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Biomedical subjects

Lawrence Steinman

Publications and source records attributed to Lawrence Steinman.

At least 55 records · Page 3Linked to original sources
PubMed2003

Severe anaphylactic reactions to glutamic acid decarboxylase (GAD) self peptides in NOD mice that spontaneously develop autoimmune type 1 diabetes mellitus.

BACKGROUND: Insulin dependent (i.e., "type 1") diabetes mellitus (T1DM) is considered to be a T cell mediated disease in which TH1 and Tc autoreactive cells attack the pancreatic islets. Among the beta-cell antigens implicated in T1DM, glutamic acid decarboxylase (GAD) 65 appears to play a key role in the development of T1DM in humans as well as in non-obese diabetic (NOD) mice, the experimental model for this disease. It has been shown that shifting the immune response to this antigen from TH1 towards TH2, via the administration of GAD65 peptides to young NOD mice, can suppress the progression to overt T1DM. Accordingly, various protocols of "peptide immunotherapy" of T1DM are under investigation. However, in mice with experimental autoimmune encephalomyelitis (EAE), another autoimmune TH1 mediated disease that mimics human multiple sclerosis, anaphylactic shock can occur when the mice are challenged with certain myelin self peptides that initially were administered with adjuvant to induce the disease. RESULTS: Here we show that NOD mice, that spontaneously develop T1DM, can develop fatal anaphylactic reactions upon challenge with preparations of immunodominant GAD65 self peptides after immunization with these peptides to modify the development of T1DM. CONCLUSIONS: These findings document severe anaphylaxis to self peptide preparations used in an attempt to devise immunotherapy for a spontaneous autoimmune disease. Taken together with the findings in EAE, these results suggest that peptide therapies designed to induce a TH1 to TH2 shift carry a risk for the development of anaphylactic reactivity to the therapeutic peptides.

Anaphylaxis↗
PubMed2003

Multiple elements of the allergic arm of the immune response modulate autoimmune demyelination.

Analysis of mRNA from multiple sclerosis lesions revealed increased amounts of transcripts for several genes encoding molecules traditionally associated with allergic responses, including prostaglandin D synthase, histamine receptor type 1 (H1R), platelet activating factor receptor, Ig Fc epsilon receptor 1 (Fc epsilon RI), and tryptase. We now demonstrate that, in the animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), mediated by T helper 1 (Th1) T cells, histamine receptor 1 and 2 (H1R and H2R) are present on inflammatory cells in brain lesions. Th1 cells reactive to myelin proteolipid protein expressed more H1R and less H2R than Th2 cells. Pyrilamine, an H1R antagonist, blocked EAE, and the platelet activating factor receptor antagonist CV6209 reduced the severity of EAE. EAE severity was also decreased in mice with disruption of the genes encoding Ig Fc gamma RIII or both Fc gamma RIII and Fc epsilon RI. Prostaglandin D synthase and tryptase transcripts were elevated in EAE brain. Taken together, these data reveal extensive involvement of elements of the immune response associated with allergy in autoimmune demyelination. The pathogenesis of demyelination must now be viewed as encompassing elements of both Th1 responses and "allergic" responses.

Animals↗
PubMed2003

Protein arrays for autoantibody profiling and fine-specificity mapping.

Protein arrays provide a powerful approach to study autoimmune disease. Autoimmune responses activate B cells to produce autoantibodies that recognize self-molecules termed autoantigens, many of which are proteins or protein complexes. Protein arrays enable profiling of the specificity of autoantibody responses against panels of peptides and proteins representing known autoantigens as well as candidate autoantigens. In addition to identifying autoantigens and mapping immunodominant epitopes, proteomic analysis of autoantibody responses will further enable diagnosis, prognosis, and tailoring of antigen-specific tolerizing therapy.

Animals↗
PubMed2003

Genomic and proteomic analysis of multiple sclerosis. Opinion.

Multiple sclerosis (MS) and other autoimmune diseases result from the dysregulation of genetic and proteomic programs. In MS, the loss of immune homeostasis leads to aberrant targeting and destruction of the myelin sheath, which manifests as the clinical syndrome of MS. The advent of technologies to perform large-scale analysis of mRNA transcript and protein expression will transform our understanding of the mechanisms underlying the initiation and progression of MS, and will yield new targets for therapeutic intervention.

