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Biomedical subjects

I R Cohen

Publications and source records attributed to I R Cohen.

At least 19 recordsLinked to original sources
PubMed2007

Treatment of new-onset type 1 diabetes with peptide DiaPep277 is safe and associated with preserved beta-cell function: extension of a randomized, double-blind, phase II trial.

BACKGROUND: Treatment with DiaPep277, a peptide derived from HSP60, has been shown to preserve beta-cell function in non-obese diabetic mouse (NOD) mice and in a trial with newly diagnosed human patients with type 1 diabetes treated over a 10-month period. This article extends the clinical trial observations to a total of 20 months of treatment to determine the safety and the effects of repeated doses of DiaPep277 on endogenous insulin secretion, metabolic control, and exogenous insulin requirements. METHODS: Thirty-five male patients (aged 16-58) with a basal C-peptide greater than 0.1 nmol/L were assigned to periodic treatment with DiaPep277 (1 mg) or placebo for a 12-month treatment and 18-month observation protocol, later extended to an additional year of treatment. Stimulated C-peptide, HbA1c, and an exogenous insulin dose were the clinical endpoints. RESULTS: At 18 months, stimulated C-peptide concentrations had fallen in the placebo group (p = 0.0005) but were maintained in the DiaPep277 group. The need for exogenous insulin was higher in the placebo group than in the DiaPep277 group. Mean HbA1c concentrations were similar in both groups. After extension of the study, patients continuing treatment with DiaPep277 and those switched from placebo to DiaPep277 manifested a trend towards a greater preservation of beta-cell function compared to patients maintained on or switched to placebo. The safety profile of DiaPep277 was similar between the treatment and placebo groups, and no drug-related adverse events occurred. CONCLUSIONS: Periodic treatment of subjects with DiaPep277 over 2 years was safe and associated preservation of endogenous insulin secretion up to 18 months was observed.

Adolescent↗
PubMed2006

Anti-ergotypic immunoregulation.

T-cell vaccination (TCV) controls pathogenic autoimmune T-cell responses via two different regulatory cell populations: anti-idiotypic and anti-ergotypic T cells. Anti-idiotypic T cells recognize clone-specific determinants, like the CDR3 region of the T-cell receptor. Anti-ergotypic T cells recognize antigenic determinants derived from activation markers, which are upregulated by activated T cells, like CD25. In this review, we analyse the different components of the anti-ergotypic response: (1) the target T cells, which can be CD8+ or CD4+ T cells that express TCRalphabeta or TCRgammadelta; (2) the ergotope, which can be a T cell-restricted ergotope not expressed by other cell types or a widely expressed, shared ergotope and (3) the anti-ergotypic T cells, which are detectable in the naive immune system, but whose numbers can be expanded during the induction of an immune response against, or as a result of TCV or specific, anti-ergotypic vaccination. Finally, we discuss possible interactions between anti-ergotypic regulators and other regulatory T cells. We propose that the expression of major histocompatibility complex class II molecules by regulatory CD4+CD25+ T cells may make possible the cross-regulation of anti-ergotypic and CD4+CD25+ regulatory T cells, fine-tuning immunoregulation in the mature immune system.

Animals↗
PubMed2006

Antigen-chip technology for accessing global information about the state of the body.

Traditionally, immunologic diagnosis has been based on an attempt to correlate each disease with a specific immune reactivity, such as an antibody or a T-cell response to a single antigen specific for the disease entity. The state of the body, however, appears to be encoded by the immune system in collectives of reactivities and not by single reactivities. Here we describe our use of microarray technology and informatics to develop an antigen chip capable of detecting global patterns of antibodies binding to hundreds of antigens simultaneously. The patterns fashion diagnostic signatures.

Animals↗
PubMed2005

Alpha tropomyosin as a self-antigen in patients with Behçet's disease.

We report for the first time a significant increased lymphoproliferative response to alpha tropomyosin as well as observing autoantibodies to tropomyosin observed in Behcet's disease (BD) patients with posterior uveitis. Peripheral blood mononuclear cells (PBMCs) from 18 BD patients with posterior uveitis, 18 patients with other forms of noninfectious uveitis, 9 patients with retinal damage due to photocoagulation as well as 18 healthy donors were evaluated for antigen-specific lymphoproliferative responses to alpha tropomyosin and its derivative peptides. The proliferative responses of PBMCs to these antigens were studied using (3)H thymidine incorporation assay. Serum samples were also screened by ELISA for autoantibodies against tropomyosin. Six of the 18 (33%) BD patients with posterior uveitis showed increased proliferative response to alpha tropomyosin or its derivative peptides, while none of the healthy, disease controls were positive. The mean lymphoproliferative responses to tropomyosin were significantly higher (P < 0.02) in the BD patients compared to healthy or disease controls. Higher titres of anti-tropomyosin antibodies were also seen in four of the 18 BD patients but none in the healthy or disease control groups (P < 0.002). The occurrence of these abnormalities supports a possible role for alpha tropomyosin as a self-antigen in a subset of patients with Behcet's disease.

