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At least 919 records · Page 51Linked to original sources
PubMed1996

Analysis of central B cell tolerance in autoimmune-prone MRL/lpr mice bearing autoantibody transgenes.

The effect of the autoimmune prone MRL/lpr (H-2k) genetic background on central B cell tolerance was studied in mice bearing 3-83 (anti-H-2Kk) Ig heavy and light chain transgenes. B cells bearing the dominant, transgene-encoded anti-H-2Kk specificity were tolerized appropriately on the MRL/lpr genetic background. Nevertheless, mice developed disease traits characteristic of the MRL/lpr strain, including lymphadenopathy and elevated levels of IgG dsDNA autoantibodies. Two transgenic lines were examined in this analysis: 3-83 mu delta, which expresses IgM and IgD forms of the 3-83 Ab, and Tol 1, which expresses only the IgM form of 3-83. The results obtained differed somewhat between the two transgenic lines. Crosses using 3-83 mu(delta) mice never demonstrated any defects in B cell self-tolerance to H-2Kk. Similarly, no Kk autoantibody production was seen in Tol 1 mice that were backcrossed onto the MRL/lpr genetic background and maintained in a specific pathogen-free facility. However, a subset of Tol 1/MRL/lpr mice that were housed in a conventional mouse facility demonstrated significant transgene-derived anti-Kk autoantibodies. Overall, these results suggest that there is no general defect in central B cell tolerance in MRL/lpr mice, despite their defect in the fas gene. These findings suggest similarities between the MRL/lpr T and B cell systems, because both fail to manifest clear central tolerance defects, but they nevertheless promote hyperplasia and autoimmunity in the peripheral immune system.

Animals↗
PubMed1996

Establishment of tissue-specific tolerance is driven by regulatory T cells selected by thymic epithelium.

Grafts of thymic epithelium (TE) rudiments restore T cell development and function in allogeneic athymic mice. These TE chimeras are specifically tolerant to grafts of peripheral tissues (e.g. skin and heart) from the TE donor strain, although they harbor peripheral immunocompetent T cells capable of rejecting those grafts. Initial analysis has shown that TE chimeras also harbor TE-selected CD4 T lymphocytes that inhibit graft rejection by tissue-reactive T cells in immunocompetent recipients. Peripheral tolerance in TE chimeras is thus maintained by dominant mechanisms dependent on regulatory CD4 T lymphocytes. Here we show that TE-selected regulatory T cells recruit nontolerant tissue-reactive CD4 and CD8 T cells to express similar regulatory functions. Only recent thymic emigrants, but not peripheral resident mature T cells are susceptible to this process of functional education, which also requires exposure to specific antigens and occurs entirely in the periphery. We propose that these mechanisms play a major role in establishing and maintaining natural self tolerance to tissue-specific antigens.

Animals↗
PubMed2000

Tyrosine hydroxylase-based DNA-vaccination is effective against murine neuroblastoma.

BACKGROUND: The disruption of self-tolerance against neuroblastoma is the ultimate goal of an effective DNA-vaccine. PROCEDURE: Here we demonstrate the induction of a protective immunity against syngeneic murine NXS2 neuroblastoma in A/J mice, following vaccination with tyrosine hydroxylase (TH) derived antigens. Oral gene delivery was accomplished using an attenuated strain of Salmonella typhimurium as a carrier harboring vectors encoding for mTH antigens. RESULTS: Vaccination was effective in protecting animals from a lethal challenge with wild-type NXS2 tumor cells. CONCLUSIONS: These results provide the first evidence of the TH self antigen being recognized by T-cells and demonstrate that a TH-based DNA vaccine is a potentially useful immunotherapeutic strategy for neuroblastoma.

Animals↗
PubMed2005

How defects in central tolerance impinge on a deficiency in regulatory T cells.

