Criteria of immunological tolerance to tissue antigens

Exposure of white New Zealand rabbits in the immediate post-natal period to heterologous tissue antigens appeared to induce tolerance as judged by immunodiffusion. However, immunofluorescence tests showed that the animals had in fact developed certain tissue-specific and human-specific antibodies, establishing that immunodiffusion is an inadequate method for demonstrating antibodies to tissue antigens.     

Production of immunological tolerance to microbial and cross-reacting mouse tissue antigens

By injectingCandida albicans vaccine into newborn CC57BR mice tolerance was obtained to the microbial antigen, a manifestation of which was inhibition of the rejection of skin grafts from C3H mice. In the tolerant animals the number of lymphocytes reacting with microbial and donor's tissue antigen in the immunoadhesion and blast-transformation reactions was reduced and their cytotoxic activity against fibroblasts of C3H mice was lowered. Tolerance to microbial and cross-reacting transplantation antigens was transferred by spleen cells to syngeneic recipients irradiated in a dose of 700 R.     

Hierarchy in the ability of T cell epitopes to induce peripheral tolerance to antigens from myelin

Nasal administration of peptide antigens has been shown to induce T cell tolerance. We have investigated the potential for peptide therapy of the autoimmune response to myelin antigens in experimental autoimmune encephalomyelitis (EAE). Three major encephalitogenic epitopes were studied for their ability to induce nasal tolerance to myelin antigens. These included epitopes Ac1 – 9 and 89 – 101 of myelin basic protein (MBP) and 139 – 151 from proteolipid protein (PLP). Peptide Ac1 – 9 from MBP effectively suppressed responses to both MBP epitopes, following immunization with whole myelin (linked suppression). The N-terminal epitope failed, however, to modify the response to epitope 139 – 151 of PLP. The second MBP epitope (89 – 101) was poorly tolerogenic for the immune response to any naturally processed myelin epitope. By contrast, PLP[139 – 151] was able to induce bystander suppression of T cells responsive to both itself and the two epitopes from MBP. Furthermore, this epitope suppressed EAE induced with peptides derived from MBP and was capable of treating ongoing disease. The mechanism of bystander suppression, mediated by PLP[139 – 151], did not correlate with an overt switch from the T helper 1 to the T helper 2 phenotype. These results demonstrate how a complex autoimmune disease may be controlled by treatment with a single peptide epitope and reveal a hierarchy in the suppressive properties of different myelin antigens.     

Rat thymic epithelium positively selects mouse T cells with specificity for rat MHC class II antigens but fails to induce detectable tolerance in the mouse T cells to the rat MHC antigens.

BALB/c (H-2d) nude mice were grafted with allogeneic AKR/J (H-2k) or xenogeneic (ACI-N rat, RT1av1) fetal thymuses which were depleted of hemopoietic cells by incubating with 2'-deoxyguanosine (2'dGuo) in vitro prior to grafting. The nylon-wool-passed LN T cells from nude mice grafted with 2'dGuo-treated AKR/J thymus showed a poor proliferative response to B10BR (H-2k) stimulator cells, confirming that mouse thymic epithelium has the capacity to induce tolerance against the mouse MHC antigens on the thymic epithelium. On the other hand, the nylon-wool-passed LN T cells from nude mice grafted with untreated or 2'dGuo-treated ACI/N rat thymus showed significant proliferative responses to ACI/N, which can be blocked by anti-rat MHC class II mAb, whereas the nylon-wool-passed LN T cells from nude mice grafted with syngeneic thymus hardly responded to the xenogeneic stimulator cells. These results suggest that rat thymic stromal cells including thymic epithelium can not induce detectable tolerance in mouse T cells to rat MHC antigens; but rat thymic epithelium may positively select mouse T cells with specificity for rat MHC class II antigens, resulting in a mouse T cell repertoire with strong xeno-reactivity.     

