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PubMed1987

Specific helper T cell reactivity against autologous erythrocytes implies that self tolerance need not depend on clonal deletion.

Using a culture system which supports primary T cell proliferative responses to various antigens we have detected mouse red blood cell (RBC)-reactive T cells in lymphoid tissues from untreated mice. The release of significant amounts of interleukin 2 (IL2) indicates that T helper (or helper/inducer) cells are activated by stimulation with RBC. Upon restimulation in vitro these cells proliferate specifically against mouse RBC with the kinetics and magnitude characteristic of a secondary response. Since autologous RBC are tolerated in vivo in spite of the presence of such specifically reactive T helper cells, these findings imply that self tolerance, even to certain nonsequestered antigens, may depend largely on regulatory mechanisms rather than on clonal deletion or inactivation.

Animals↗
PubMed1997

Regulation of self-tolerance by CD80/CD86 interactions.

Antigen presentation by CD80/CD86-positive 'professional APCs' induces T-cell activation, whereas antigen presentation in the absence of sufficient CD80/CD86 costimulation may induce a form of tolerance. Blocking CD80/CD86 constimulation inhibits autoimmune disease progression in a variety of animal models, but whether these effects result from restoration of self-tolerance or temporary disease blockade is still unclear. The individual roles of CD80 and CD86 in autoimmune diseases are complicated by multiple factors in vivo. Data from B7 gene knockout mice further clarify the importance of CD80/CD86 in the regulation of T-cell activation and tolerance.

Animals↗
PubMed1990

Self-tolerance to HLA focuses the response of immunized HLA-transgenic mice on production of antibody to precise polymorphic HLA alloantigens.

HLA class I-transgenic mice express HLA antigen on their tissues and establish self-tolerance to the expressed monomorphic and polymorphic determinants. When challenged with skin grafts and lymphoid cells of a second HLA-transgenic mouse expressing a different HLA molecule, a specific immune response is elicited that is focused on the determinants specified by the allelic HLA differences between donor and recipient transgenic mice. In the studies described, this has led to the production of a number of monoclonal antibodies with specificity for the HLA-Cw3 and HLA-B7 crossreactive groups of class I antigens. These results indicate that immunization of appropriate transgenic strains of mice with murine cells expressing a different HLA allelic transgene should permit the generation of monoclonal antibodies of narrow specificity against virtually any polymorphic epitope on HLA antigens.

Animals↗
PubMed1989

Alternative T cell receptor gene usage induced by self tolerance.

Ab-restricted, H-Y-specific T cell clones from C57BL/6 mice were found to use predominantly V beta 6 T cell receptor genes, conferring Mls-1a reactivity. However, the expression of Mls-1a as a self antigen in (DBA/2 x C57BL/6)F1 mice did not turn these mice into nonresponders to H-Y. Instead of V beta 6, they used other T cell receptor genes in this response. Thus, self tolerance appears to bias the repertoire of T cell receptor genes used in response to foreign antigens, without necessarily impairing the immune responsiveness to these antigens.

Animals↗
PubMedDate not supplied

Arsenite induced sensitization and self-tolerance of Reuber H35 hepatoma cells.

Our data show that a short incubation with arsenite (30-300 microM) induces a biphasic change in cellular sensitivity towards a second exposure to arsenite. A transient sensitization was followed by the development of self-tolerance. Sensitization was measured using the step-down protocol; i.e., application of a high dose of arsenite pretreatment (100 or 300 microM) followed immediately by incubation in a low dose of arsenite (1-30 microM), with extensive rinsing in between. Whereas no effect of 1 and 3 microM on cellular survival is observed without pretreatment, a large decrease in cell survival can be established when these low doses of arsenite are applied immediately after a 1 hr pretreatment with 100 or 300 microM arsenite. According to the step-down protocol, a high dose of toxic compounds is applied and is followed by prolonged incubation in a lower concentration of the initial toxic compound. This might be a more accurate model for studying the effects of toxic insults on cells and organisms in the manner in which they occur in their natural environment. The level of tolerance was determined by a 1 hr test treatment with 300 microM arsenite applied at different times after pretreatment. Using this fractionated treatment protocol, it was established that tolerance increases with the increasing time intervals between the sodium arsenite treatments, during the 6 hr studied. These observations suggest that sensitization gradually decreases, whereas tolerance develops. Furthermore, our data indicate that the condition of pretreatment determines the extent to which the early sensitivity increases, as well as the development of tolerance later on. A relatively high arsenite concentration leads to more sensitized cells, which are transformed into more tolerant cells in comparison with the effect of a lower arsenite concentration.