Both central (thymic) and peripheral (nonthymic) mechanisms are important for the induction and maintenance of T cell tolerance. Mice with a defect in Foxp3, required for the generation and activity of CD4(+)CD25(+) regulatory T cells, exhibit massive lymphoproliferation and severe inflammatory infiltration of multiple organs, in particular the lungs, liver, and skin. We have explored how this phenotype is influenced by an additional defect in central tolerance induction, generated by either crossing in a null mutation of the Aire gene or substituting the nonobese diabetic (NOD) genetic background. The double-deficient mice had fulminant autoimmunity in very early life and a gravely shortened lifespan vis-à-vis single-deficient littermates. They showed massive lymphoproliferation and exacerbated inflammatory damage, particularly in the lungs and liver. Yet, the range of affected sites was not noticeably extended, and, surprisingly, many organs, or regions of organs, remained untouched, suggesting additional important mechanisms to enforce immunological self-tolerance.

Animals↗
PubMed1997

Apoptosis with FasL+ cell infiltration in the periphery and thymus of corrected autoimmune mice.

Fas (CD95) ligand (L) is a death factor that binds to its receptor, Fas, and induces apoptotic cell death, a crucial process in immunological tolerance. gld (generalized lymphoproliferative disorder) mice, which have a point mutation in the FasL gene, develop spontaneous systemic autoimmune syndromes characterized by hypergammaglobulinaemia and lymphoid hyperplasia owing to accumulation of abnormal B220+ CD3+ cells. Transplantation of wild-type (wt) bone marrow cells into old gld mice on the same strain background results in normalization of autoimmune syndromes. We characterized the cellular mechanisms (functionally and histologically) of the above phenomena in gld mice after bone marrow transplantation (BMT) to determine the role of apoptosis via Fas/FasL interactions in inducing and maintaining self-tolerance in vivo. Activated splenocytes from wt and BMT (wt to gld) mice showed significant cytotoxic activity against Fas transfectant cells while those from BMT (gld to gld) mice did not. Cells in the thymus, spleen and lymph nodes of gld mice uniformly upregulated Fas expression and were sensitive to Fas-mediated apoptosis compared with those in wt mice. Cells sensitive to Fas-mediated apoptosis in gld mice resided not only among abnormal B220+ CD3+ cells but also among conventional lymphocytes. More importantly, histological analysis revealed that cells in the spleen, lymph nodes and thymus frequently underwent apoptosis with infiltration of FasL+ cells in BMT (wt to gld) mice compared with BMT (gld to gld) mice. Our results indicated that apoptosis via Fas/FasL interactions can directly eliminate pathogenic cells responsible for autoimmunity in the periphery and possibly in the thymus in vivo.

Animals↗
PubMed1983

Neonatal tolerance of major histocompatibility complex antigens alters Ir gene control of the cytotoxic T cell response to vaccinia virus.

The K region of H-2 controls the Tc cell response to vaccinia-Db. The Kb, Kd, and Kq alleles allow good Tc cell responses against vaccinia-Db. In contrast, the presence of Kk in H-2 recombinants 2R (Kk,Db) and 4R (Kk,Db) or in F1 hybrids greatly reduces the anti-vaccinia-Db response. The defect does not lie in antigen presentation, as infected 4R cells can stimulate anti-vaccinia-Db Tc cells in vitro. Furthermore, nonresponder animals possess Tc cell precursors for vaccinia-Db, as transfer of F1 nonresponder spleen cells into infected, lethally irradiated responder recipients allowed generation of anti-vaccinia-Db effector Tc cells. Secondary responses to vaccinia-Db can also be obtained in vitro from T cells of 4R animals. Feedback inhibition was excluded in experiments with mixed chimeras in which Kk and Db were expressed on separate cell populations. Neonatal tolerance of B10 animals to Kk suppressed the anti-vaccinia-Db response but did not affect anti-vaccinia-Kb, anti-lymphocytic choriomeningitis virus, or anti-H-2d responses. In cold target competition experiments, H-2k competitors inhibited vaccinia-Db-specific target cell lysis by Tc cells, which suggests that anti-vaccinia-Db and anti-H-2Kk Tc cells may cross-react. Therefore, we propose that the suppressive influence of Kk on anti-vaccinia-Db Tc cell responses is a consequence of self-tolerance and that suppression of anti-Kk Tc cells results in cross-reactive suppression of anti-vaccinia-Db Tc cells.

