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C A Janeway

Publications and source records attributed to C A Janeway.

At least 55 records · Page 3Linked to original sources
PubMed1999

Insulin-dependent diabetes mellitus and its animal models.

Major questions are still unanswered in the understanding of the pathogenesis of type 1 diabetes, including the important question of the nature of the autoantigen(s) recognised in the development of disease. In the nonobese diabetic mouse model, there is new evidence that insulin plays an important role: not only is it an antigen for pathogenic CD4+ T cells but also it is recognised by highly diabetogenic CD8+ T cells. Further studies using transgenic mice have also highlighted the role of glutamic acid decarboxylase as an autoantigen. It remains to be seen whether one or both of these autoantigens can be used in strategies to prevent human diabetes.

Animals↗
PubMed1999

Innate immunity.

Explore the source record for details and available documents.

Animals↗
PubMed1999

Designing and maintaining the mature TCR repertoire: the continuum of self-peptide:self-MHC complex recognition.

Peripheral T cell maintenance requires a survival signal delivered upon T cell receptor (TCR)-major histocompatibility complex (MHC) molecule interaction. Since self-peptides play a critical role in the intrathymic positive selection of the mature TCR repertoire, we hypothesized an equally important role in T cell persistence. We used mice with a normal expression of MHC class II molecules but a restricted self-peptide complexity (H-2M alpha-/-) to show that an MHC class II-restricted T cell specificity that displays a deficient positive selection in the H-2M alpha-/- thymus shows an impaired persistence after adoptive transfer in H-2M alpha-/- recipients. Finally, a wild-type CD4+ TCR repertoire is incompletely maintained in H-2M alpha-/- recipients. These observations suggest that, similar to intrathymic positive selection, the maintenance of the mature TCR repertoire relies on the recognition of self-peptide:self-MHC complexes.

Adoptive Transfer↗
PubMed1999

Cross-antagonism of a T cell clone expressing two distinct T cell receptors.

Inhibition of T cell activation can be mediated by analogs of the original antigenic peptide (TCR antagonists). Here, a T cell clone expressing two distinct TCR was used to investigate whether such inhibition involves an active mechanism by examining whether an antagonist for one TCR could influence responses stimulated by the other TCR engaging its agonist. Our results demonstrate functional cross-inhibition under these conditions involving the ability of antagonist: TCR interactions to diminish Lck enzymatic activity associated with the agonist-recognizing second TCR, apparently through enhancement of SHP-1 association with these receptors. Our findings reveal that inhibition of cellular responses by antagonists arises at least in part from active negative regulation of proximal TCR signaling and identify elements of the biochemical process.

Animals↗
PubMed1999

Identification of an MHC class I-restricted autoantigen in type 1 diabetes by screening an organ-specific cDNA library.

Type 1 diabetes is an autoimmune disease in which the insulin-producing pancreatic beta cells are destroyed at an early age by an immune process that involves both CD4 and CD8 T lymphocytes. The identification of autoantigens in diabetes is very important for the design of antigen-specific immunotherapy. By screening a pancreatic islet cDNA library, we have identified the autoantigen recognized by highly pathogenic CD8 T cells in the non-obese diabetic mouse, one of the best animal models for human diabetes. This is the first identification, to our knowledge, of a CD8 T-cell epitope in an autoimmune disease. The peptide recognized by the cells is in the same region of the insulin B chain as the epitope recognized by previously isolated pathogenic CD4 T cells. This has very important implications for the potential use of insulin in preventative therapy.

Amino Acid Sequence↗
PubMed1999

The discovery of T cell help for B cell antibody formation: a perspective from the 30th anniversary of this discovery.

Thirty years ago, Miller and Mitchell described the bone-marrow origin of antibody-forming cells and the thymic origin of the help needed to activate the bone-marrow-derived antibody formation. Since then, there has been a continuous stream of discovery in Australia, from Zinkernagel and Doherty's description of MHC-restricted antigen recognition to Goodnow's dissection of the maturation and tolerization of antigen-specific B cells. All of these discoveries, and many more described in the text, contribute to the modern synthesis in immunology.

Allergy and Immunology↗
PubMed1999

Transgenes and knockout mutations in animal models of type 1 diabetes and multiple sclerosis.

In this article, we will examine the roles of transgenic and knockout animals that aid us in understanding two autoimmune diseases-type 1 (insulin-dependent) diabetes and multiple sclerosis. The first sections will focus on studies in type 1 diabetes to show how genetically altered animals have given insight into the role of various immune cell types, autoantigens, co-stimulatory molecules, cytokines and, finally, the role of various effector pathways in the pathogenesis of diabetes. The second section concentrating on the animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), will show how animals that express a T-cell receptor derived from a clone able to cause disease have given insight into the pathogenesis of EAE.

Animals↗
PubMed1999

MHC and T cell development.

