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Biomedical subjects

L Steinman

Publications and source records attributed to L Steinman.

At least 109 records · Page 6Linked to original sources
PubMed1994

Minimum structural requirements for peptide presentation by major histocompatibility complex class II molecules: implications in induction of autoimmunity.

The precise mechanisms of failure of immunological tolerance to self proteins are not known. Major histocompatibility complex (MHC) susceptibility alleles, the target peptides, and T cells with anti-self reactivity must be present to cause autoimmune diseases. Experimental autoimmune encephalomyelitis (EAE) is a murine model of a human autoimmune disease, multiple sclerosis. In EAE, residues 1-11 of myelin basic protein (MBP) are the dominant disease-inducing determinants in PL/J and (PL/J x SJL/J)F1 mice. Here we report that a six-residue peptide (five of them native) of MBP can induce EAE. Using peptide analogues of the MBP-(1-11) peptide, we demonstrate that only four native MBP residues are required to stimulate MBP-specific T cells. Therefore, this study demonstrates lower minimum structural requirements for effective antigen presentation by MHC class II molecules. Many viral and bacterial proteins share short runs of amino acid similarity with host self proteins, a phenomenon known as molecular mimicry. Since a six-residue peptide can sensitize MBP-specific T cells to cause EAE, these results define a minimum sequence identity for molecular mimicry in autoimmunity.

Amino Acid Sequence↗
PubMed1994

Repeated treatment with chimeric anti-CD4 antibody in multiple sclerosis.

We treated 21 multiple sclerosis patients with two to four doses of cM-T412, a chimeric monoclonal antibody against the CD4 antigen found on helper/inducer T lymphocytes. The mean number (+/- standard error) of circulating CD4 lymphocytes decreased from 888 (+/- 81) cells/mm3 at baseline to 246 (+/- 18) after treatment. At 1 year after the last treatment, the CD4 count had recovered to only 335 (+/- 32). The antibody had no effect on CD8 lymphocytes, B lymphocytes, or other leukocytes. Side effects were minimal. Despite the prolonged depletion of CD4 lymphocytes, no opportunistic infections occurred. Only 1 patient had a possible allergic reaction. Most patients were clinically stable, but a few progressed. We conclude that repeated treatment with cM-T412 is effective in reducing the number of circulating CD4 lymphocytes and has no limiting side effects.

Adult↗
PubMed1994

Myelin basic protein peptide specificity and T-cell receptor gene usage of HPRT mutant T-cell clones in patients with multiple sclerosis.

Characterization of T cells responding to autoantigens is central to understanding autoimmune disease. We have used somatic mutation at the hypoxanthine guanine phosphoribosyltransferase (HPRT) gene as an index of T-cell amplification in vivo. With this strategy we previously showed that myelin basic protein-reactive T cells can be isolated only from the HPRT mutant T-cell population cultured from the peripheral blood of multiple sclerosis patients and not from normal individuals. In this study, 165 HPRT mutant and 104 wild-type clones were examined for their reactivity to myelin basic protein and overlapping peptides of myelin basic protein. Five HPRT mutant clones that recognized myelin basic protein and myelin basic protein peptides along with three clones that responded to myelin basic protein peptide alone were isolated. All but one of the eight clones recognized peptides derived from the carboxy terminus of myelin basic protein (p84-168). Sequence analysis showed heterogeneous expression of T-cell receptor V alpha and V beta genes and CDR3s. These studies showed that in vivo amplified autoimmune T cells from patients with long-standing disease use diverse T-cell receptor elements in the recognition of C-terminal myelin basic protein peptides.

Adult↗
PubMed1994

Cell adhesion molecules: a selective therapeutic target for alleviation of IDDM.

Selective homing of autoreactive lymphocytes to the pancreatic islets of Langerhans is essential for triggering the cascade of molecular and cellular interactions which culminate in the specific destruction of the insulin-producing beta-cells. Based upon the sequential multistep model of lymphocyte adhesion to the endothelium, we investigated the possibility of preventing the progression of insulin-dependent diabetes mellitus (IDDM) by selectively blocking L-selectin and alpha 4-integrin homing receptors, which function at different stages of the adhesion process. Treatment of NOD mice with mAb specific for L-selectin or alpha 4-integrin resulted in a significant inhibition of lymphocytic infiltration (insulitis). Both spontaneous development and acute transfer of IDDM were completely prevented by administration of anti-alpha 4-integrin antibody and partially inhibited by anti-L-selectin antibody. The protective effect was of long duration. Interestingly, the autoimmune T cell responses to a panel of beta cell autoantigens and the lymphocytic infiltration of salivary glands (sialadenitis) appeared unaffected by anti-L-selectin or anti-alpha 4-integrin treatment. These data suggest that prevention of lymphocyte homing to the pancreatic islets may provide a selective target for prevention/treatment of IDDM in patients.