Animals↗
PubMed2004

Intrinsic and extrinsic regulation of T lymphocyte quiescence.

The outcome of an immune response is dependent on the interplay and complex interactions of positive (stimulatory) and negative (inhibitory) pathways and a major goal of modern immunology is to dissect these physiologic interactions in order to apply these physiologic mechanisms therapeutically. The balance of stimulatory and inhibitory signals is critical for maximizing the ability of the adoptive immune response to defend the host while maintaining immunologic tolerance and preventing autoimmunity. Cellular quiescence is a state characterized by decreased cell size and metabolic activity. The quiescent state of unstimulated T lymphocytes is thought to be due to the lack of activation signals. However, recent studies have shown that quiescence in lymphocytes is not a default state, but an actively maintained gene program. This program regulates intrinsic expression of quiescence factors in T lymphocytes. In addition to intrinsic mechanisms regulating T cell quiescence, CD4 + CD25 + regulatory T cells (Treg) naturally arising in the thymus, engage in the maintenance of immunological self-tolerance by preventing autoimmunity in vivo in a non cell-autonomous manner. Although there is still only a rudimentary knowledge of the molecular mechanisms that govern the activity of the intrinsic quiescence factors and the development of Treg, it is now clear that immune quiescence is regulated by constitutively ongoing active mechanisms.

Animals↗
PubMed1992

T cell recognition of self-human histocompatibility leukocyte antigens (HLA)-DR peptides in context of syngeneic HLA-DR molecules.

It has been suggested that self major histocompatibility complex (MHC) peptides bound to self MHC molecules may be involved in the intrathymic induction of self tolerance. We studied the antigenicity of synthetic peptides derived from the first domain of DR beta 1*0101 chain in a DR beta 1*0101 responder. We found that a peptide corresponding to residues 21-42 of the beta chain could elicit the proliferation of autoreactive T cells. A T cell line (TCL-SUN) and 7 of 9 T cell clones (TCC) derived from TCL-SUN specifically recognized peptide 21-42 in the presence of APCs carrying the DR beta 1*0101 allele. DR beta 1*0101 positive APCs stimulated the TCCs in the absence of peptide, although the magnitude of the response was much lower than in cultures with peptide. This suggests that self DR1 molecules are continuously processed into peptides that are presented by the DR1 molecules on the surface of the cells. The data indicate that some T cells whose TCR binds to self MHC peptides presented by self MHC molecules are not deleted, although their ligand is continuously present. TCCs specific for peptide 21-42 presented in the context of DR1 were also stimulated by cells heterozygous for DR beta 1*0301 and 1601, indicating that some DR peptide-specific autoreactive T cells participate in alloreactivity.

Antibodies, Monoclonal↗
PubMed2006

Control of NK cell functions by CD4+CD25+ regulatory T cells.

Regulatory T cells (Treg) are key players in the maintenance of peripheral tolerance. As a result of suppressive effects on CD4+ and CD8+ effector T cells, Treg control the adaptive immune system and prevent autoimmunity. In addition, they inhibit B lymphocytes, dendritic cells, and monocytes/macrophages. It is interesting that several recent papers show that CD4+CD25+ Treg are also able to inhibit NK cells. Thus, Treg exert their control on immune responses from the onset (triggering of innate immune cells) to the effector phase of adaptive immunity (B and T cell-mediated responses). That Treg inhibit NK cells suggests that their uncontrolled activation might break self-tolerance and induce "innate" autoimmune pathology. Conversely, Treg-mediated suppression of NK cell functions might have negative effects, as these cells are important in defense against infections and cancer. It is conceivable that Treg might dampen efficient activation of NK cells in these diseases.