Failure to induce organ-specific autoimmunity by breaking of tolerance: importance of the microenvironment

Peripheral tolerance is considered to be a safeguard against autoimmunity. Using a TCR-transgenic mouse system displaying peripheral tolerance against a liver-specific MHC class I K^b antigen, we investigated whether the breaking of tolerance would result in autoimmunity. Reversal of tolerance was achieved by simultaneous challenge with cells expressing the K^b autoantigen and IL-2. Tolerance could not be broken with IL-2 alone or when K^b- and IL-2-expressing cells were applied to different sites of the mice. However, despite the presence of activated autoreactive T cells that were able to reject K^b-positive grafts no autoaggression against the K^b-positive liver was observed. These results indicate that breaking of tolerance per se is not sufficient to cause liver-specific autoimmunity. However, when in addition to breaking tolerance the mice were infected with a liver-specific pathogen, autoaggression occurred. Thus, in this system at least two independent steps seem to be required for organ-specific autoimmunity: reversal of peripheral tolerance resulting in functional activation of autoreactive T cells and conditioning of the liver microenvironment which enables the activated T cells to cause tissue damage.     

供者抗原经门静脉输注诱导特异性免疫耐受的研究

目的 探讨供者特异性抗原在诱导免疫耐受中的作用和地位。方法 采用大鼠异位（颈部）心脏移植模型,通过门静脉途径输注不同类型供者特异性抗原。结果 发现供乾持异性输血（ＤＳＴ）供者特异性脾细胞（ＤＳＳＬ）和供者特异性骨髓细胞（ＤＳＢＭ）能诱导受体对供体移植物产生免疫耐受。结论 这类免疫耐受的产生可能与肝脏特殊免疫功能有关,Ｋｕｐｆｆｅｒ细胞可能其中起重要作用,但门静脉耐受对外周血ＣＤ８细胞的影响不明显。     

Oral tolerance to protein antigens

Oral tolerance is an active non-response to antigens delivered via the oral route. Mechanisms governing tolerance induction have been well characterized in mouse. Similar studies in man are lacking, although there is evidence that tolerance can be induced. In disease states, tolerance is altered and this may account for the presence of mucosal inflammation. In food hypersensitivity there is evidence that allergens may be handled differently and this may play a role in disease expression.     

Oral antigens induce rheumatoid arthritis-like inflammation in a rat model

Background and aims

The pathogenesis of rheumatoid arthritis (RA) is to be further elucidated. The present study aims to investigate the role of oral antigen in the induction of RA-like inflammation in the articular joints of rats.

Methods

An RA animal model was developed by gavage-feeding with antigen and aspirin, and lipopolysaccharide intraperitoneal injection. The gut epithelial barrier function was assessed by the absorption of mannitol and lactose. The absorption of the specific antigen was observed by the immune fluorescent method. The frequency of antigen specific CD4+ T cells in the peripheral system was assessed by flow cytometry. The inflammation in the ankle joints was evaluated by light microscopy and immunohistochemistry.

Results

Rats treated with aspirin showed intestinal barrier dysfunction; high contents of the specific antigen were absorbed into the lamina propria. The antigen specific CD4+ T cells were detected in the spleen that could be activated by exposure to the specific antigen as well as the extracts of joint tissue. High levels of proinflammatory cytokines were detected in the sera. Antigen specific immune complexes were localized in the ankle joints. Heavy extravasation was observed in the synovial cavity. The histology showed an inflammatory feature in the ankle joints.

Conclusions

Oral antigen can induce RA-like inflammation in the articular joints under certain environment such as gut epithelial barrier dysfunction.     

Self-encounters of the third kind: lymph node stroma promotes tolerance to peripheral tissue antigens

Multiple mechanisms have evolved to maintain tolerance among CD8⁺ T cells to innocuous antigens that arise in cutaneous and mucosal tissues. In the thymus, medullary thymic epithelial cells directly present peripheral tissue antigens (PTAs) and incite the deletion of self-reactive thymocytes. Cross-presentation of PTAs by functionally immature, CD8α⁺ dendritic cells can lead to the deletion of self-reactive CD8⁺ T cells in secondary lymphoid organs. A third mechanism of deletional tolerance has recently been uncovered in which lymph node-resident stromal cells of non-hematopoietic origin present endogenously expressed PTAs to circulating CD8⁺ T cells. Emerging data suggest that lymph node stroma is a unique niche for controlling self-reactive T cells.     

