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At least 649 records · Page 36Linked to original sources
PubMed2000

Role of Qa-1(b)-binding receptors in the specificity of developing NK cells.

NK cells acquire the ability to recognize MHC class I molecules during development. Studies with Qa-1(b) tetramers (Qa-1 tetramers) showed that nearly all NK1.1(+) cells from newborn C57BL/6 mice express Qa-1-binding receptors. Cytotoxic activity of these cells is fully inhibited by Qa-1 ligands on target cells. In contrast, neither receptors for H-2K(b) nor H-2D(b) were observed on NK1.1(+) cells from newborn mice. After birth, frequencies of Qa-1 tetramer(+)/ NK1.1(+) cells gradually decrease as the number of Ly49(+) /NK1.1(+) cells increases. Cell transfer studies showed that Qa-1 tetramer(+) cells from newborn mice do not lose expression of Qa-1 receptors, but that they further acquire expression of Ly49 molecules. Acquisition of Qa-1-binding receptors appears largely independent of host MHC class I molecules, as observed in studies using beta2-microglobulin-deficient (beta2m(-/-)) mice as well as K(b)/ D(b-/-) and K(b)/D(b)/beta2m(-/-) mice. The present results suggest that Qa-1-binding receptors play an important role in the specificity of developing NK cells, and suggest that these cells rely mainly on inhibitory receptors specific for non-classical MHC class I molecules to maintain self tolerance during the first weeks of life.

Adoptive Transfer↗
PubMed2005

Do autoantigens define autoimmunity or vice versa?

The basic function of the adaptive immune system is to distinguish self from foreign. The failure of self tolerance can result in autoimmunity, which comes in many forms but still targets a limited selection of the total available autologous determinants. This selectivity must reflect the underlying mechanisms of the autoimmune reaction, as well as the particular features of the autoantigens that are targeted. Here I discuss the overall paradigm of autoimmunity, and what kinds of mechanisms might play a role. It is likely that multiple different pathways are critical in various diseases, and even in a single condition.

Autoantigens↗
PubMed2002

Autoimmune hepatitis after liver transplantation and other lessons of self-intolerance.

Autoimmune hepatitis has been described as recurrent or de novo disease after transplantation. The legitimacy of these diagnoses and the bases for their occurrence are unknown. To better understand these aspects of allograft dysfunction, the purported pathogenic mechanisms of classical autoimmune hepatitis were reviewed and extrapolated to recurrent and de novo disease after transplantation. Loss of self-tolerance may relate to defects in the negative selection of autoreactive immunocytes and the clonal expansion of promiscuous lymphocytes that are cross-reactive to homologous antigens (molecular mimicry). Repopulation of the allograft with recipient antigen-presenting cells and the presence of primed promiscuous cytotoxic T cells within the recipient are likely factors for recurrent disease. Targets may be the same peptides that triggered the original disease, donor-derived class II antigens of the major histocompatibility complex, or homologous antigens associated with unidentified hepatotrophic viruses. De novo disease is probably due to similar mechanisms, but its predilection for children suggests that thymic dysfunction associated with cyclosporine treatment may be a factor. Corticosteroid therapy is effective in each condition. In conclusion, recurrent and de novo autoimmune hepatitis after transplantation are examples of self-intolerance. The mechanisms that perturb immunologic homeostasis in this human model of the classical disease must be studied more rigorously.

Autoimmunity↗
PubMed2005

CD4+ regulatory cells as a potential immunotherapy.

CD4(+) regulatory T (T(R)) cells represent a unique lineage of thymically generated lymphocytes capable of powerfully suppressing immune responses. A large body of experimental data has now confirmed the key role played by these cells in the maintenance of self-tolerance. Increasingly, the importance of these cells is also being recognized in a host of other clinically relevant areas such as transplantation, tumour immunity, allergy and microbial immunity. Additionally, it is also possible to generate T(R) cells by using a variety of ex vivo experimental approaches. We will focus here on harnessing the suppressive abilities of both these families of regulatory cells and how this should give us access to a potent cell-based immunotherapy appropriate for clinical application.

