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Biomedical subjects

Stephen D Miller

Publications and source records attributed to Stephen D Miller.

54 records · Page 3Linked to original sources
PubMed2003

Immunoregulation of a viral model of multiple sclerosis using the synthetic cannabinoid R+WIN55,212.

Theiler murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) is a mouse model of chronic-progressive multiple sclerosis (MS) characterized by Th1-mediated CNS demyelination and spastic hindlimb paralysis. Existing MS therapies reduce relapse rates in 30% of relapsing-remitting MS patients, but are ineffective in chronic-progressive disease, and their effects on disability progression are unclear. Experimental studies demonstrate cannabinoids are useful for symptomatic treatment of spasticity and tremor in chronic-relapsing experimental autoimmune encephalomyelitis. Cannabinoids, however, have reported immunosuppressive properties. We show that the cannabinoid receptor agonist, R+WIN55,212, ameliorates progression of clinical disease symptoms in mice with preexisting TMEV-IDD. Amelioration of clinical disease is associated with downregulation of both virus and myelin epitope-specific Th1 effector functions (delayed-type hypersensitivity and IFN-gamma production) and the inhibition of CNS mRNA expression coding for the proinflammatory cytokines, TNF-alpha, IL1-beta, and IL-6. Clinical trials investigating the therapeutic potential of cannabinoids for the symptomatic treatment of MS are ongoing, and this study demonstrates that they may also have potent immunoregulatory properties.

Animals↗
PubMed2003

Regulation of experimental autoimmune encephalomyelitis (EAE) by CD4+CD25+ regulatory T cells.

Multiple endogenous mechanisms exist to inhibit thymic development of functional autoreactive T cells. In spite of this, autoreactive CD4+ T cell populations persist in normal individuals and retain the capacity to initiate autoimmune disease. Thus, additional regulatory mechanisms operative in the peripheral immune system are required to protect against both the generation of self-directed immune responses and the initiation of autoimmune diseases. One such mechanism involves the active inhibition of T cell responses by CD4+CD25+ regulatory T (T(reg)) cells. In this study, we investigated the protective role of T(reg) cells during experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). Our findings indicate that T(reg) cells confer significant protection from the development of MOG(35-55)-induced EAE that may result from the promotion of a protective Th2 response and decreased homing of autoreactive cells to the CNS. Importantly, T(reg) cells differentially expressed elevated levels of ICAM1 and P selectin, molecules which may facilitate T-T cell interactions and contribute to the mechanism by which T(reg) cells inhibit CD4+ T cell responses. Collectively, these findings support a role for T(reg) cells as an active regulatory mechanism that may protect individuals from the onset of MS, as well as other autoimmune diseases.

Animals↗
PubMed2002

Cutting edge: CD4+CD25+ regulatory T cells suppress antigen-specific autoreactive immune responses and central nervous system inflammation during active experimental autoimmune encephalomyelitis.

Autoreactive CD4(+) T cells exist in normal individuals and retain the capacity to initiate autoimmune disease. The current study investigates the role of CD4(+)CD25(+) T-regulatory (T(R)) cells during autoimmune disease using the CD4(+) T cell-dependent myelin oligodendrocyte glycoprotein (MOG)-specific experimental autoimmune encephalomyelitis model of multiple sclerosis. In vitro, T(R) cells effectively inhibited both the proliferation of and cytokine production by MOG(35-55)-specific Th1 cells. In vivo, adoptive transfer of T(R) cells conferred significant protection from clinical experimental autoimmune encephalomyelitis which was associated with normal activation of autoreactive Th1 cells, but an increased frequency of MOG(35-55)-specific Th2 cells and decreased CNS infiltration. Lastly, transferred T(R) cells displayed an enhanced ability to traffic to the peripheral lymph nodes and expressed increased levels of the adhesion molecules ICAM-1 and P-selectin that may promote functional interactions with target T cells. Collectively, these findings suggest that T(R) cells contribute notably to the endogenous mechanisms that regulate actively induced autoimmune disease.

Adoptive Transfer↗
PubMed2002

Functional activation of myelin-specific T cells by virus-induced molecular mimicry.