T-helper cell tolerance to ubiquitous nuclear antigens

Systemic autoimmune diseases are characterized by the development of antinuclear autoantibodies. In order to understand the immunologic events leading to the development of such antibodies, knowledge of mechanisms of immune tolerance to nuclear antigens is required. By utilizing adoptive T-cell transfer strategies with transgenic mouse models expressing nuclear neo-self antigens, T-cell tolerance to the lupus-related nuclear antigens human La and nRNP A has been demonstrated. These findings also indicate the existence in normal animals of autoreactive B cells continuously presenting nuclear antigen, suggesting that nuclear antigens are not sequestered from the immune system. Investigations of CD4+ T-cell tolerance to non-nuclear antigens have revealed a number of mechanisms that protect the host from autoreactivity, including autoreactive T-cell deletion, regulatory T-cell development and anergy induction. Recent studies using T-cell receptor and neo-self nuclear antigen transgenic mice are revealing the importance of such mechanisms in maintaining tolerance to nuclear antigens. Mechanisms of tolerogenic antigen presentation, identification of tolerogenic antigen source(s) and the pathways leading to loss of tolerance to nuclear antigens in systemic autoimmune disease states are currently being sought.     

Maintenance of peripheral tolerance to islet antigens

Reestablishment of immune tolerance to the insulin-producing beta cells is the desired goal for type 1 diabetes (T1D) treatment and prevention. Immune tolerance to multiple islet antigens is defective in individuals with T1D, but the mechanisms involved are multifaceted and may involve loss of thymic and peripheral tolerance. In this review we discuss our current understanding of the varied mechanisms by which peripheral tolerance to islet antigens is maintained in healthy individuals where genetic protection from T1D is present and how this fails in those with genetic susceptibility to disease. Novel findings in regards to expression of neo-islet antigens, non-classical regulatory cell subsets and the impact of specific genetic variants on tolerance induction are discussed.     

Immunotherapy as a means to induce transplantation tolerance

There have been several recent advances in the use of immunotherapy to induce transplantation tolerance. These include newer and safer protocols to create hematopoietic chimerism, the development of more-powerful T cell depleting antibodies, the identification of additional costimlulatory pathways as molecular targets and the identification of a role for suppressor cells in transplant tolerance.     

Immune responses to dietary antigens: oral tolerance

The concept of immunologically mediated tolerance to food antigens through exposure to mucosal antigen has been the subject of continuous scientific debate. After a decline in interest in the mid-1980s, oral tolerance has again attracted the attention of immunologists. Here, Stephan Strobel and Allan Mowat discuss how this central immunological principle has potential new therapeutic applications for the treatment of autoimmune, inflammatory and possibly food-allergic diseases.     

Myoblasts fail to stimulate T cells but induce tolerance

Recent interest in myoblast transfer and in the use of myoblastsas vehicles in gene therapy has made it important to understandthe potential immunogenicity of allogeneic or neoantlgen-expresslngmyoblasts. Given the problems of producing a pure populationof myoblasts, In this study we used a tumour-derived musclecell line (TE671), with phenotyplc features of myoblasts, whichwe transfected to express HLA-DR1. However, this cell line wasunable to stimulate either established HLA-DR1-specific alloreactlveT cell clones or a primary alloresponse. Nor could it presenthaemagglutlnln peptide HA 306–324 to DR1-restricted, HA306–324-speciflc T cell clones or lines. Indeed, prelncubatlonwith DR1-expressing TE671 and HA 306–324 rendered suchT cells tolerant as Judged by their subsequent inability toproliferate in response to a DR1⁺ B cell line plus peptide HA306–324. These results imply that myoblasts do not providecostlmulatory signals, and are therefore unlikely to stimulateallospeclfic T cells following myoblasts transplantation orto initiate neoantlgen-speclfic immune responses following Invivo transfection.     

Chimerism as a tool to induce clinical transplantation tolerance

The principle that the induction of (mixed) hematopoietic chimerism can lead to transplantation tolerance to another organ from the same donor has been verified in rodents, in large animals including non-human primates and recently in a selected group of renal transplant recipients. The wide application of this tool depends on the development of more gentle, non-toxic induction protocols and reliable assays with which to detect the establishment of stable donor-specific tolerance.