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Biomedical subjects

Lawrence Steinman

Publications and source records attributed to Lawrence Steinman.

At least 37 records · Page 2Linked to original sources
PubMed2005

Lipid microarrays identify key mediators of autoimmune brain inflammation.

Recent studies suggest that increased T-cell and autoantibody reactivity to lipids may be present in the autoimmune demyelinating disease multiple sclerosis. To perform large-scale multiplex analysis of antibody responses to lipids in multiple sclerosis, we developed microarrays composed of lipids present in the myelin sheath, including ganglioside, sulfatide, cerebroside, sphingomyelin and total brain lipid fractions. Lipid-array analysis showed lipid-specific antibodies against sulfatide, sphingomyelin and oxidized lipids in cerebrospinal fluid (CSF) derived from individuals with multiple sclerosis. Sulfatide-specific antibodies were also detected in SJL/J mice with acute experimental autoimmune encephalomyelitis (EAE). Immunization of mice with sulfatide plus myelin peptide resulted in a more severe disease course of EAE, and administration of sulfatide-specific antibody exacerbated EAE. Thus, autoimmune responses to sulfatide and other lipids are present in individuals with multiple sclerosis and in EAE, and may contribute to the pathogenesis of autoimmune demyelination.

Animals↗
PubMed2005

Treatment of autoimmune neuroinflammation with a synthetic tryptophan metabolite.

Local catabolism of the amino acid tryptophan (Trp) by indoleamine 2,3-dioxygenase (IDO) is considered an important mechanism of regulating T cell immunity. We show that IDO transcription was increased when myelin-specific T cells were stimulated with tolerogenic altered self-peptides. Catabolites of Trp suppressed proliferation of myelin-specific T cells and inhibited production of proinflammatory T helper-1 (T(H)1) cytokines. N-(3,4,-Dimethoxycinnamoyl) anthranilic acid (3,4-DAA), an orally active synthetic derivative of the Trp metabolite anthranilic acid, reversed paralysis in mice with experimental autoimmune encephalomyelitis, a model of multiple sclerosis (MS). Trp catabolites and their derivatives offer a new strategy for treating T(H)1-mediated autoimmune diseases such as MS.

Adoptive Transfer↗
PubMed2005

A suppressive oligodeoxynucleotide enhances the efficacy of myelin cocktail/IL-4-tolerizing DNA vaccination and treats autoimmune disease.

Targeting pathogenic T cells with Ag-specific tolerizing DNA vaccines encoding autoantigens is a powerful and feasible therapeutic strategy for Th1-mediated autoimmune diseases. However, plasmid DNA contains abundant unmethylated CpG motifs, which induce a strong Th1 immune response. We describe here a novel approach to counteract this undesired side effect of plasmid DNA used for vaccination in Th1-mediated autoimmune diseases. In chronic relapsing experimental autoimmune encephalomyelitis (EAE), combining a myelin cocktail plus IL-4-tolerizing DNA vaccine with a suppressive GpG oligodeoxynucleotide (GpG-ODN) induced a shift of the autoreactive T cell response toward a protective Th2 cytokine pattern. Myelin microarrays demonstrate that tolerizing DNA vaccination plus GpG-ODN further decreased anti-myelin autoantibody epitope spreading and shifted the autoreactive B cell response to a protective IgG1 isotype. Moreover, the addition of GpG-ODN to tolerizing DNA vaccination therapy effectively reduced overall mean disease severity in both the chronic relapsing EAE and chronic progressive EAE mouse models. In conclusion, suppressive GpG-ODN effectively counteracted the undesired CpG-induced inflammatory effect of a tolerizing DNA vaccine in a Th1-mediated autoimmune disease by skewing both the autoaggressive T cell and B cell responses toward a protective Th2 phenotype. These results demonstrate that suppressive GpG-ODN is a simple and highly effective novel therapeutic adjuvant that will boost the efficacy of Ag-specific tolerizing DNA vaccines used for treating Th1-mediated autoimmune diseases.

Amino Acid Sequence↗
PubMed2005

Virtues and pitfalls of EAE for the development of therapies for multiple sclerosis.

Experimental autoimmune encephalomyelitis (EAE) is a useful model for aiding the development of new treatments for MS. All therapies approved for MS ameliorate EAE. Two approved medications, glatiramer acetate and Natalizumab, were developed directly from studies in EAE. Several trials are ongoing in MS after success in EAE, including altered peptide ligands of myelin, DNA vaccines and statins. However, EAE has failed to predict the outcome of certain approaches. The reasons underlying such failures are discussed here.

Animals↗
PubMed2005

Design of effective immunotherapy for human autoimmunity.

