in which IL-10 deficiency was restricted to B cells but not T cells. In the absence of IL-10 production by B cells, the pro-inflammatory type 1 immune response persisted and mice did not recover. These data show that B cell-derived IL-10 plays a key role in controlling autoimmunity.

Animals↗