Animals↗
PubMed2005

Systemic transforming growth factor-beta1 gene therapy induces Foxp3+ regulatory cells, restores self-tolerance, and facilitates regeneration of beta cell function in overtly diabetic nonobese diabetic mice.

BACKGROUND: Type 1 diabetes results from auto-aggressive T-cell-mediated destruction of beta cells of the pancreas. Recent data suggest that restoration of self-tolerance may facilitate islet-cell regeneration/recovery. In view of the immunoregulatory activity of transforming growth factor (TGF)-beta1, we investigated whether systemic TGF-beta1 gene therapy blocks islet destructive autoimmunity and facilitates regeneration of beta-cell function in overtly diabetic nonobese diabetic (NOD) mice. METHODS: We used site-directed mutagenesis to create cysteine to serine mutation at sites 224 and 226 and constructed a replication deficient adenovirus (Ad) vector encoding active form of human TGF-beta1 (Ad-hTGF-beta1). Overtly diabetic NOD mice received intravenous injection of Ad-hTGF-beta1. Seven to 14 days after the injection, the mice received transplants with 500 syngeneic islets under the kidney capsule. Islet-graft survival and regeneration of endogenous beta-cell function were examined. RESULTS: Syngeneic islet grafts failed by day 17 in all untreated mice, whereas Ad-hTGF-beta1 therapy prolonged survival of islet grafts. Islet grafts from treated mice showed well-preserved islets with a peri-islet infiltrate primarily of CD4+ T cells and expression of CD25 and Foxp3. Systemic TGF-beta1 gene therapy was associated with islet regeneration in the native pancreas. Native pancreas of treated mice revealed islets staining strongly for insulin. Similar to what was found in the syngeneic islet graft, there were well-demarcated peri-islet infiltrates that were positive for CD4, TGF-beta1, and Foxp3. CONCLUSIONS: Our data demonstrate that systemic TGF-beta1 gene therapy blocks islet destructive autoimmunity, facilitates islet regeneration, and cures diabetes in diabetic NOD mice.

Animals↗
PubMed1986

Self-tolerance and H-2 antigen expression in semi-allogeneic radiation chimeras are controlled by the extrathymic host environment.

Experiments with thymus-grafted radiation chimeras have implicated the H-2 type of the radio-resistant portion of the thymus as determining self for H-2 restricted T-cell responses. (P1 X P2)F1----P1 chimeras, shown to be fully reconstituted with donor haemopoietic cells, have displayed intolerance to P2 H-2 antigens and expressed aberrant levels of P2 H-2 on their spleen cells. We used semi-allogeneic radiation chimeras grafted with fetal thymuses from parental strain donors to compare the relative contributions of the thymus and the extrathymic periphery in determining self-tolerance and in modulating the H-2 phenotype of heterozygous chimeric spleen cells. As analysed by the rosetting titres of anti-H-2 antisera on chimeric spleen cells, by parental skin graft rejection, and by spleen cell anti-parent cytotoxicity after culture with parental stimulators, the decreased expression of non-host parental H-2 antigens was associated with anti-P2 T-cell reactivity, regardless of the H-2 type of the thymus. The donor thymus did not affect tolerance to parental H-2 or cause aberrant expression of H-2 antigens on spleen cells of syngeneic F1----F1 thymus-grafted chimeras.

Animals↗
PubMed1988

Suppressor T cells and self-tolerance. Active suppression required for normal regulation of anti-erythrocyte autoantibody responses in spleen cells from nonautoimmune mice.