A better understanding of the molecules involved in immune responses has identified many potential targets for the treatment of autoimmune diseases. But although successful therapies have been found for immune disorders in animal studies, few have passed the much harder test of treating human diseases. So far, non-antigen-specific approaches, such as the blocking of tumour-necrosis factor, are achieving some success but the same is not true for antigen-specific approaches. Future therapies will probably include both non-antigen-specific strategies that target cytokines (cell-cell signalling molecules) or block the molecules that stimulate immune responses, and antigen-specific therapies that induce tolerance to self antigens.

Antigens↗
PubMed2005

Therapeutic considerations for disease progression in multiple sclerosis: evidence, experience, and future expectations.

In the management of patients with multiple sclerosis (MS), providers are all faced with the highly formidable challenge of ascertaining whether, and to what degree, disease-modifying therapy is effective in the individual patient. While much has been learned in randomized, controlled clinical trials, we cannot simply extrapolate the outcomes of these initiatives and apply them to the care of a single patient. In the future, the application of pharmacogenetic techniques, proteomics, and microarray analysis will yield novel profiling information on individual patients that will substantially refine the specific therapeutic questions of relevance: (1) What is the best treatment for an individual patient? (2) Which patients require intensive therapeutic combination regimens to optimize control of the disease process? (3) What are the appropriate drug dosing targets for an individual patient? and (4) Which patients will be predisposed to the development of drug-related adverse events? Such data may provide a novel variable of drug responsiveness that will mandate its inclusion into the process of covariate analyses for clinical trials.

Disease Progression↗
PubMed2005

Drug Insight: using statins to treat neuroinflammatory disease.

Statins, a family of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are used primarily to reduce atherogenesis and cardiovascular morbidity. Surprisingly, they have also been shown to have immunomodulatory properties that might be of benefit for the treatment of autoimmune disorders. Statins can prevent and even reverse ongoing paralysis in experimental autoimmune encephalomyelitis--the mouse model for multiple sclerosis--and on the basis of these findings, statins are now being tested in patients with multiple sclerosis in clinical trials.

Animals↗
PubMed2005

Blocking adhesion molecules as therapy for multiple sclerosis: natalizumab.

Immunologists have long hypothesized that particular 'molecular addresses' govern lymphocyte entry to a given organ. In 1992, alpha4beta1 integrin was identified as the key molecule involved in homing to inflamed regions of the brain. An antibody to alpha4beta1integrin blocked paralysis in an animal model of multiple sclerosis, and the humanized monoclonal antibody natalizumab, which binds alpha4beta1 integrin, reduced relapses 66% in clinical trials in multiple sclerosis. Three months after its expedited approval by the FDA, natalizumab was removed from the market after two cases of deadly progressive multifocal leukoencephalopathy were reported among the few thousand patients who had taken this drug in those clinical trials.

Animals↗
PubMed2004

Immunity to the extracellular domain of Nogo-A modulates experimental autoimmune encephalomyelitis.

Nogo-66, the extracellular 66 aa loop of the Nogo-A protein found in CNS myelin, interacts with the Nogo receptor and has been proposed to mediate inhibition of axonal regrowth. It has been shown that immunization with Nogo-A promotes recovery in animal models of spinal cord injury through induction of Ab production. In this report, studies were performed to characterize the immune response to Nogo-66 and to determine the role of Nogo in experimental autoimmune encephalomyelitis (EAE). Immunization of EAE-susceptible mouse strains with peptides derived from Nogo-66 induced a CNS immune response with clinical and pathological similarities to EAE. The Nogo-66 peptides elicited strong T cell responses that were not cross-reactive to other encephalitogenic myelin Ags. Using a large scale spotted microarray containing proteins and peptides derived from a wide spectrum of myelin components, we demonstrated that Nogo-66 peptides also generated a specific Ab response that spreads to several other encephalitogenic myelin Ags following immunization. Nogo-66-specific T cell lines ameliorated established EAE, via Nogo-66-specific Th2 cells that entered the CNS. These results indicate that some T cell and B cell immune responses to Nogo-66 are associated with suppression of ongoing EAE, whereas other Nogo-66 epitopes can be encephalitogenic.

Adoptive Transfer↗
PubMed2004

Immune therapy for autoimmune diseases.

Our increasing understanding of the pathophysiology of autoimmune disease has revealed a number of checkpoints that can be targeted with immune therapy, including key mediators of lymphocyte adhesion and migration, destructive cytokines involved in tissue damage, and the complex of molecules critical in the presentation of self-antigen and the activation of autoaggressive T lymphocytes. In many organ-specific autoimmune diseases, the identity of the molecules attacked by T cells and autoantibodies is known and attempts are under way to tolerize the immune system with a high level of specificity to these targets.

