Search PubMed⌕ Search

Biomedical subjects

P M Allen

Publications and source records attributed to P M Allen.

At least 73 records · Page 4Linked to original sources
PubMed1995

Specific T cell recognition of minimally homologous peptides: evidence for multiple endogenous ligands.

The T cell receptor (TCR) can interact with a spectrum of peptides as part of its ligand, including the immunogenic peptide, variants of this peptide,and apparently unrelated peptides. The basis of this broad specificity for ligand was investigated by substitution analysis of a peptide antigen and functional testing using a B cell apoptosis assay. A peptide containing as few as 1 aa in common with this peptide could stimulate a specific T cell response. Two endogenous ligands, an agonist and a partial agonist, were readily identified from a search of the SwissProt database, indicating that multiple endogenous ligands likely exist for a given T cell. These findings strongly support the concept that one TCR has the ability to interact productively with multiple different ligands, and provide evidence that such ligands exist in the endogenous peptide repertoire.

Amino Acid Sequence↗
PubMed1994

Partial T cell signaling: altered phospho-zeta and lack of zap70 recruitment in APL-induced T cell anergy.

Studies of T cell responses to altered peptide ligands (APLs) have provided functional evidence that a T cell receptor (TCR) can interpret subtle changes in its ligand, resulting in different phenotypic outcomes. One dramatic effect of APL stimulation with live antigen-presenting cells (APCs) is the induction of energy as opposed to proliferation. We investigated the intracellular signaling events involved in generating this unresponsiveness by comparing protein-tyrosine phosphorylation patterns after stimulation with anergy-inducing APL or the immunogenic peptide. In resting T cell clones, presentation with APL/live APC stimulated a unique pattern of TCR phospho-zeta species and a subsequent lack of association with zap70. This demonstrates that the TCR-CD3 complex can engage selective intracellular biochemical signaling pathways as a direct consequence of the nature of the ligand recognized and the initial phosphotyrosine pattern of the TCR-CD3 proteins, leading to different phenotypes.

Amino Acid Sequence↗
PubMed1994

Th2 cell clonal anergy as a consequence of partial activation.

We have demonstrated Th2 clonal anergy as a consequence of partial T cell activation by immunogenic peptide and chemically fixed APC, as well as by altered peptide ligand and live antigen-presenting cells (APC). Either stimulation resulted in a profound inability of the T cells to proliferate upon restimulation with antigen and functional APC, a similar phenomenon to that found with Th1 cells. The anergic state was long lasting and was restricted to proliferation, since the T cells retained the ability to produce cytokines upon restimulation, albeit at slightly reduced levels. Th2 anergy induction was inhibited by cyclosporine A, but not by provision of exogenous costimulation or growth factors. The data presented unify Th1 and Th2 cells with regard to anergy and suggest that the fundamental control during anergy for both subsets is prevention of clonal expansion, thus blocking amplification of the immune response.

Amino Acid Sequence↗
PubMed1994

Promethean viruses?

Explore the source record for details and available documents.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Antagonism of superantigen-stimulated helper T-cell clones and hybridomas by altered peptide ligand.

T-cell activation by an immunogenic peptide can be antagonized by nonstimulatory analogs of that peptide. We investigated this T-cell receptor antagonism by using staphylococcal enterotoxin superantigen to stimulate hemoglobin-specific helper T (Th) cells because its activation pathway may differ from that of conventional antigen. Interestingly, superantigen activation of these Th cells was antagonized by hemoglobin peptide analogs even though agonist (superantigen) and antagonist (analog peptide) bind at different sites on the major histocompatibility complex-encoded molecule and the T-cell receptor. The antagonism appeared to be a fundamental block in T-cell activation, as phosphoinositol generation, cytokine production, and proliferation were reduced in Th1 clones, and, similarly, proliferative and cytokine responses were inhibited in Th2 cells. Even T-cell hybridoma activation (cytokine production and apoptosis) was inhibited by peptide antagonists. Furthermore, analog peptides that functioned as partial agonists for these Th cells also antagonized superantigen-induced proliferation and thus were a subset of the peptide antagonists. In summary, our results demonstrate that analogs of immunogenic peptide are potent antagonists for Th cell responses induced by superantigen as well as immunogenic peptide.

Amino Acid Sequence↗
PubMed1994

Regulation of the costimulator B7, not class II major histocompatibility complex, restricts the ability of murine kidney tubule cells to stimulate CD4+ T cells.