Animals↗
PubMed2003

Transcriptional analysis of targets in multiple sclerosis.

Large-scale analyses of messenger RNA transcripts and autoantibody responses, taken from the actual sites of disease, provide us with an unprecedented view of the complexity of autoimmunity. Despite an appreciation of the large number of pathways and pathological processes that are involved in these diseases, a few practical targets and several new strategies have emerged from these studies. This review focuses on multiple sclerosis and on the approaches that are being used to identify new targets that might be manipulated to control this disease.

Autoantibodies↗
PubMed2003

Statins as potential therapeutic agents in neuroinflammatory disorders.

PURPOSE OF REVIEW: Multiple sclerosis is a central nervous system inflammatory demyelinating disease that is thought to have an autoimmune pathogenesis. Recent results indicate that 'statins', 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, which are the most commonly used oral cholesterol-lowering drugs, have immunomodulatory properties. In this article we will review those findings that indicate that statins may be beneficial in the treatment of multiple sclerosis, neurodegenerative disease, and ischemic stroke. RECENT FINDINGS: It was reported that statin treatment could either inhibit or reverse chronic and relapsing experimental autoimmune encephalomyelitis, a model of multiple sclerosis. Several immunomodulatory properties of statins may account for their beneficial clinical effect: Statins decreased the migration of leukocytes into the central nervous system, inhibited MHC class II and costimulatory signals required for activation of proinflammatory T cells, induced a T(H)2 phenotype in T cells, and decreased the expression of inflammatory mediators in the central nervous system, including nitric oxide and tumor necrosis factor alpha. It was also demonstrated that statin use significantly reduced beta-amyloid secretion in the cerebrospinal fluid of experimental animals. Clinically, there is emerging evidence that statins have beneficial effects in patients with multiple sclerosis, Alzheimer's disease, and ischemic stroke. SUMMARY: In-vitro studies have indicated that statins may have anti-inflammatory properties. Results from in-vivo animal models suggest that statins may be beneficial in treatment of different central nervous system conditions. Larger scale, randomized, double-blind trials are needed to validate the role of statins as a treatment of inflammatory central nervous system diseases.

Alzheimer Disease↗
PubMed2003

Microarray profiling of antibody responses against simian-human immunodeficiency virus: postchallenge convergence of reactivities independent of host histocompatibility type and vaccine regimen.

We developed antigen microarrays to profile the breadth, strength, and kinetics of epitope-specific antiviral antibody responses in vaccine trials with a simian-human immunodeficiency virus (SHIV) model for human immunodeficiency virus (HIV) infection. These arrays contained 430 distinct proteins and overlapping peptides spanning the SHIV proteome. In macaques vaccinated with three different DNA and/or recombinant modified vaccinia virus Ankara (rMVA) vaccines encoding Gag-Pol or Gag-Pol-Env, these arrays distinguished vaccinated from challenged macaques, identified three novel viral epitopes, and predicted survival. Following viral challenge, anti-SHIV antibody responses ultimately converged to target eight immunodominant B-cell regions in Env regardless of vaccine regimen, host histocompatibility type, and divergent T-cell specificities. After challenge, responses to nonimmunodominant epitopes were transient, while responses to dominant epitopes were gained. These data suggest that the functional diversity of anti-SHIV B-cell responses is highly limited in the presence of persisting antigen.

Amino Acid Sequence↗
PubMed2003

Statins and their potential targets in multiple sclerosis therapy.

Multiple sclerosis (MS) is a CNS-demyelinating disease characterised by relapsing and chronic neurological impairment. While traditionally CNS autoantigen-specific CD4(+) T cells have been considered the culprits in the initial phase of the disease, recent observations have altered this concept. It is now recognised that other T lymphocyte subclasses can initiate CNS demyelination. In addition, other cell types and molecules may play an important role in MS pathogenesis. There is overwhelming evidence that MS is a dynamic process, in which recurrent episodes of blood-brain barrier disruption and CNS inflammation play a crucial role in early disease stages, leading eventually to the largely irreversible changes of demyelination, gliosis and axonal degeneration. These observations may have important therapeutic implications. Within the last ten years, several medications have been approved for MS treatment. These agents, all of which are given parenterally, are only partially effective and are often associated with adverse effects and potential toxicities. The number and different types of medications used for MS are likely to increase in the near future, as several novel therapies are currently tested in clinical trials. 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors, 'statins', are cholesterol-lowering drugs that are given orally, are safe and have biological effects independent of their cholesterol-reducing properties. Recent reports have shown that statins have anti-inflammatory and neuroprotective properties that may be beneficial in the treatment of MS. This article will outline experimental evidence that suggests potential clinical benefits of statins for MS patients.