Animals↗
PubMed1994

Infection and multiple sclerosis: a possible role for superantigens?

The association of infection with autoimmune diseases is enigmatic, partly because cause and effect are difficult to establish in chronic diseases. Microorganisms might initiate multiple sclerosis and trigger relapses of disease. Superantigens might be involved in autoimmunity through the (re)activation of T cells, including autoreactive cells, expressing certain T cell receptor beta chain variable regions.

Bacterial Infections↗
PubMed1994

Restricted heterogeneity of T cell receptor variable alpha chain transcripts in hearts of Chagas' disease cardiomyopathy patients.

The role of autoimmunity in the pathogenesis and progression of heart lesions in the chronic phase of Chagas' disease is controversial. In the absence of parasites in situ, the T cell infiltrate seen in heart lesions may be the primary determinant of tissue damage ultimately leading to heart failure and death. We used the polymerase chain reaction to amplify each known T cell receptor (TCR) V alpha and V beta subfamily-specific sequence in transcripts derived from heart samples obtained from Chagas' cardiomyopathy patients. The average number of TCR V alpha subfamilies (7.1 per tissue sample) was significantly lower than that for TCR V beta subfamilies (15.1 per sample). The average percentage of tissue samples positive per TCR V alpha and V beta subfamily was respectively 39.6% vs. 73.5%. These data suggest that, in Chagas' heart lesions, the detectable TCR V alpha repertoire is significantly narrower than TCR V beta repertoire. On the other hand, in normal heart tissue, diversity of V alpha and V beta TCR is similar among the scarce circulating T cell population. Such evidence of restricted TCR V region repertoire has been described in experimental and human autoimmune diseases. Our results are consistent with the possibility that T cells responsible for heart damage in chronic Chagas' cardiomyopathy may be recognizing a few heart-specific antigenic targets.

Base Sequence↗
PubMed1994

'Lupus-prone' mice are susceptible to organ-specific autoimmune disease, experimental allergic encephalomyelitis.

Immunization with the multideterminant autoantigen myelin basic protein (MBP) causes experimental allergic encephalomyelitis (EAE), a T-cell-mediated autoimmune disease that serves as a model for multiple sclerosis (MS). MBP peptides Ac1-11 and p35-47 induce potent EAE in mice of the H-2u haplotype. T cells specific for Ac1-11 predominantly utilize one T-cell receptor (TCR) V beta gene segment, V beta 8.2. All T-cell clones and hybridomas analyzed, regardless of TCR V beta usage, utilize D beta 2 and J beta 2 elements. The NZW mouse strain (H-2z), which contributes to the spontaneous 'lupus-like' illness in (NZB x NZW)F1 mice, has a genomic deletion encompassing D beta 2 and J beta 2 gene segments. The NZW strain expresses class II (I-A and I-E) genes which share identical sequences with H-2u class II. We investigated whether these strains are susceptible to EAE induced with intact MBP and known encephalitogenic MBP peptides. In vitro analysis demonstrated that NZW antigen-presenting cells (APC) can present MBP and MBP peptide Ac1-11 to an encephalitogenic T-cell clone derived from an H-2u mouse, confirming the functional identity of NZW class-II (I-A) molecules with their respective H-2u class-II gene products. In vivo results demonstrated that NZW and (NZB x NZW)F1 mice are susceptible to EAE induced with intact MBP and Ac1-11. MBP p35-47 caused EAE in (NZB x NZW)F1 mice, which express alleles for both the normal (NZB) TCR beta-gene locus, and the abnormal (NZW) TCR beta-gene locus containing the J beta 2 deletion.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1994

Homologies between T cell receptor junctional sequences unique to multiple sclerosis and T cells mediating experimental allergic encephalomyelitis.

The selection of T cell clones with mutations in the hypoxanthine guanine phosphoribosyltransferase (hprt) gene has been used to isolate T cells reactive to myelin basic protein (MBP) in patients with multiple sclerosis (MS). These T cell clones are activated in vivo, and are not found in healthy individuals. The third complementarity determining regions (CDR3) of the T cell receptor (TCR) alpha and beta chains are the putative contact sites for peptide fragments of MBP bound in the groove of the HLA molecule. The TCR V gene usage and CDR3s of these MBP-reactive hprt-T cell clones are homologous to TCRs from other T cells relevant to MS, including T cells causing experimental allergic encephalomyelitis (EAE) and T cells found in brain lesions and in the cerebrospinal fluid (CSF) of MS patients. In vivo activated MBP-reactive T cells in MS patients may be critical in the pathogenesis of MS.

Amino Acid Sequence↗
PubMed1994

Reversal of experimental autoimmune encephalomyelitis with a hydroxamate inhibitor of matrix metalloproteases.