The proximal segment of murine kidney tubule cells (KTC) constitutively expresses low levels of class II major histocompatibility complex (MHC) that are upregulated during local and systemic inflammation. It is not known if KTC also express the costimulator molecules necessary for them to productively participate in immune responses and stimulate T cells. To answer this question, we studied the ability of KTC to present antigens to four Th1 clones. KTC did not induce T cell proliferation to specific antigen, superantigen, or concanavalin A. However, T cell receptors did engage the peptide/MHC ligand presented by KTC, as indicated by T cell enlargement and upregulation of interleukin-2 receptor expression. Importantly, KTC failed to express the Th1 costimulator, B7, as detected by fluorescence cytometry and reverse transcription polymerase chain reaction. We directly demonstrated that lack of B7 expression accounted for at least part of the KTC presentation defect, in that a KTC line transfected with the cDNA for B7 stimulated T cell proliferation to antigen. Our results suggest that epithelial cells expressing class II MHC have developed mechanisms to prevent costimulator expression and limit parenchymal tissue destruction. Failure of class II-expressing epithelial cells to limit costimulator expression may be an important component of organ-specific autoimmunity.

Animals↗
PubMed1993

Hen egg-white lysozyme-specific T cells elicited in hen egg-white lysozyme-transgenic mice retain an imprint of self-tolerance.

The characteristics of T cell self-tolerance were examined in hen egg-white lysozyme (HEL)-transgenic (Tg) mice that were tolerant to a dose of HEL that was immunogenic in non-Tg littermates. HEL-specific T cells were identified in the periphery of the Tg mice after immunization with 100-times more HEL than was required to achieve a response in normal littermates. The Tg T cells were functional in vivo as they were capable of providing help to generate a HEL-specific antibody response. Selective deletion of T cells specific for the dominant T cell determinant of the native protein was not the primary mechanism of T cell tolerance in the HEL-Tg mice because, similar to non-Tg littermates, the majority of lymph node (LN) and T cell clones from HEL-Tg mice were specific for the dominant T cell determinant of HEL. Rather, our findings support the idea that the HEL-reactive T cells were anergic in vivo, but could be partially activated with a strong stimulus to the immune system (i.e., 20 nmol HEL and CFA). This conclusion is based on three observations: 1) proliferation in vitro to HEL by Tg LN T cells was subnormal (25% of control) and required 2 log more Ag to proliferate when compared with proliferation of LN from non-Tg littermates; 2) T cell clones isolated from HEL-Tg mice also proliferated poorly upon stimulation with HEL and Con A, although lymphokine production from the same stimuli was similar to that obtained from non-Tg clones; 3) invariably, upon repeated antigenic stimulation in vitro, the Tg T cell clones acquired full proliferative capacity to Ag and mitogens.

Animals↗
PubMed1993

Induction of T-cell anergy by altered T-cell-receptor ligand on live antigen-presenting cells.

Activation of CD4+ T helper cells results from the occupancy of the T-cell receptor (TCR) by immunogenic peptide bound to a class II major histocompatibility complex (MHC) molecule, together with a co-stimulatory signal from the antigen-presenting cell (APC). This activation leads to proliferation, cytokine production (Th1 or Th2 profile) and cytolysis. Engagement of the TCR in the absence of co-stimulation causes Th1 cells to become unresponsive to subsequent antigenic stimulation. We have previously demonstrated that analogues of an immunogenic peptide could stimulate Th1 and Th2 cells to carry out some effector functions without inducing proliferation, a phenomenon we term partial activation. Here we study the consequences of such partial activation through the TCR of two Th1 clones using peptide analogues presented by a live APC. A peptide analogue that is unable to stimulate clonal proliferation or production of cytokine or inositol phosphate can induce the T cells to become profoundly unresponsive to subsequent stimulation with the immunogenic peptide. Thus, altering the ligand of the TCR by using a peptide analogue on a functional APC sends a signal to Th1 clones that results in anergy.

Antigen-Presenting Cells↗
PubMed1993

Separation of T helper 1 clone cytolysis from proliferation and lymphokine production using analog peptides.