Adult↗
PubMed2002

The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease.

Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, which are approved for cholesterol reduction, may also be beneficial in the treatment of inflammatory diseases. Atorvastatin (Lipitor) was tested in chronic and relapsing experimental autoimmune encephalomyelitis, a CD4(+) Th1-mediated central nervous system (CNS) demyelinating disease model of multiple sclerosis. Here we show that oral atorvastatin prevented or reversed chronic and relapsing paralysis. Atorvastatin induced STAT6 phosphorylation and secretion of Th2 cytokines (interleukin (IL)-4, IL-5 and IL-10) and transforming growth factor (TGF)-beta. Conversely, STAT4 phosphorylation was inhibited and secretion of Th1 cytokines (IL-2, IL-12, interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha) was suppressed. Atorvastatin promoted differentiation of Th0 cells into Th2 cells. In adoptive transfer, these Th2 cells protected recipient mice from EAE induction. Atorvastatin reduced CNS infiltration and major histocompatibility complex (MHC) class II expression. Treatment of microglia inhibited IFN-gamma-inducible transcription at multiple MHC class II transactivator (CIITA) promoters and suppressed class II upregulation. Atorvastatin suppressed IFN-gamma-inducible expression of CD40, CD80 and CD86 co-stimulatory molecules. l-Mevalonate, the product of HMG-CoA reductase, reversed atorvastatin's effects on antigen-presenting cells (APC) and T cells. Atorvastatin treatment of either APC or T cells suppressed antigen-specific T-cell activation. Thus, atorvastatin has pleiotropic immunomodulatory effects involving both APC and T-cell compartments. Statins may be beneficial for multiple sclerosis and other Th1-mediated autoimmune diseases.

Adoptive Transfer↗
PubMed2002

Late pregnancy suppresses relapses in experimental autoimmune encephalomyelitis: evidence for a suppressive pregnancy-related serum factor.

Women with multiple sclerosis have significantly diminished disease activity during pregnancy. The purpose of our study was to identify the underlying mechanism for the diminished disease activity. We found that during the period of late pregnancy there is protection against paralysis, during both the induction and effector phases of relapsing experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. We did not find any changes in the cytokine secretion profiles or the proliferative activity of autoreactive T cells from mice induced during late pregnancy compared with virgin controls. In mice mated after disease onset, the inflammatory histologic lesions did not clear, despite marked clinical improvement during pregnancy. We found evidence for a serum factor present in late pregnancy that suppresses T cell activation. In the presence of sera taken from mice late in pregnancy, the proliferative response and IL-2 production of proteolipid protein p139-151-specific T cells were significantly diminished as compared with stimulation in the presence of normal mouse sera. In conclusion, serum from late pregnancy has the capacity to down-regulate T cell responses and might be associated with the amelioration of disease activity in experimental autoimmune encephalomyelitis.

Adoptive Transfer↗
PubMed2002

Autoantibody profiling for the study and treatment of autoimmune disease.

Proteomics technologies enable profiling of autoantibody responses using biological fluids derived from patients with autoimmune disease. They provide a powerful tool to characterize autoreactive B-cell responses in diseases including rheumatoid arthritis, multiple sclerosis, autoimmune diabetes, and systemic lupus erythematosus. Autoantibody profiling may serve purposes including classification of individual patients and subsets of patients based on their 'autoantibody fingerprint', examination of epitope spreading and antibody isotype usage, discovery and characterization of candidate autoantigens, and tailoring antigen-specific therapy. In the coming decades, proteomics technologies will broaden our understanding of the underlying mechanisms of and will further our ability to diagnose, prognosticate and treat autoimmune disease.

Antibody Formation↗