Forkhead Transcription Factors↗
PubMed2004

Induction of autoantibody production but not autoimmune disease in HEL transgenic mice vaccinated with HEL in combination with CpG or control oligodeoxynucleotides.

CpG oligodeoxynucleotides (ODN) are synthetic DNA sequences that mimic bacterial DNA, and bind to the TLR9 receptor. The cells that express TLR9, B cells and dendritic cells, are stimulated by CpG ODN and induce innate and acquired immune responses. Because CpG ODN induce antigen-independent immune activation there has been much interest in the possibility that they may break self tolerance. To test this hypothesis we used a tolerance model with hen egg lysozyme (HEL)-transgenic (Tg) mice, anti-HEL Ig-Tg mice and double (Dbl)-Tg mice injected with CpG ODN alone or together with HEL self antigen. When cultured in vitro, tolerant B cells responded to CpG ODN in a similar way as the non-tolerant Ig-Tg B cells in terms of cell proliferation, NFkappaB activation and CD69 expression. Despite these potent in vitro stimulatory effects of CpG ODN alone, HEL-Tg mice injected with CpG ODN alone, or in combination with low dose antigen (4 microg HEL), surprisingly did not produce any detectable anti-HEL Ab. However, HEL-Tg or Dbl-Tg mice immunized with CpG ODN plus higher doses of self antigen showed strong antigen-specific humoral responses. Surprisingly, control non-CpG ODN also had partial activity for breaking tolerance and inducing autoantibody production when administered in combination with self antigen, though not when used alone. Despite the production of high titers of anti-HEL Ab in the immunized HEL-Tg mice, no evidence of autoimmune disease was detected. We conclude that immunization with CpG or control ODN in the presence of a high dose of exogenous self antigen, but not treatment with ODN alone, can break tolerance to self antigen without inducing autoimmune disease in this system.

Animals↗
PubMed2004

Mounting evidence for vitamin D as an environmental factor affecting autoimmune disease prevalence.

Low vitamin D status has been implicated in the etiology of autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, insulin-dependent diabetes mellitus, and inflammatory bowel disease. The optimal level of vitamin D intake required to support optimal immune function is not known but is likely to be at least that required for healthy bones. Experimentally, vitamin D deficiency results in the increased incidence of autoimmune disease. Mechanistically, the data point to a role for vitamin D in the development of self-tolerance. The vitamin D hormone (1,25-dihydroxy vitamin D(3)) regulates T helper cell (Th1) and dendritic cell function while inducing regulatory T-cell function. The net result is a decrease in the Th1-driven autoimmune response and decreased severity of symptoms. This review discusses the accumulating evidence pointing to a link between vitamin D and autoimmunity. Increased vitamin D intakes might decrease the incidence and severity of autoimmune diseases and the rate of bone fracture.

Animals↗
PubMed2005

T cell hyperactivity in lupus as a consequence of hyperstimulatory antigen-presenting cells.

Sle3 is an NZM2410-derived lupus susceptibility locus on murine chromosome 7. Congenic recombination has resulted in a novel mouse strain, B6.Sle3, associated with serum antinuclear autoantibodies (ANAs), T cell hyperactivity, and elevated CD4/CD8 ratios. An OVA-specific TCR transgene was used as a tool to demonstrate that Sle3 facilitated heightened T cell expansion in vitro, and in vivo, following antigen challenge. Indeed, continued T cell expansion was noted even in response to a tolerogenic signal. However, these phenotypes did not appear to be T cell intrinsic but were dictated by hyperstimulatory B6.Sle3 APCs. Importantly, B6.Sle3-derived DCs and macrophages appeared to be significantly more mature/activated, less apoptotic, and more proinflammatory and were better at costimulating T cells in vitro, compared with the B6 counterparts. Finally, the adoptive transfer of B6.Sle3-derived DCs into healthy B6 recipients elicited increased CD4/CD8 ratios and serum ANAs, 2 cardinal Sle3-associated phenotypes. We posit that their heightened expression of various costimulatory molecules, including CD80, CD106, I-A, and CD40, and their elevated production of various cytokines, including IL-12 and IL-1beta, may explain why Sle3-bearing DCs may be superior at breaching self tolerance. These studies provide mechanistic evidence indicating that intrinsic abnormalities in DCs and possibly other myeloid cells may dictate several of the phenotypes associated with systemic lupus, including ANA formation and T cell hyperactivity.