In this report, we investigate the activation of Th1 clones using altered TCR ligand. By changing the immunogenic peptide, cytolytic function can be separated from proliferative and lymphokine responses. These three responses were examined and dissected in two Th1 clones using analogs of the murine hemoglobin [Hb(64-76)] peptide. This analysis was focused on amino acids in the immunogenic peptide that were possible T cell contact residues. Typically, several amino acids were identified as critical contact residues for a Th1 proliferative response. An examination of lymphokine production (IFN-gamma or IL-3) revealed the same pattern of response to the analog peptides indicating that the proliferative and lymphokine responses were directly related. However, for cytolysis, fewer amino acid residues were identified as critical contact residues for effector function. Thus, some altered peptide ligands allowed the disassociation of the cytolytic function from the proliferative and lymphokine responses in Th1 clones. To extend these findings, the activation of T cell hybridomas created from the Th1 clones were similarly examined using the altered TCR ligands. The lymphokine response (IL-2) of the T cell hybridomas identified the same critical amino acids as did the cytolytic response of the Th1 clones. Thus, analog peptides partially activated the Th1 clones such that cytolysis occurred independent from proliferative and lymphokine responses.

Amino Acid Sequence↗
PubMed1993

Tickling the TCR: selective T-cell functions stimulated by altered peptide ligands.

Recent observations of T-cell responses following T-cell receptor (TCR) interaction with altered peptide ligands have highlighted the complexity of this signalling system. The indications are that the TCR responds to minor changes in ligand with gradations of T-cell activation and effector functions. Brian Evavold, Joanne Sloan-Lancaster and Paul Allen review these studies and present a model in which partial T-cell activation and TCR antagonism are related events in a continuum of signalling through the TCR.

Amino Acid Sequence↗
PubMed1993

Critical components of obstetric management of chemically dependent women.

Providing prenatal care to chemically dependent women presents multiple dilemmas and challenges to clinicians. It is a complex task and one that is incongruent with the usual perceptions of the obstetric experience. However, it must be viewed as an opportunity to bring these alienated women into the health care system. Pregnancy represents a period in most women's lives when they recognize the need for and are receptive to caring and responsive intervention. By optimizing the prenatal experience of chemically dependent women, maternal-fetal outcomes will be improved and the groundwork laid for the ongoing therapeutic services that are needed to maintain the health and well-being of the mother and child.

Adolescent↗
PubMed1993

Tolerance to self and the processing and presentation of self antigens.

Antigen processing and presentation is critical to the generation and maintenance of self tolerance. The hemoglobin system has provided important data on self antigen processing and presentation in vivo. Hemoglobin/Ia complexes were detectable in the thymus before the time of positive and negative selection. In addition, thymic epithelial cells were shown to lack the costimulatory factors necessary to trigger T cell clone proliferation. We have extended these findings to the renal proximal tubule. This class II MHC-expressing epithelial cell was demonstrated to process and present foreign as well as self antigens to T cell hybridomas. Current studies are examining whether this epithelial cell possesses the costimulatory factors required to fully stimulate T cell clones, or whether the proximal tubule may play an important role in the maintenance of self tolerance. In addition we describe the exciting model of murine autoimmune myocarditis. We have demonstrated that this is a T cell mediated disease and believe that cardiac antigen presenting cells constitutively process and present the inciting self antigen, myosin. These studies may provide important insights into autoimmunity and self tolerance.

Animals↗
PubMed1992

Expression of myosin-class II major histocompatibility complexes in the normal myocardium occurs before induction of autoimmune myocarditis.

Determining how an autoimmune response is initiated is essential to understanding the mechanisms of autoimmunity. Self-reactive T cells, self-protein, and a failure of tolerance to that self-protein are all involved in the pathogenesis of autoimmune disease; yet it is not clear how self-reactive T cells find the target self-protein to initiate an autoimmune response. Although a variety of self-proteins have been shown to be presented on both class I and class II major histocompatibility complex (MHC) molecules, the relationship of these self-proteins to autoimmune disease has not been established. To explore this further, we generated a T-cell hybridoma that recognizes mouse cardiac myosin, the self-protein that induces murine autoimmune myocarditis. Using this hybridoma as a probe to detect myosin-class II MHC complexes, we isolated a class II MHC+/CD45+ residential antigen-presenting cell (APC) population directly from the hearts of normal mice and looked for evidence of endogenous processing of cardiac myosin by these APC. In this report we show that myosin-class II MHC complexes are found on residential APC in the normal mouse heart. Induction of autoimmune myocarditis increased the expression of myosin-class II MHC in the heart and enhanced their APC functions. This result is a direct demonstration that epitopes of a self-antigen involved in initiating an autoimmune disease are endogenously processed and presented within the target organ.

Animals↗