Animals↗
PubMed2004

Induction of tolerance to self-antigens using genetically modified bone marrow cells.

The challenge of finding a lasting cure for autoimmune disease(s) has not been met. Although the use of systemic anti-inflammatory agents still dominates the treatment of these diseases, there is a push towards developing novel and more specific strategies. In addressing autoimmunity, there is the intrinsic need to understand the mechanisms that lead to the development and maintenance of immunological tolerance to self-antigens. Experimental evidence has shown that directed antigen expression in the thymus can induce immunological tolerance to that antigen. This forms the cornerstone of one strategy directed towards the cure of autoimmunity. In this strategy, individuals with autoimmune disease are transplanted with bone marrow stem cells that have been genetically modified and in this way allow expression of the self-antigen in the thymus.

Animals↗
PubMed2004

Complement receptors and the shaping of the natural antibody repertoire.

Complement and complement receptors have been known for several decades to play important roles in immune effector mechanisms related to pathogen elimination and tissue inflammation. In addition, studies over the last 10 years have clearly demonstrated a key role for the complement C3d activation fragment receptor designated CR2 (complement receptor type 2) in the switched-isotype, high-affinity and memory humoral immune responses to T-dependent foreign antigens. More recent studies have extended those observations to include a key role for CR2 and C3d in the humoral immune response to T-independent foreign antigens. Conversely, as these studies have proceeded, a parallel series of analyses have linked defects in expression or function of complement C4 and other classical pathway activation pathway proteins, as well as CR2 and the closely related CR1, to the loss of self tolerance to nuclear antigens such as double-stranded DNA and chromatin in systemic lupus erythematosus. With regard to the topic of this issue, it is now becoming increasingly clear that CR2 also plays a major role in the development of the natural antibody repertoire. Specifically, in the absence of this receptor natural IgM and IgG develop in the naïve animal that demonstrate clearly altered recognition patterns for specific natural antibody targets. This repertoire change is important physiologically in at least one setting because these CR2-dependent natural antibodies are necessary for the recognition of ischemic self tissues. In addition, it is possible that certain of the phenotypes manifest by CR2-deficient mice may be strongly influenced not only by effects on later stages of B cell activation and maturation, as commonly thought, but also by alterations in the pre-existing pool of natural antibodies that are influenced by this receptor. This review will examine the evidence that has accumulated over the last few years supporting these hypotheses.

Animals↗
PubMed1990

Determinants of the B-cell response against a transgenic autoantigen.

The failure to induce self-tolerance of simian virus 40 large tumor antigen (T antigen) expressed in the pancreatic beta cells of transgenic mice results in an autoimmune response against this protein and the cells that synthesize it. In every transgenic mouse with delayed onset of T-antigen expression and consequent nontolerance, B cells, T cells, and macrophages are attracted to and infiltrate the pancreatic islets. In contrast, the incidence, onset, and intensity of the B-cell response to produce anti-T-antigen autoantibodies vary considerably with genetic background. Thus the initial attraction of lymphocytes to the cells synthesizing a non-self antigen can be separated from the activation of a B-cell response against it. Haplotypes of the major histocompatibility complex (MHC) differentially influence the character of the autoimmune response, with H-2d and H-2k conferring a high incidence of humoral autoimmunity. Additional non-MHC linked genes are also implicated in control of the B-cell response.

Animals↗
PubMedDate not supplied

IFNbeta-1a treatment and reestablishment of Th1 regulation in MS patients: dose effects.