Gelatinases, belonging to the matrix metalloproteases, contribute to tissue destruction in inflammatory demyelinating disorders of the central nervous system such as multiple sclerosis. We used experimental autoimmune encephalomyelitis (EAE) as an animal model to evaluate the effect of a hydroxamate matrix metalloprotease inhibitor (GM 6001) on inflammatory demyelination. A single dose of the inhibitor, given intraperitoneally, provided sufficient levels in the cerebrospinal fluid of animals with EAE to induce at least a partial inhibition of the gelatinase activity in the cerebrospinal fluid. When administered daily either from the time of disease induction or from the onset of clinical signs, GM 6001 suppressed the development or reversed clinical EAE in a dose-dependent way, respectively. Animals returned to the same clinical course as the nontreated group after cessation of treatment. Animals treated from the onset of clinical signs had normal permeability of the blood-brain barrier, compared with the enhanced permeability in nontreated animals. These results indicate that matrix metalloprotease inhibition can reverse ongoing EAE. This effect appears to be mediated mainly through restoration of the damaged blood-brain barrier in the inflammatory phase of the disease, since, the degree of demyelination and inflammation did not differ between the treatment groups.

Animals↗
PubMed1993

Genetic factors in multiple sclerosis.

OBJECTIVE: To evaluate the role of candidate genes in the susceptibility to multiple sclerosis (MS) and describe the role of T-cell receptor (TCR) gene rearrangements in the MS brain lesion in identifying a major target of the immune response in this disease. DATA SOURCES: MEDLINE, bibliography review of published data, and unpublished studies. STUDY SELECTION: Published studies using novel molecular approaches to analyze the role of the major histocompatibility complex (MHC) and TCR gene complexes, as well as other candidate genes, in susceptibility to MS. We analyze epigenetic events involving TCR genes in individuals with MS and describe recent clinical trials in which immunotherapy has been attempted. DATA SYNTHESIS: Consistent with a polygenic model for disease predisposition, MHC and TCR gene associations with MS are relatively weak. Despite intensive research, no other putative "MS genes" have been firmly established. The analysis of TCR rearrangements in the brain lesion has helped to identify a major target of the immune response in MS. CONCLUSION: Understanding the genetic basis for autoimmune demyelination will offer new possibilities for the treatment of this illness.

Animals↗
PubMed1993

Inhibition of insulitis and prevention of diabetes in nonobese diabetic mice by blocking L-selectin and very late antigen 4 adhesion receptors.

Leukocyte adhesion to the endothelial venules in the pancreatic islets is thought to be one of the initial steps in the development of insulin-dependent diabetes mellitus. It has been suggested that leukocyte adhesion to endothelium is a sequential multistep process involving various different homing receptors. We report here that blocking different homing receptors--namely, L-selectin and very late antigen 4 (VLA-4)--which function during different stages of the adhesion process, by specific monoclonal antibodies inhibits insulitis and prevents diabetes in mice. Moreover, leukocyte attachment to the inflamed vessels within pancreatic sections could be inhibited by anti-L-selectin and anti-VLA-4 antibodies. Interestingly, anti-L-selectin or anti-VLA-4 antibody did not appear to influence the autoimmune response to a panel of pancreatic beta-cell autoantigens. These data suggest that L-selectin and VLA-4 receptors are involved in mediating leukocyte homing to the islets and that intervention of these two adhesion pathways may provide a novel approach for treatment of autoimmune diseases such as insulin-dependent diabetes mellitus.

Animals↗
PubMed1993

Induction of relapsing paralysis in experimental autoimmune encephalomyelitis by bacterial superantigen.

The role of infection in the pathogenesis of clinical relapses that occur in most autoimmune diseases, including multiple sclerosis, remains to be established. Experimental autoimmune encephalomyelitis (EAE) serves as a model for multiple sclerosis, with episodes of relapsing paralysis. In certain strains of mice, T-lymphocytes expressing the V beta 8 T-cell receptor (TCR) engage the amino-terminal epitope Ac1-11 of myelin basic protein, leading to EAE. The bacterial superantigen staphylococcal enterotoxin B (SEB) activates V beta 8-expressing T cells. Here we show that after immunization with Ac1-11, or after transfer of encephalitogenic T-cell lines or clones reactive to Ac1-11, SEB induces exacerbation or relapses of paralytic disease in mice that are in clinical remission following an initial episode of paralysis, and triggers paralysis in mice with subclinical disease. Tumour necrosis factor has a critical role in the mechanism underlying SEB-induced exacerbation of disease, because anti-tumour necrosis factor antibody given in vivo delays the onset of paralysis triggered by SEB. On reactivation of autoaggressive cells through their T-cell receptor, superantigens may induce clinical relapses of autoimmune disease.

Amino Acid Sequence↗