The ability to discriminate self from non-self is a fundamental property of the immune system. In the case of T lymphocytes, the first level of this discrimination takes place in the thymus, where most lymphocytes carrying an alphabeta T cell receptor (TCR) become tolerant to self-epitopes represented within the thymic microenvironment and differentiate into CD4+ or CD8+ single positive thymocytes. In the periphery, these subsets correspond respectively to helper and cytolytic lymphocytes able to react to non-self antigens presented in the context of MHC class II and I molecules. Apart from an early phase, the development of alphabeta T cells is based on a TCR-MHC interaction which is allele-specific and, depending on its nature, leads to either protection from apoptosis and maturation (positive selection) or physical elimination of thymocytes (negative selection). Thus, these positive and negative selection processes concomitantly allow the rescue of the useful fraction and the elimination of the potentially harmful fraction of the TCR repertoire. Recent advances have provided important elements for the comprehension of the development of alphabeta T cells. In accordance with previous in vitro studies related to differentiation of CD8+ thymocytes, in vivo derived data have established that the positive selection of CD4+ thymocytes is a peptide-specific process: it is based on the intrathymic TCR recognition of self-peptide:self-MHC molecular complexes. Despite this fact, it is now clear that the TCR reactivity to non-self MHC molecules or alloreactivity--a major characteristic of the mature TCR repertoire--does not result from intrathymic T cell selection, but rather is an intrinsic property of germline-encoded TCR domains. Finally, a significant number of experiments indicate that, in secondary lymphoid organs, a repeated TCR-MHC low affinity interaction is required to maintain the mature peripheral T cell pool and therefore the mature TCR repertoire. Such a TCR-MHC interaction-induced protection from apoptosis is remarkably reminiscent of the intrathymic positive selection phenomenon. Thus, the role of self-MHC recognition in TCR repertoire development and survival may account for the influence of MHC genotype on susceptibility to specific autoimmune diseases.

Animals↗
PubMed1998

Subtle conformational changes induced in major histocompatibility complex class II molecules by binding peptides.

Intracellular trafficking of major histocompatibility complex (MHC) class II molecules is characterized by passage through specialized endocytic compartment(s) where antigenic peptides replace invariant chain fragments in the presence of the DM protein. These changes are accompanied by structural transitions of the MHC molecules that can be visualized by formation of compact SDS-resistant dimers, by changes in binding of mAbs, and by changes in T cell responses. We have observed that a mAb (25-9-17) that is capable of staining I-Ab on the surface of normal B cells failed to interact with I-Ab complexes with a peptide derived from the Ealpha chain of the I-E molecule but bound a similar covalent complex of I-Ab with the class II binding fragment (class II-associated invariant chain peptides) of the invariant chain. Moreover, 25-9-17 blocked activation of several I-Ab-reactive T cell hybridomas but failed to block others, suggesting that numerous I-Ab-peptide complexes acquire the 25-9-17(+) or 25-9-17(-) conformation. Alloreactive T cells were also able to discriminate peptide-dependent variants of MHC class II molecules. Thus, peptides impose subtle structural transitions upon MHC class II molecules that affect T cell recognition and may thus be critical for T cell selection and autiommunity.

Amino Acid Sequence↗
PubMed1998

The role of lymphocyte subsets in accelerated diabetes in nonobese diabetic-rat insulin promoter-B7-1 (NOD-RIP-B7-1) mice.

B7-1 transgene expression on the pancreatic islets in nonobese diabetic (NOD) mice leads to accelerated diabetes, with >50% of animals developing diabetes before 12 wk of age. The expression of B7-1 directly on the pancreatic beta cells, which do not normally express costimulator molecules, converts the cells into effective antigen-presenting cells leading to an intensified autoimmune attack. The pancreatic islet infiltrate in diabetic mice consists of CD8 T cells, CD4 T cells, and B cells, similar to diabetic nontransgenic NOD mice. To elucidate the relative importance of each of the subsets of cells, the NOD-rat insulin promoter (RIP)-B7-1 animals were crossed with NOD.beta2microglobulin -/- mice which lack major histocompatibility complex class I molecules and are deficient in peripheral CD8 T cells, NOD.CD4 -/- mice which lack T cells expressing CD4, and NOD.muMT -/- mice which lack B220-positive B cells. These experiments showed that both CD4 and CD8 T cells were necessary for the accelerated onset of diabetes, but that B cells, which are needed for diabetes to occur in normal NOD mice, are not required. It is possible that B lymphocytes play an important role in the provision of costimulation in NOD mice which is unnecessary in the NOD-RIP-B7-1 transgenic mice.

Adoptive Transfer↗
PubMed1998

Innate immune recognition and control of adaptive immune responses.

The immune system of higher vertebrates consists of two components: innate and adaptive. The innate immune system relies on a set of germ-line encoded receptors that recognize conserved molecular patterns found only in microorganisms. The adaptive immune system uses somatically generated antigen receptors which are clonally distributed on the two types of lymphocytes: T cells and B cells. These antigen receptors are generated by random processes and, as a consequence, the general design of the adaptive immune system is based on clonal selection of lymphocytes expressing receptors with particular specificities. Here we discuss the essential role of the innate immune system in the clonal selection of lymphocytes and activation of the adaptive immune responses.

Animals↗
PubMed1998

An ancient system of host defense.

Research over the past few years has begun to provide significant advances in our understanding of the interplay between the innate and adaptive immune systems. New findings in several model systems reveal remarkable parallels and conservation of ancient host defense pathways in organisms separated by over a billion years of evolution.

Animals↗