Adoptive Transfer↗
PubMed1995

A minimal model for T-cell vaccination.

We have developed a mathematical model for the regulation of the growth of autoreactive T cells (the T cells responsible for autoimmunity). The model is very simple in that it is based only on the fundamental properties of T cells. However, despite this simplicity, it can account for a variety of phenomena referred to as T-cell vaccination. The purpose of T-cell vaccination is to create resistance to autoimmunity. This can be achieved by injecting either a subpathogenic quantity of autoreactive T cells, or attenuated autoreactive cells, or cells that recognize the autoreactive cells. The results of our model are based on the assumption that the self antigens involved in T-cell vaccination are normally not expressed; thus the autoreactive T lymphocytes are neither activated nor negatively selected. Self tolerance, therefore, corresponds to a 'passive' state. T-cell vaccination induces a transition from this passive state of tolerance to an active state of tolerance. In this state the autoreactive cells are controlled by regulator cells which recognize the autoreactive cells. The model predicts a qualitative difference between vaccination with normal autoreactive cells and vaccination with attenuated autoreactive cells. Normal cells may give rise to a permanent switch to the vaccinated state; attenuated cells, however, can provide only transient protection, which is dose dependent. Preliminary experimental data confirm this prediction. Finally, we propose a speculative explanation for relapsing autoimmune disease.

Animals↗
PubMed2005

Targeting positive regulatory domain I-binding factor 1 and X box-binding protein 1 transcription factors by multiple myeloma-reactive CTL.

Growing evidence indicates that multiple myeloma (MM) and other malignancies are susceptible to CTL-based immune interventions. We studied whether transcription factors inherently involved in the terminal differentiation of mature B lymphocytes into malignant and nonmalignant plasma cells provide MM-associated CTL epitopes. HLA-A*0201 (A2.1) transgenic mice were used to identify A2.1-presented peptide Ag derived from the plasma cell-associated transcriptional regulators, positive regulatory domain I-binding factor 1 (PRDI-BF1) and X box-binding protein 1 (XBP-1). A2.1-restricted CTL specific for PRDI-BF1 and XBP-1 epitopes efficiently killed a variety of MM targets. PRDI-BF1- and XBP-1-reactive CTL were able to recognize primary MM cells from A2.1(+) patients. Consistent with the expression pattern of both transcription factors beyond malignant and nonmalignant plasma cells, PRDI-BF1- and XBP-1-specific CTL activity was not entirely limited to MM targets, but was also associated with lysis of certain other malignancies and, in defined instances, with low-to-intermediate level recognition of a few types of normal cells. Our results also indicate that the A2.1-restricted, PRDI-BF1- and XBP-1-specific human CD8(+) T cell repertoire is affected by partial self tolerance and may thus require the transfer of high-affinity TCR to break tolerance. We conclude that transcription factors governing terminal cellular differentiation may provide MM- and tumor-associated CTL epitopes.

Animals↗
PubMed2003

TRAIL, Bim, and thymic-negative selection.

Negative selection is a process whereby autoreactive lymphocytes are deleted through apoptosis. Negative selection is essential for self-tolerance and its breakdown may lead to the development of autoimmune diseases. Although the phenomenon of negative selection is well-recognized, its underlying molecular mechanisms are unclear. Recent studies using gene-knockout mice have provided new insights into the mechanisms of negative selection. In this review, we discuss the newly discovered roles of TRAIL and Bim in negative selection. Our main focus will be on T cells and T cell mediated autoimmune diseases.

Animals↗
PubMed2003

Cooperative effect between immunotherapy and antiangiogenic therapy leads to effective tumor rejection in tolerant Her-2/neu mice.