Spleen cells from young, nonautoimmune strains of mice cultured with syngeneic E do not develop a significant anti-mouse E response in vitro, consistent with a state of self-tolerance to this Ag. In order to study the role of active suppression in regulating mouse RBC-(MRBC) specific cells in nonautoimmune cell populations, the effect of depleting T cell subsets on the generation of anti-MRBC autoantibodies by nonautoimmune spleen cells was determined. Spleen cells from young BALB/c and C57BL/6 mice were found to generate significant numbers of IgM and IgG anti-MRBC autoantibody-forming cells in culture with MRBC after depletion of Ly-2+ cells by anti-Ly-2 and C treatment. The response which develops is Ag dependent, Ag specific, and dependent upon L3T4+ Th. The magnitude and isotype of this response is similar to the anti-MRBC response generated by spleen cells from 12-mo-old, autoimmune NZB mice and young NZB mice also treated to remove Ly-2+ cells. Addition of isolated Ly-2+ T cells, but not L3T4+ or Ly-2- T cells, to spleen cells depleted of Ly-2+ cells restores apparently normal regulation of the anti-MRBC response in vitro. These data demonstrate that control of a specific autoantibody response to MRBC by nonautoimmune spleen cell populations requires active regulation by an Ly-2+ T cell subset.

Animals↗
PubMed1993

The maintenance of self-tolerance.

Two signal models for lymphocyte activation build on the Talmage/Burnet concept that receptor diversity is generated within the immune system by a random process, and that individual lymphocytes carry a single receptor on their surface that determines their specificity. Such models cannot use a concept of signal one anergy (or deletion) to explain the maintenance of self-tolerance in terms of the Bretscher/Cohn theory if they abandon the concept of associative recognition.

Allergy and Immunology↗
PubMed2006

Bacterial lipoprotein-induced self-tolerance and cross-tolerance to LPS are associated with reduced IRAK-1 expression and MyD88-IRAK complex formation.

Tolerance to bacterial cell-wall components may represent an essential regulatory mechanism during bacterial infection. We have demonstrated previously that the inhibition of nuclear factor (NF)-kappaB and mitogen-activated protein kinase activation was present in bacterial lipoprotein (BLP) self-tolerance and its cross-tolerance to lipopolysaccharide (LPS). In this study, the effect of BLP-induced tolerance on the myeloid differentiation factor 88 (MyD88)-dependent upstream signaling pathway for NF-kappaB activation in vitro was examined further. When compared with nontolerant human monocytic THP-1 cells, BLP-tolerant cells had a significant reduction in tumor necrosis factor alpha (TNF-alpha) production in response to a high-dose BLP (86+/-12 vs. 6042+/-245 ng/ml, P < 0.01) or LPS (341+/-36 vs. 7882+/-318 ng/ml, P < 0.01) stimulation. The expression of Toll-like receptor 2 (TLR2) protein was down-regulated in BLP-tolerant cells, whereas no significant differences in TLR4, MyD88, interleukin-1 receptor-associated kinase 4 (IRAK-4), and TNF receptor-associated factor 6 expression were observed between nontolerant and BLP-tolerant cells, as confirmed by Western blot analysis. The IRAK-1 protein was reduced markedly in BLP-tolerant cells, although IRAK-1 mRNA expression remained unchanged as revealed by real-time reverse transcriptase-polymerase chain reaction analysis. Furthermore, decreased MyD88-IRAK immunocomplex formation, as demonstrated by immunoprecipitation, was observed in BLP-tolerant cells following a second BLP or LPS stimulation. BLP pretreatment also resulted in a marked inhibition in total and phosphorylated inhibitor of kappaB-alpha (IkappaB-alpha) expression, which was not up-regulated by subsequent BLP or LPS stimulation. These results demonstrate that in addition to the down-regulation of TLR2 expression, BLP tolerance is associated with a reduction in IRAK-1 expression, MyD88-IRAK association, and IkappaB-alpha phosphorylation. These findings further elucidate the molecular mechanisms underlying bacterial peptide tolerance.

Adaptor Proteins, Signal Transducing↗
PubMed1986

Reestablishment of self tolerance by suppressor T-cells after active Heymann's nephritis.

Adoptive transfer experiments were performed to obtain evidence that the down-regulation of the autoimmune response in rats with active Heymann's nephritis (HN) is due to suppressor T cells. Late in the course of HN antigen-specific OX8+ suppressor T cells were found in the spleen, but never in the draining lymph nodes. These cells were shown to suppress the autoimmune response when transferred to naive recipients that were subsequently challenged. By mixing B cells or helper T cells from rats with HN with suppressor T cells from high-dose tolerant rats we showed that OX8+ suppressor T cells appeared to have a direct suppressive effect on autoreactive B cells. A profound suppressive effect on helper T cells appeared after 10 weeks. Possible mechanisms to account for the failure of Lewis rats to maintain self tolerance are discussed.