The authors evaluated the relationships between clinical and pharmacologic parameters and the Th1/Th2/Th3 cytokine network in patients with relapsing-remitting multiple sclerosis treated with differing doses of interferon-beta1a (IFN-beta1a). Their results show that low doses are ineffective but that high doses restore Th1 regulation of the maturation and activation of monocytes, T cells, immature dendritic cells, dendritic cells, and T regulatory cells for central and peripheral self-tolerance. Interaction between interleukin (IL)-10, IL-12 p70, and IL-6 production appears to play an important role in the control of the maturation and activation states of dendritic cells and T regulatory cells, and is at the basis of the benefit of high doses. The results also indicate that the physiologic mechanisms involved in aging help immunologic reestablishment in IFNbeta-1a-treated patients. Finally, it would appear that the failure of IFNbeta-1a therapy to resolve multiple sclerosis completely is due to the suppression of IL-12 p70 mechanisms (responsible for the physiologic deletion of self-reactive cells) in activation conditions, probably by IFNbeta-1a itself.

Adult↗
PubMed1989

Expression in transgenic mice of class I histocompatibility antigens controlled by the metallothionein promoter.

To study the effects of increased expression of major histocompatibility complex class I molecules on the development of self-tolerance, transgenic mice were produced that expressed the H-2Kb gene under the control of the metallothionein promoter. Administration of zinc enhanced transgene expression in liver, kidney and exocrine pancreas. No evidence suggestive of an autoimmune response was found in transgene-expressing tissues in mice otherwise allogeneic to H-2Kb. Despite this lack of responsiveness in vivo, T cells could be stimulated in vitro to lyse H-2Kb-bearing target cells. No infiltration was detected in transgenic mice after irradiation and reconstitution with bone marrow cells. When spleen cells were used for reconstitution, however, dense lymphocytic infiltration was seen, particularly in the portal tracts of the liver, and this was accompanied by piecemeal necrosis and apoptosis of periportal hepatocytes. This aggressive response progressively diminished with time, and by 12 weeks after reconstitution many of the portal tracts were free of infiltration while the others showed no accompanying necrosis. The picture at this stage was similar to that seen in chronic persistent hepatitis. These results suggest that, in addition to negative selection in the thymus, peripheral mechanisms not involving clonal deletion or permanent clonal anergy can prevent immune responses to self molecules.

Animals↗
PubMed2005

Homeostatic maintenance of natural Foxp3(+) CD25(+) CD4(+) regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization.

Interleukin (IL)-2 plays a crucial role in the maintenance of natural immunologic self-tolerance. Neutralization of circulating IL-2 by anti-IL-2 monoclonal antibody for a limited period elicits autoimmune gastritis in BALB/c mice. Similar treatment of diabetes-prone nonobese diabetic mice triggers early onset of diabetes and produces a wide spectrum of T cell-mediated autoimmune diseases, including gastritis, thyroiditis, sialadenitis, and notably, severe neuropathy. Such treatment selectively reduces the number of Foxp3-expressing CD25(+) CD4(+) T cells, but not CD25(-) CD4(+) T cells, in the thymus and periphery of normal and thymectomized mice. IL-2 neutralization inhibits physiological proliferation of peripheral CD25(+) CD4(+) T cells that are presumably responding to normal self-antigens, whereas it is unable to inhibit their lymphopenia-induced homeostatic expansion in a T cell-deficient environment. In normal naive mice, CD25(low) CD4(+) nonregulatory T cells actively transcribe the IL-2 gene and secrete IL-2 protein in the physiological state. IL-2 is thus indispensable for the peripheral maintenance of natural CD25(+) CD4(+) regulatory T cells (T reg cells). The principal physiological source of IL-2 for the maintenance of T reg cells appears to be other T cells, especially CD25(low) CD4(+) activated T cells, which include self-reactive T cells. Furthermore, impairment of this negative feedback loop via IL-2 can be a cause and a predisposing factor for autoimmune disease.

Animals↗
PubMed1997

Enforced Bcl-2 expression inhibits antigen-mediated clonal elimination of peripheral B cells in an antigen dose-dependent manner and promotes receptor editing in autoreactive, immature B cells.