Adolescent↗
PubMed2004

T cell vaccination in multiple sclerosis relapsing-remitting nonresponders patients.

Myelin autoreactive T cells are involved in the pathogenesis of multiple sclerosis (MS) and lead to propagation of the disease. We evaluated the efficacy of T cell vaccination (TCV) therapy for patients with aggressive relapsing-remitting MS who failed to respond to immunomodulatory treatments. Twenty nonresponders relapsing-remitting MS patients were immunized with autologous attenuated T cell lines after activation with synthetic myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) encephalitogenic peptides. Each patient received three vaccinations in 6- to 8-week intervals. Annual relapse rate decreased from 2.6 to 1.1, P = 0.026. Neurological disability stabilized as compared with the 2- and 1-year pretreatment progression rates. Significant reduction in the number and volume of active lesions, as well as reduction in T2 lesion burden, was demonstrated by quantitative MRI analysis. No serious adverse events were observed. Our findings suggest that TCV has beneficial clinical effects in MS patients who, in spite of immunomodulatory treatments, continue to deteriorate. TCV could serve as a potential alternative therapy for this subgroup of nonresponders patients.

Adult↗
PubMed2002

Peptide therapy for Type I diabetes: the immunological homunculus and the rationale for vaccination.

The autoimmune process that produces Type I (insulin-dependent) diabetes mellitus seems to respond favourably to therapeutic vaccination with a peptide of the 60 kDa heat shock protein. This article is a personal review of the observations and the thinking that gave rise to the idea of therapeutic peptide vaccination. The rationale for vaccination therapy is compared to other approaches aimed at specific immunological treatment for autoimmune disease.

Animals↗
PubMed2002

Autoimmunization to epidermal growth factor, a component of the immunological homunculus.

Epidermal growth factor (EGF) is being tried as a vaccine in cancer immunotherapy with the aim of inducing neutralizing antibodies that might affect EGF-dependent tumors. Here we summarize our experience using the EGF self-molecule as an autoimmunigen. We report here that IgG anti-EGF antibodies are prevalent in healthy people and that augmentation of the response to EGF requires conjugation to an effective carrier and an adjuvant. Paradoxically, the response to EGF immunization could be enhanced by an 'immunosuppressive' treatment with cyclophosphamide, most probably by suppressing active control mechanisms. EGF is expressed in the thymus. Thus, EGF may be added to the immunological homunculus, the class of self-antigens to which there is both natural autoimmunity and natural regulation of the autoimmunity. The results using EGF as a vaccine can teach us about the homunculus and how to activate it.

Adjuvants, Immunologic↗
PubMed2001

T-cell vaccination for autoimmune disease: a panorama.

T-cell vaccination refers to a form of cell therapy, usually autologous, aimed at curing or ameliorating autoimmune diseases. This review considers five questions: What is TCV? How is it done? How does it work? Why does it work? And what is its future?

Autoimmune Diseases↗
PubMed2001

Beta-cell function in new-onset type 1 diabetes and immunomodulation with a heat-shock protein peptide (DiaPep277): a randomised, double-blind, phase II trial.