Animals↗
PubMed1988

In-vivo macrophage-erythrocyte-rosettes within haemolymph nodes as evidence of loss of self-tolerance.

Many earlier authors have observed autologous erythrocyte-rosette formation within reddish haemolymph nodes but how and why these are formed has not been studied. In this study we traced the histogenesis of this phenomenon. Since macrophage-erythrocyte-rosettes (MER) mostly occur in the deep sinus we suggest that changes in the red blood cells caused by stagnation, aging or the loss of viability due to deoxygenation may result in development of some unusual sites on these cells. Polar formation of macrophage processes around each rosette erythrocyte in-vivo suggests loss of self-tolerance.

Animals↗
PubMed1997

Loss of self-tolerance to ICA69 in nonobese diabetic mice.

Islet cell antigen p69 (ICA69) is a target autoantigen in IDDM. Studies of T-cells from newly diabetic children suggested possible antigenic mimicry between human ICA69 (in particular the Tep69 T-cell epitope, aa 36-47) and the ABBOS region in bovine serum albumin (BSA; aa 152-169), one of several cow's milk proteins that evoke abnormal immunity in diabetes-prone hosts. We recently found the sequence of Tep69 regions to be identical in the four alternatively spliced human and rodent ICA69 isoforms. Immunization of nonobese diabetic (NOD) mice with BSA or ICA69 generates fully cross-reactive T-cell responses to both Tep69 and ABBOS as the immunodominant, naturally generated, and presented T-cell mimicry epitopes. Such responses are absent or weak in healthy strains of mice. NOD mouse recipients of adoptive spleen cell grafts from diabetic donors spontaneously generate easily detectable pools of T-cells specific for ICA69/BSA, as well as the unrelated GAD65. NOD mice injected neonatally with ABBOS or Tep69 show cross-tolerance, but ABBOS-induced tolerance is transient. Neonatal injection of Tep69 reduces disease incidence (23 vs. 68% IDDM, P < 0.02), while neonatal injection of ABBOS has little effect. In contrast, systemic immunization of young NOD females with ABBOS (but not Tep69) reduces the diabetes incidence and delays disease expression, with protected mice generating ABBOS-specific T-cell repertoires unable to recognize the Tep69 mimicry antigen. Our observations demonstrate a loss of self-tolerance to ICA69 in NOD mice, and they establish antigenic mimicry between the two T-cell epitopes in ICA69 and BSA. Further studies are necessary to understand the molecular basis of this mimicry and how either T-cell peptide can modify the disease course.

Adoptive Transfer↗
PubMed2004

Inducing experimental arthritis and breaking self-tolerance to joint-specific antigens with trackable, ovalbumin-specific T cells.

The importance of T cell Ag specificity and Th1 vs Th2 phenotype in synovial inflammation remains controversial. Using OVA-specific TCR transgenic T cells from DO11.10 mice, we demonstrate that mice receiving Th1, but not Th2, cells display a transient arthritis following immunization that is characterized by synovial hyperplasia, cellular infiltration, and cartilage erosion. OVA-specific T cells also accumulated in inflamed joints, suggesting that they could exert their inflammatory effect locally in the joint or in the draining lymph node. Importantly, this pathology was accompanied by a breakdown in self-tolerance, as evidenced by the induction of collagen-specific T and B cell responses. This model directly demonstrates a pivotal role for Th1 cells of an irrelevant specificity in the development of inflammatory arthritis. Furthermore, the ability to track these cells in vivo will make feasible studies revealing the dynamic role of T cells in arthritis.

Animals↗
PubMed1988

Maternal autoimmune disease influences self-tolerance in offspring: the role of suppressor cells and materno-foetal cell traffic.