Immunotherapy is an attractive strategy for cancer treatment. However, self-tolerance is one of the major mechanisms that dampen immune responses against self-tumor antigens. We have demonstrated that Her-2/neu transgenic mice (neu mice) are tolerant to neu antigens and contain only a low avidity repertoire for neu. However, this repertoire has antitumor activity. Immunizations of neu mice are capable of activating the low-avidity T cells that, at best, retard the tumor growth. To increase the efficacy of the antitumor responses in neu mice, we hypothesized that immunotherapy in combination with antiangiogenic therapy would be a more efficient strategy for tumor eradication. The rationale for using this combination was that by decreasing the growth rate of the tumor with an antiangiogenic therapy, the low-avidity repertoire of neu mice stimulated by immunotherapeutic intervention would be more effective in destroying the slow growing tumor. To test this hypothesis, we stably expressed a soluble form of the Flt-1 vascular endothelial growth factor receptor (sFlt-1) on N202.1A cells, using a retrovirus vector. Expression of sFlt-1 on N202.1A (N202-Flt) cells significantly inhibited the tumor growth compared with N202.1A parental cells. In contrast to the application of immunotherapy alone or antiangiogenic therapy alone, which delayed the tumor growth, the combination of the two therapies provided complete inhibition of tumor growth in Her-2/neu mice. These results indicate that the use of tumor targeting with immunotherapy in simultaneous combination with antiangiogenic therapy provides a more efficient strategy for the treatment of solid tumors.

Animals↗
PubMed1985

Behaviorally active oxytocin fragments simultaneously attenuate heroin self-administration and tolerance in rats.

Maintenance of intravenous heroin self-administration and the degree of tolerance to the analgesic effect of self-injected heroin were simultaneously measured in heroin-tolerant rats. Subcutaneous injection of oxytocin (OXT-(1-9)) and of its behaviorally active fragments desglycinamide9-oxytocin (OXT-(1-8)) and [pGlu4,Cyt6]-oxytocin-(4-8) (OXT-(4-8)) decreased the amount of heroin self-injected. The C-terminal tripeptide of oxytocin (prolyl-leucyl-glycinamide, PLG, OXT-(7-9)) and desglycinamide9-[Arg]8-vasopressin (AVP-(1-8] were ineffective in this respect. In spite of the lower amount of self-injected heroin after pretreatment with oxytocin fragments, no differences in the antinociceptive effect of self-injected heroin, as assessed by the lick response using a hot plate device, were observed after pretreatment with placebo and oxytocin fragments. These findings suggest that oxytocin and some of its behaviorally active fragments attenuate heroin tolerance and that this effect may result in a diminished heroin intake in tolerant animals self-injecting heroin.

Analgesics↗
PubMed1996

Modulating autoimmune responses to GAD inhibits disease progression and prolongs islet graft survival in diabetes-prone mice.

In nonobese diabetic (NOD) mice, beta-cell reactive T-helper type 1 (Th1) responses develop spontaneously and gradually spread, creating a cascade of responses that ultimately destroys the beta-cells. The diversity of the autoreactive T-cell repertoire creates a major obstacle to the development of therapeutics. We show that even in the presence of established Th1 responses, it is possible to induce autoantigen-specific anti-inflammatory Th2 responses. Immune deviation of T-cell responses to the beta-cell autoantigen glutamate decarboxylase (GAD65), induced an active form of self-tolerance that was associated with an inhibition of disease progression in prediabetic mice and prolonged survival of syngeneic islet grafts in diabetic NOD mice. Thus, modulation of autoantigen-specific Th1/Th2 balances may provide a minimally invasive means of downregulating established pathogenic autoimmune responses.

Adoptive Transfer↗
PubMed2005

A peripheral circulating compartment of natural naive CD4 Tregs.