BACKGROUND: Type 1 diabetes results from autoimmune destruction of insulin-producing pancreatic beta cells. The 60 kDa heat-shock protein (hsp60) is one of the known target self antigens. An immunomodulatory peptide from hsp60, p277, arrested beta-cell destruction and maintained insulin production in newly diabetic NOD mice. We did a randomised, double-blind, phase II study of peptide treatment in patients with newly diagnosed (<6 months) type 1 diabetes. METHODS: 35 patients with type 1 diabetes and basal C-peptide concentrations above 0.1 nmol/L were assigned subcutaneous injections of 1 mg p277 and 40 mg mannitol in vegetable oil (DiaPep277; n=18) at entry, 1 month, and 6 months, or three placebo injections (mannitol in vehicle; placebo; n=17). The primary endpoint was glucagon-stimulated C-peptide production. Secondary endpoints were metabolic control and T-cell autoimmunity to hsp60 and to p277 (assayed by cytokine secretion). 31 patients completed 10 months of follow-up and were included in the intention-to-treat analysis. FINDINGS: At 10 months, mean C-peptide concentrations had fallen in the placebo group (n=16) but were maintained in the DiaPep277 group (n=15; 0.26 [SD 0.11] vs 0.93 [0.35] nmol/L; p=0.039). Need for exogenous insulin was higher in the placebo than in the DiaPep277 group (0.67 [0.33] vs 0.43 [0.17] U/kg; p=0.042). Haemoglobin A1c concentrations were low (around 7%) in both groups. T-cell reactivity to hsp60 and p277 in the DiaPep277 group showed an enhanced T-helper-2 cytokine phenotype. No adverse effects were noted. INTERPRETATION: Although this study was small, treatment of newly diagnosed type 1 diabetes with DiaPep277 seems to preserve endogenous insulin production, perhaps through induction of a shift from T-helper-1 to T-helper-2 cytokines produced by the autoimmune T cells.

Adult↗
PubMed2001

Protective autoimmunity is a physiological response to CNS trauma.

Primary damage caused by injury to the CNS is often followed by delayed degeneration of initially spared neurons. Studies in our laboratory have shown that active or passive immunization with CNS myelin-associated self-antigens can reduce this secondary loss. Here we show, using four experimental paradigms in rodents, that CNS trauma spontaneously evokes a beneficial T cell-dependent immune response, which reduces neuronal loss. (1) Survival of retinal ganglion cells in rats was significantly higher when optic nerve injury was preceded by an unrelated CNS (spinal cord) injury. (2) Locomotor activity of rat hindlimbs (measured in an open field using a locomotor rating scale) after contusive injury of the spinal cord (T8) was significantly better (by three to four score grades) after passive transfer of myelin basic protein (MBP)-activated splenocytes derived from spinally injured rats than in untreated injured control rats or rats similarly treated with splenocytes from naive animals or with splenocytes from spinally injured rats activated ex vivo with ovalbumin or without any ex vivo activation. (3) Neuronal survival after optic nerve injury was 40% lower in adult rats devoid of mature T cells (caused by thymectomy at birth) than in normal rats. (4) Retinal ganglion cell survival after optic nerve injury was higher (119 +/- 3.7%) in transgenic mice overexpressing a T cell receptor (TcR) for MBP and lower (85 +/- 1.3%) in mice overexpressing a T cell receptor for the non-self antigen ovalbumin than in matched wild types. Taken together, the results imply that CNS injury evokes a T cell-dependent neuroprotective response.

Animals↗
PubMed2001

Modulation of proteinase-K resistant prion protein by prion peptide immunization.

Prion diseases are caused by conformational alterations in the prion protein (PrP). The immune system has been assumed to be non-responsive to the self-prion protein, therefore, PrP autoimmunity has not been investigated. Here, we immunized various strains of mice with PrP peptides, some selected to fit the MHC class II-peptide binding motif. We found that specific PrP peptides elicited strong immune responses in NOD, C57BL/6 and A/J mice. To test the functional effect of this immunization, we examined the expression of proteinase-K-resistant PrP by a scrapie-infected tumor transplanted to immunized syngeneic A/J mice. PrP peptide vaccination did not affect the growth of the infected tumor transplant, but significantly reduced the level of protease-resistant PrP. Our results demonstrate that self-PrP peptides are immunogenic in mice and suggest that this immune response might affect PrP-scrapie levels in certain conditions.

Amino Acid Sequence↗
PubMed2001

Antigenic mimicry, clonal selection and autoimmunity.

The triggering of autoimmunity by infection or immunization is often blamed on antigenic mimicry. But the concept of antigen mimicry impinges on our understanding of adaptive immunity in general, and not only on autoimmunity. Here are some thoughts about the consequences of immune mimicry.

Animals↗
PubMed2001

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. Moreover, SLE anti-DNA antibodies also recognize this type of anti-p53 antibody. Indeed, binding of affinity-purified anti-DNA both to DNA and to the anti-p53 antibody could be blocked by a p53 peptide derived from the DNA-binding domain. This mimicry of the p53 DNA-binding domain by the SLE anti-DNA antibodies is functional: activation of the p53 molecule could be inhibited by such anti-DNA antibodies. Thus, anti-DNA antibodies may arise in SLE patients by a chain of idiotypic autoimmunity centered around p53 autoimmunity. The SLE anti-DNA and anti-p53 antibodies can functionally block p53 activation, and so could affect apoptosis.