The mechanisms that establish immune tolerance in immature and mature B cells appear to be distinct. Membrane-bound autoantigen is thought to induce developmental arrest and receptor editing in immature B cells, whereas mature B cells have shortened lifespans when exposed to the same stimulus. In this study, we used Emu-bcl-2-22 transgenic (Tg) mice to test the prediction that enforced expression of the Bcl-2 apoptotic inhibitor in B cells would rescue mature, but not immature, B cells from tolerance induction. To monitor tolerance to the natural membrane autoantigen H-2Kb, we bred 3-83mudelta (anti-Kk,b) Ig Tg mice to H-2(b) mice or to mice expressing transgene-driven Kb in the periphery. In 3-83mudelta/bcl-2 Tg mice, deletion of autoreactive B cells induced by peripheral Kb antigen expression in the liver (MT-Kb Tg) or epithelia (KerIV-Kb Tg), was partly or completely inhibited, respectively. Furthermore, Bcl-2 protected peritoneal B-2 B cells from deletion mediated by acute antigen exposure, but this protection could be overcome by higher antigen dose. In contrast to its ability to block peripheral self-tolerance, Bcl-2 overexpression failed to inhibit central tolerance induced by bone marrow antigen expression, but instead, enhanced the receptor editing process. These studies indicate that apoptosis plays distinct roles in central and peripheral B cell tolerance.

Animals↗
PubMed1997

Protection against autoimmune diabetes in mixed bone marrow chimeras: mechanisms involved.

After bone marrow transplantation, complete nonobese diabetic (NOD) into (NOD x C57Bl/10)F1 chimeras developed insulitis in 100% (7/7) and diabetes in 58% (7/12) of cases. In contrast, when mixed chimerism was induced, a near complete protection against insulitis (3/23, p < 0.0001 vs complete chimeras) and diabetes (0/25, p < 0.001 vs complete chimeras) was achieved even in chimeras with as few as 5% F1 cells. In cotransfer experiments, splenocytes from mixed chimeras failed to prevent diabetes, thus overruling a role for suppressor cells in protection. Whereas splenocytes from complete chimeras transferred diabetes into young irradiated NOD mice in all cases, NOD splenocytes from mixed chimeras only rarely transferred diabetes (3/16, p < 0.01 vs complete chimeras), suggesting that the latter cells had developed tolerance toward beta cells. To achieve this tolerance, the presence of an F1 thymus was not needed. Indeed, whereas splenocytes isolated from complete chimeras were diabetogenic when transferred into neonatally thymectomized irradiated NOD recipients (3/4), they failed to induce diabetes when transferred into neonatally thymectomized irradiated F1 recipients in case again a state of mixed chimerism was induced (0/4, p < 0.001 vs NOD recipients). Finally, a role for non-MHC Ags was demonstrated by experiments in F1 mice crossed between NOD and C57Bl/6, a strain congenic to C57Bl/10. Here protection against disease was only seen in the presence of high levels of F1 cells (>25%). In conclusion, mixed bone marrow chimerism can induce self-tolerance in autoimmunity prone NOD immune cells. This can be achieved extrathymically but may depend on non-MHC Ags and the level of chimerism.

Adoptive Transfer↗
PubMed2005

Removal of dying cells and systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a very heterogeneous systemic autoimmune disease, in which autoantibody synthesis against nuclear constituents is the main immunological characteristic. These autoantibodies underwent affinity maturation and isotype switching. Additionally, T-cell tolerance against nuclear autoantigens should be affected in these autoimmune patients. Nuclear material derived from apoptotic and/or necrotic cells may serve as an important source of autoantigens. However, dead and dying cells as well as cellular debris are rapidly removed from tissues by phagocytes without eliciting inflammation or immune responses under healthy conditions. During apoptosis nuclear components are strongly modified through enzymatic reactions. If these cells are not timely cleared, those autoantigens may be released, taken up, and presented by dendritic cells in tissues or presented by follicular dendritic cells in lymph nodes to T and B cells, respectively. This could be a mechanism for breaking the peripheral self-tolerance. In this article we focus on the deficient clearance of apoptotic cells in SLE patients and its importance in development of this autoimmune disease.

Journal Article↗