Immunoregulation: studies of physiological and therapeutic autoreactivity by T cell vaccination

Monoclonal antibody to a DNA-binding domain of p53 mimics charge structure of DNA: anti-idiotypes to the anti-p53 antibody are anti-DNA

Antibodies to DNA are important markers of various autoimmune diseases and can be pathogenic; however, their generation is not understood. We previously reported that anti-DNA antibodies could be induced in mice by idiotypic immunization to PAb-421, an antibody to a DNA-binding domain of p53. We now report that two monoclonal antibodies of moderate affinity (K(D) asymptotically equal to 10(-7)), raised from PAb-421-immunized mice, specifically recognized both PAb-421 and DNA. These antibodies feature multiple arginine residues in the antigen-binding site, a unique characteristic of disease-associated anti-DNA antibodies; nevertheless, these anti-DNA antibodies show specific complementarity …

Inhibition of the mixed lymphocyte reaction by T cell vaccination

Immunization with attenuated activated autoreactive T cell lines and clones induces a response in syngeneic animals which can induce protection or recovery from autoimmune disease. This process has been termed T cell vaccination. The aim of the present study was to investigate the effect of immunization with MHC-reactive T cells on the mixed lymphocyte reaction (MLR). By injecting attenuated activated T cells primed for an alloantigen, we markedly reduced the MLR in both rats and mice. This depression appeared to be mediated by active suppression; lymphoid cells from T cell-vaccinated animals suppressed the MLR responsiveness of T cells from naive animals. Suppression of the MLR was not res…

Autoimmunity to the p53 protein is a feature of systemic lupus erythematosus (SLE) related to anti-DNA antibodies.

The induction of anti-DNA autoantibodies in systemic lupus erythematosus (SLE) patients is problematic because mammalian DNA is poorly immunogenic at best. Here we demonstrate a chain of connected antibodies in SLE patient sera that could account for the induction of anti-DNA antibody, and possibly for some of the pathogenic features of SLE. We now report that SLE patients, in addition to anti-DNA, produce antibodies to the carboxy-terminal domain of the tumour suppressor molecule p53; this p53 domain recognizes damaged DNA. Hence, these anti-p53 antibodies could mimic damaged DNA immunologically. Indeed, SLE sera do contain anti-idiotypic antibodies to a prototypic anti-p53 antibody. Moreo…

Autoimmune Diabetes Induced by the β-cell Toxin STZ: Immunity to the 60-kDa Heat Shock Protein and to Insulin

Administered at a suitably low dose, the toxin streptozotocin (STZ) can trigger an autoimmune process leading to destruction of the beta-cells of the pancreatic islets. In this study, we examined specific immunological reactions in mice before and during the development of STZ-induced autoimmune diabetes. We now report that the development of spontaneous autoantibodies to insulin can serve as a marker of susceptibility to a low dose of STZ. Susceptible male mice of the C57BL/KsJ strain manifested such anti-insulin antibodies, and resistant female mice did not. Administration of a low dose of STZ (five daily doses each of 30 mg/kg) induced transient hyperglycemia approximately 20-30 days lat…

Treatment of Recent-Onset Type 1 Diabetic Patients With DiaPep277: Results of a Double-Blind, Placebo-Controlled, Randomized Phase 3 Trial.

OBJECTIVE To evaluate safety and efficacy of DiaPep277 in preserving β-cell function in type 1 diabetic patients. RESEARCH DESIGN AND METHODS DIA-AID 1 is a multinational, phase 3, balanced-randomized, double-blind, placebo-controlled, parallel-group clinical study. Newly diagnosed patients (N = 457, aged 16–45 years) were randomized to subcutaneous injections of DiaPep277 or placebo quarterly for 2 years. The primary efficacy end point was the change from baseline in the area under the glucagon-stimulated C-peptide curve. Secondary end points were the change from baseline in mixed-meal stimulated C-peptide secretion and in fasting C-peptide and achieving target HbA1c ≤7% (≤53 mmol/mol). P…

Induction of the anti-ergotypic response.

The injection of syngeneic activated T cells into rodents can induce a T cell response against activation markers of the T cells, ergotopes. The responding anti-ergotypic T cells have been shown to suppress experimental autoimmune encephalomyelitis (EAE). This paper reports the characteristics of the anti-ergotypic response. It was found that irradiated activated T cells were as good as untreated living activated T cells in inducing anti-ergotypic cells in vivo. Glutardialdehyde-fixed (0.3%) cells were poor stimulators in vivo and non-stimulatory in vitro. Dilution of glutardialdehyde to 0.003% before fixation preserved the stimulatory capacity in vitro. Fixation or irradiation of T cells a…

Experimental autoimmune hepatitis: Disease induction, time course and t-cell reactivity

This study describes a murine model of autoimmune hepatitis: experimental autoimmune hepatitis. Experimental autoimmune hepatitis could be induced most effectively in male C57BL/6 mice by intraperitoneal immunization with the 100,000 g supernatant of syngeneic liver homogenate (S-100) in complete Freund's adjuvant. BALB/C and C3H mice were less susceptible than C57BL/6 mice. Experimental autoimmune hepatitis could not be induced in Lewis rats. Intraperitoneal immunization was more effective than intramuscular or subcutaneous injections, and the amount of protein administered above a threshold was of little influence. A single intraperitoneal injection of S-100 in complete Freund's adjuvant …

Prevalence of Autoantibodies to the p53 Protein in Autoimmune Hepatitis

The target antigens of anti-nuclear autoantibodies in autoimmune hepatitis (AIH) are poorly characterised. Since antibodies to the p53 nuclear protein have been reported in various autoimmune diseases, we have assessed the prevalence of these antibodies in patients with AIH (n = 45), primary biliary cirrhosis (n = 60), hepatitis B (n = 22), hepatitis C (n = 55), and in a control group of subjects with various non-liver diseases (n = 56). A significant proportion of patients with AIH (31%) had elevated levels of autoantibodies to the p53 protein. In contrast, the prevalence of these antibodies in primary biliary cirrhosis (8%) and viral hepatitis (6%) was similar to that in the control group…

Mechanisms of resistance to autoimmune disease induced by T-cell vaccination.

Many human autoimmune diseases tend to progress slowly. Phases of rapid progression may come to a halt and may be followed by transient or even permanent remissions. Autoimmune diseases in animals either arise spontaneously or are induced. The former tend to be slowly progressive, the latter mostly acute to subacute, and usually followed by spontaneous remissions. The mechanisms at work that prevent rapid disease progression and can effect remissions are poorly understood, but they may provide us with a clue both to natural self-tolerance and to the therapeutic induction of self-tolerance.