Antibodies, Antinuclear↗
PubMed2001

Autoantibodies to pancreatic hsp60 precede the development of glucose intolerance in patients with cystic fibrosis.

Persons expressing the genetic disease cystic fibrosis (CF) suffer from a high risk of developing impaired glucose tolerance and diabetes. The development of diabetes in CF has been attributed, in the past, to the destruction of pancreatic islets and their resident beta-cells secondary to the destruction of the surrounding tissue by mechanical clogging of the pancreatic exocrine ducts. However, the discovery that autoimmunity to the 60-kDa heat shock protein (hsp60) may cause type I diabetes in NOD mice raises the possibility that hsp60 autoimmunity may be involved in CF diabetes too; could the hyperimmunization to bacterial hsp60 characteristic of CF spread to self-hsp60 and hence to autoimmune diabetes? We now report that rising levels of IgG autoantibodies to hsp60 do indeed precede the appearance of glucose intolerance and diabetes in CF patients. We produced a recombinant human pancreatic hsp60 protein and investigated the IgG antibody response to hsp60 in prediabetic and non-diabetic patients with CF. To detect hsp60 autoantibodies in the presence of high levels of antibodies to bacterial hsp60, we absorbed test sera with the 60-kDa GroEL of Pseudomonas aeruginosa and used an immunostaining technique. Using this technique, 32 prediabetic CF patients were evaluated over a five-year period, three years, on the average, before the onset of glucose intolerance. We found that a significant increase in hsp60 autoantibody preceded impaired glucose tolerance (P=0.042, n=17), diabetes (P=0.011, n=15) and glucose intolerance (P=0.005, n=32). As has been observed in NOD mice and in type I diabetic patients, the hsp60 autoantibodies decline at the outbreak of glucose intolerance in the CF patients. The association of CF diabetes with the rise and fall of hsp60 autoimmunity suggests that the pathogenesis of the diabetes may not be merely mechanical, but arise in the wake of bacterial hyperimmunisation.

Adolescent↗
PubMed2001

Autoantibody patterns in diabetes-prone NOD mice and in standard C57BL/6 mice.

Autoantibodies are commonly found in healthy individuals and strains of mice that are not prone to autoimmunity. The present study was undertaken to identify self antigens recognized by serum autoantibodies from unimmunized mice of two strains: NOD mice prone to spontaneously develop autoimmune diabetes and C57BL/6 mice known to be relatively resistant to autoimmune disease. IgM and IgG autoantibodies detected in the sera of NOD and C57BL/6 mice manifested different patterns of reactivity. The IgM autoantibodies from C57BL/6 serum reacted with more self antigens and showed higher OD values than the IgM autoantibodies from NOD mice. In contrast, the IgG autoantibodies from NOD serum reacted with more antigens and displayed higher OD readings than did IgG autoantibodies from C57BL/6 mice. Among the antigens recognized by the autoantibodies, particularly of the IgG class, were self antigens known to induce experimental autoimmune diseases in NOD and C57BL/6 mice. In addition, IgG autoantibodies from NOD mice reacted with self antigens reported to mark the spontaneous autoimmune diabetes that characterizes this strain of mice. These results suggest that naturally occurring IgG autoantibodies reflect susceptibility to induction of specific autoimmune diseases. In addition, the results suggest that IgM autoantibodies may by associated with mechanisms that might prevent autoimmune disease.

Animals↗
PubMed2001

Modeling the influence of TH1- and TH2-type cells in autoimmune diseases.

A sharp TH1/TH2 dichotomy has often been used to define the effects of cytokines on autoimmune diseases. However contradictory results in recent research indicate that the situation may be more complex. Here, we build a simple mathematical model aimed at settling the contradictions. The model is applied using Ordinary Differential Equations (ODE). We show here that a TH1/TH2 paradigm is only an external view of a complex multivariate system.

Animals↗
PubMed2001

Self prion protein peptides are immunogenic in Lewis rats.

Prion diseases are caused by abnormal folding of the prion protein. The paradigm is that the prion protein is not immunogenic because the immune system must be tolerant to such a self protein. In an attempt to identify immunogenic prion peptides, we immunized Lewis rats with peptides that fitted the MHC class II RT1.B(1)motif. Both humoral and cellular immunity to the prion peptides were obtained without any harmful effects to young animals. However, when 8-month-old rats were immunized, a sixth (6/36) of the rats developed severe skin inflammation with concomitant hair loss. These findings suggest that immunity to self-prion peptides can be readily induced in Lewis rats and that this immune response may have pathogenic consequences in older rats.

Age Factors↗