Autoimmune haemolytic anaemia (AIHA) was induced in normal strain (CBA/Ca/T6) mice by repeated intraperitoneal injection of rat red blood cells (RRBC). Antibody production to cross-reactive antigens on mouse red blood cells (MRBC) and foreign antigens on RRBC was measured by the direct antiglobulin test (DGAT) and serum haemagglutination, respectively. RRBC primed female or male mice and sheep red blood cell (SRBC) primed controls were mated with naive partners and their progeny immunized with RRBC in adult life. The offspring of mothers but not fathers with active autoimmune disease showed a significant reduction in antibody response to self (MRBC) antigens, whereas the response to non-self (RRBC) was unaffected. Transfer of 30 X 10(6) spleen cells from the progeny of RRBC primed mothers into non-irradiated normal recipients resulted in selective suppression of the anti-self response following challenge with RRBC, provided that the cell donors had been boosted with RRBC 7-10 days before the transfer was performed. Thus the progeny of mothers with AIHA possessed self-reactive memory suppressor cells (Ts) shown previously to belong to the Thy-1+ I-J+ Ly-2+ T cell subset in this model. To test whether the Ts were of maternal or foetal origin the suppressor assay was repeated with spleen cells from the F1 offspring of RRBC primed B10.A(3R) (I-Jb) mothers and normal CBA(I-Jk) fathers. Pretreatment with anti-I-Jb serum plus complement completely abrogated suppression on adoptive transfer but anti-I-Jk serum failed to do so, indicating that the Ts were derived from the mothers. These findings emphasize the potential importance of Ts in induction of self tolerance during early ontogeny.

Anemia, Hemolytic, Autoimmune↗
PubMed1985

Natural suppressor cell inhibiting T killer responses against retroviruses: a model for self tolerance.

We previously reported the characterization of a spontaneous suppressor T cell population (NSC) present in naive mice and able to suppress the cytotoxic response (CTL) against tumor cells induced only by endogenous Gross virus (GLV). In this study we demonstrate the existence of such NSC inhibiting the CTL activity against tumor cells induced by the normally exogenous Moloney virus (M-MLV) in mice of the Mov-13 (V+) strain in which the M-MLV has been artificially endogenized and which express the virus during the embryonal life. These NSC are not found in other Mov strains in which the endogenized M-MLV is not expressed during fetal life. The implication of these data in the mechanism of self tolerance is discussed.

Animals↗
PubMed1991

The inability of thyroid allografts to induce self-tolerance of organ-specific antigens in foetal lambs.

Foetal lambs in the eighth week of gestation were submitted to thyroidectomy followed by the immediate implantation of a thyroid allograft from a donor of similar age. Excised thyroid glands were transplanted to nude mice and maintained there for approximately 2 months, after which they were re-implanted in the original donor. Some foetuses also received second allografts of thyroid tissue from the original donors at this time. Several weeks later, foetuses were killed to permit histological examination of the original thyroid allografts and of subsequent autografts and allografts. Examination revealed heavy lymphocytic infiltration, interpreted as autoimmune thyroiditis, in reimplanted autografts. Thyroid allografts which had been transferred in the eighth week occasionally showed limited areas of lymphocytic infiltration but their most notable feature was a highly abnormal follicular morphology. Whilst these primary allografts had not been rejected, second thyroid allografts from the same donors were all rapidly destroyed. The failure of foetal lambs which had experienced thyroidectomy and receipt of a thyroid allograft to acquire self-tolerance to thyroid tissue was attributed to the inadequacy of thyroid-specific antigens to achieve this when presented exclusively on allogeneic thyroid cells.

Animals↗
PubMed1992

Failed self-tolerance and autoimmunity in IgG anti-DNA transgenic mice.

Transgenic mice were generated that express both the H and L chain genes derived from a hybridoma secreting an IgG2a mAb specific for ds- and ssDNA. This hybridoma is derived from a lupus mouse and can accelerate nephritis in young NZB x NZW F1 female mice and induce clinical nephritis in BALB/c mice. Some transgenic B cells did not exhibit allelic exclusion; they expressed both transgene-derived IgG and endogenous IgM intracellularly. Most of the B cells in transgenic mice expressed endogenous IgM, some of them expressed low levels of IgG on cell membranes. The transgenic mice, created in a strain not prone to SLE, expressed elevated serum IgG anti-DNA, and some developed clinical nephritis. The affinity of the spontaneously secreted IgG antibodies for dsDNA were similar in nephritic NZB x NZW F1 and transgenic mice. In contrast to the nontransgenic littermates, immunization of transgenic mice with murine DNA further enhanced serum levels of IgG anti-DNA in transgenic mice. Therefore, expression of transgene-encoded IgG anti-DNA mainly in the secreted form does not provide the signals necessary for allelic exclusion or self-tolerance. Expression of this Ig is sufficient to induce a mild form of autoimmune disease.

Animals↗