CD4CD25 Tregs play a central role in the maintenance of peripheral self tolerance by keeping autoreactive T cells in check. Whereas the thymic origin of CD4CD25 Tregs, as a distinct lineage, has been inferred, understanding of their developmental pathways has remained elusive. In both mice and humans, peripheral CD4CD25 Treg populations have been described as composed of antigen-experienced T cells that fail to significantly proliferate following TCR stimulation but suppress proliferation and effector functions of CD25 T cells. Here we show that analysis of CD25 expression in human circulating CD4 T lymphocytes with respect to their in vivo differentiation stages identifies a distinct subset of CD25CCR7CD62LCTLA-4FOXP3 cells contained in the CD45RA/RO naive fraction. The subset, which we have named natural naive Tregs (NnTregs), is prominent in young adults and decreases with age together with the total naive CD4 population. NnTregs are anergic following stimulation in the absence of IL-2 and exert ex vivo cell-cell contact-mediated suppressor functions. In addition, they proliferate in response to stimulation with autologous APCs, which indicates a high enrichment in T cells bearing self-reactive TCRs. The definition of this subset has important implications for the analysis of human naturally occurring Tregs and for their targeting in therapeutic immune interventions.

Adult↗
PubMed2002

A role for the src family kinase Fyn in NK cell activation and the formation of the repertoire of Ly49 receptors.

NK cell function is regulated by a dual receptor system, which integrates signals from triggering receptors and MHC class I-specific inhibitory receptors. We show here that the src family kinase Fyn is required for efficient, NK cell-mediated lysis of target cells, which lack both self-MHC class I molecules and ligands for NKG2D, an activating NK cell receptor. In contrast, NK cell inhibition by the MHC class I-specific receptor Ly49A was independent of Fyn, suggesting that Fyn is specifically required for NK cell activation via non-MHC receptor(s). Compared to wild type, significantly fewer Fyn-deficient NK cells expressed the inhibitory Ly49A receptor. The presence of a transgenic Ly49A receptor together with its H-2(d) ligand strongly reduced the usage of endogenous Ly49 receptors in Fyn-deficient mice. These data suggest a model in which the repertoire of inhibitory Ly49 receptors is formed under the influenced of Fyn-dependent NK cell activation as well as the respective MHC class I environment. NK cells may acquire Ly49 receptors until they generate sufficient inhibitory signals to balance their activation levels. Such a process would ensure the induction of NK cell self-tolerance.

Animals↗
PubMed2005

License to heal: bidirectional interaction of antigen-specific regulatory T cells and tolerogenic APC.

Naturally occurring CD4(+)CD25(+) regulatory T (T(R)) cells, a component of the innate immune response, which play a key role in the maintenance of self-tolerance, have become the focus of numerous studies over the last decade. These cells inhibit the immune response in an Ag-nonspecific manner, interacting with other T cells. Much less is known about adaptive T(R) cells, which develop in response to chronic antigenic stimulation, and act directly on professional and nonprofessional APC, rendering them tolerogenic and able to elicit the differentiation of CD8(+) and CD4(+) T cells with suppressive activity. In this review, we will discuss data pertaining to the bidirectional interaction between Ag-specific T(R) with APC and their clinical relevance.

Animals↗
PubMed2006

Establishment and functioning of intrathymic microenvironments.

The thymus supports the production of self-tolerant T cells from immature precursors. Studying the mechanisms regulating the establishment and maintenance of stromal microenvironments within the thymus therefore is essential to our understanding of T-cell production and ultimately immune system functioning. Despite our ability to phenotypically define stromal cell compartments of the thymus, the mechanisms regulating their development and the ways by which they influence T-cell precursors are still unclear. Here, we review recent findings and highlight unresolved issues relating to the development and functioning of thymic stromal cells.

Animals↗
PubMed2004

Ligand-independent redistribution of Fas (CD95) into lipid rafts mediates clonotypic T cell death.

Clonotypic elimination of activated T cells through Fas-Fas ligand (CD95-CD95L) interactions is one mechanism of peripheral self-tolerance. T cell receptor (TCR) stimuli trigger FasL synthesis but also sensitize activated T cells to Fas-mediated apoptosis through an unknown mechanism. Here we show that TCR restimulation of activated human CD4(+) T cells resulted in Fas translocation into lipid raft microdomains before binding FasL, rendering these cells sensitive to apoptosis after stimulation with bivalent antibody or FasL. Disruption of lipid rafts reduced sensitivity to Fas-mediated apoptosis after TCR restimulation. Thus, the redistribution of Fas and other tumor necrosis factor family receptors into and out of lipid rafts may dynamically regulate the efficiency and outcomes of signaling by these receptors.

Apoptosis↗