Animals↗
PubMed2004

Statins as potential therapeutic agents in multiple sclerosis.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (ie, statins) are oral cholesterol-lowering drugs. Statins are well tolerated and have an excellent safety record. These agents competitively inhibit HMG CoA reductase, which is the enzyme that catalyzes the conversion of HMG CoA to L-mevalonate. Although L-mevalonate is a key intermediate in cholesterol synthesis, several of its metabolites are involved in post-translational modification of specific proteins involved in cell proliferation and differentiation. Thus, independent of their cholesterol-reducing properties, statins have important pleiotropic biologic effects. Recent reports indicate that statins have anti-inflammatory and neuroprotective properties. Whether statins will be of clinical benefit for patients with multiple sclerosis and other neurodegenerative diseases of the central nervous system will only be known after they are evaluated in prospective randomized clinical trials.

Humans↗
PubMed2004

Elaborate interactions between the immune and nervous systems.

The immune system and the nervous system maintain extensive communication, including 'hardwiring' of sympathetic and parasympathetic nerves to lymphoid organs. Neurotransmitters such as acetylcholine, norepinephrine, vasoactive intestinal peptide, substance P and histamine modulate immune activity. Neuroendocrine hormones such as corticotropin-releasing factor, leptin and alpha-melanocyte stimulating hormone regulate cytokine balance. The immune system modulates brain activity, including body temperature, sleep and feeding behavior. Molecules such as the major histocompatibility complex not only direct T cells to immunogenic molecules held in its cleft but also modulate development of neuronal connections. Neurobiologists and immunologists are exploring common ideas like the synapse to understand properties such as memory that are shared in these two systems.

Animals↗
PubMed2004

High-throughput methods for measuring autoantibodies in systemic lupus erythematosus and other autoimmune diseases.

Numerous groups have now validated high-throughput approaches to autoantibody profiling in a variety of systems. Recently, we have used autoantigen microarray technology to identify distinct autoantibody profiles in H-2 congenic MRL/lpr mice (Sekine et al., manuscript in preparation), and we are expanding this platform to study human and mouse models of IDDM and RA. We are also developing protein arrays for multiplex analysis of serum antibody isotypes. Multiplexed methods for autoantibody profiling will undoubtedly continue to uncover novel aspects of autoimmunity and B cell biology. It is now time to move these technologies beyond the proof-of-concept phase, and start addressing the next series of important questions. These include, but certainly are not limited to: identifying "autoantibody signatures" associated with disease state or outcome; profiling autoantibodies during the natural course of murine and human disease; and monitoring changes in autoantibody profiles of patients in response to therapeutic intervention. However, the next set of challenges is just right around the corner. As data and statistical analysis tools become more robust, it will be possible to generate and approach new hypotheses at an unprecedented pace.

Autoantibodies↗
PubMed2003

An immunomodulatory GpG oligonucleotide for the treatment of autoimmunity via the innate and adaptive immune systems.

Bacterial DNA and immunostimulatory CpG oligodeoxynucleotides (ODNs) activate the innate immune system to produce proinflammatory cytokines. Shown to be potent Th1-like adjuvants, stimulatory CpG motifs are currently used as effective therapeutic vaccines for various animal models of infectious diseases, tumors, allergies, and autoimmune diseases. In this study, we show that the application of an immunomodulatory GpG ODN, with a single base switch from CpG to GpG, can effectively inhibit the activation of Th1 T cells associated with autoimmune disease. Moreover, this immunomodulatory GpG ODN suppresses the severity of experimental autoimmune encephalomyelitis in mice, a prototypic Th1-mediated animal disease model for multiple sclerosis.

Adjuvants, Immunologic↗
PubMed2003

Protein microarrays guide tolerizing DNA vaccine treatment of autoimmune encephalomyelitis.

The diversity of autoimmune responses poses a formidable challenge to the development of antigen-specific tolerizing therapy. We developed 'myelin proteome' microarrays to profile the evolution of autoantibody responses in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS). Increased diversity of autoantibody responses in acute EAE predicted a more severe clinical course. Chronic EAE was associated with previously undescribed extensive intra- and intermolecular epitope spreading of autoreactive B-cell responses. Array analysis of autoantigens targeted in acute EAE was used to guide the choice of autoantigen cDNAs to be incorporated into expression plasmids so as to generate tolerizing vaccines. Tolerizing DNA vaccines encoding a greater number of array-determined myelin targets proved superior in treating established EAE and reduced epitope spreading of autoreactive B-cell responses. Proteomic monitoring of autoantibody responses provides a useful approach to monitor autoimmune disease and to develop and tailor disease- and patient-specific tolerizing DNA vaccines.

Animals↗
PubMed2003

Diverse targets for intervention during inflammatory and neurodegenerative phases of multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune central nervous system (CNS) demyelinating disease that causes relapsing and chronic neurologic impairment. Recent observations have altered certain traditional concepts regarding MS pathogenesis. A greater diversity of cell types and molecules involved in MS is now evident. While remyelination can occur during the early inflammatory phase when damage may be reversible, it is impaired in the later stages, which involve axonal death. These observations have important therapeutic implications.

Animals↗