Molecular mimicry is the process by which T cells activated in response to determinants on an infecting microorganism cross-react with self epitopes, leading to an autoimmune disease. Normally, infection of SJL/J mice with the BeAn strain of Theiler's murine encephalomyelitis virus (TMEV) results in a persistent CNS infection, leading to a chronic progressive, CD4(+) T cell-mediated demyelinating disease. Myelin damage is initiated by T cell responses to virus persisting in CNS APCs, and progressive demyelinating disease (50 days postinfection) is perpetuated by myelin epitope-specific CD4(+) T cells activated by epitope spreading. We developed an infectious model of molecular mimicry by inserting a sequence encompassing the immunodominant myelin epitope, proteolipid protein (PLP) 139-151, into the coding region of a nonpathogenic TMEV variant. PLP139-TMEV-infected mice developed a rapid onset paralytic inflammatory, demyelinating disease paralleled by the activation of PLP139-151-specific CD4(+) Th1 responses within 10-14 days postinfection. The current studies demonstrate that the early onset demyelinating disease induced by PLP139-TMEV is the direct result of autoreactive PLP139-151-specific CD4(+) T cell responses. PLP139-151-specific CD4(+) T cells from PLP139-TMEV-infected mice transferred demyelinating disease to naive recipients and PLP139-151-specific tolerance before infection prevented clinical disease. Finally, infection with the mimic virus at sites peripheral to the CNS induced early demyelinating disease, suggesting that the PLP139-151-specific CD4(+) T cells could be activated in the periphery and traffic to the CNS. Collectively, infection with PLP139-151 mimic encoding TMEV serves as an excellent model for molecular mimicry by inducing pathologic myelin-specific CD4(+) T cells via a natural virus infection.

Amino Acid Sequence↗
PubMed2002

Differential abilities of central nervous system resident endothelial cells and astrocytes to serve as inducible antigen-presenting cells.

Microglial cells and astrocytes are capable of processing and presenting antigens for efficient activation of T cells. However, the antigen-presenting function and role of cerebrovascular endothelial cells (CVEs) in central nervous system inflammatory responses remain controversial. We compared the expression of necessary accessory molecules and the functional antigen-presenting capacity of cloned SJL/J CVEs and primary astrocytes in response to the pro-inflammatory cytokines interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). Astrocytes and CVEs up-regulated major histocompatibility complex (MHC) class II, and primarily B7-1 as opposed to B7-2, in response to IFN-gamma. TNF-alpha inhibited the IFN-gamma-induced up-regulation of MHC class II on CVEs correlating to a decrease in the mRNA for the class II transactivator (CIITA), whereas CIITA expression in astrocytes was unaffected. Unlike astrocytes, CVEs did not elicit significant MHC class II-restricted T-cell responses. Furthermore, we have found that CVE monolayers are altered following T-cell contact, implicating CVE/T-cell contact in the breakdown of the blood-brain barrier during neuro-inflammatory responses.

Animals↗
PubMed2002

De novo central nervous system processing of myelin antigen is required for the initiation of experimental autoimmune encephalomyelitis.

We demonstrate the absolute requirement for a functioning class II-restricted Ag processing pathway in the CNS for the initiation of experimental autoimmune encephalomyelitis (EAE). C57BL/6 (B6) mice deficient for the class II transactivator, which have defects in MHC class II, invariant chain (Ii), and H-2M (DM) expression, are resistant to initiation of myelin oligodendrocyte protein (MOG) peptide, MOG(35-55)-specific EAE by both priming and adoptive transfer of encephalitogenic T cells. However, class II transactivator-deficient mice can prime a suboptimal myelin-specific CD4(+) Th1 response. Further, B6 mice individually deficient for Ii and DM are also resistant to initiation of both active and adoptive EAE. Although both Ii-deficient and DM-deficient APCs can present MOG peptide to CD4(+) T cells, neither is capable of processing and presenting the encephalitogenic peptide of intact MOG protein. This phenotype is not Ag-specific, as DM- and Ii-deficient mice are also resistant to initiation of EAE by proteolipid protein peptide PLP(178-191). Remarkably, DM-deficient mice can prime a potent peripheral Th1 response to MOG(35-55), comparable to the response seen in wild-type mice, yet maintain resistance to EAE initiation. Most striking is the demonstration that T cells from MOG(35-55)-primed DM knockout mice can adoptively transfer EAE to wild-type, but not DM-deficient, mice. Together, these data demonstrate that the inability to process antigenic peptide from intact myelin protein results in resistance to EAE and that de novo processing and presentation of myelin Ags in the CNS is absolutely required for the initiation of autoimmune demyelinating disease.

Adoptive Transfer↗
PubMed2002

Expression of functional NK-1 receptors in murine microglia.

Cells of myeloid origin such as microglia have the potential to contribute significantly to the development of inflammatory responses in the CNS. The ability of the neuropeptide substance P to augment proinflammatory responses by other myeloid cell types such as macrophages and dendritic cells is well recognized. In the present study, we demonstrate the presence of mRNA encoding NK-1 (substance P) receptors in murine microglia cell lines. Importantly, we have utilized specific antibodies developed by our laboratory to detect the expression of the NK-1 receptor protein in murine microglia cell lines by Western blot analysis and flow cytometry. Furthermore, we have investigated the presence of this receptor on primary murine microglia and report the presence of authentic NK-1 receptors as determined by Western blot analysis and flow cytometry. In addition, we demonstrate that NK-1 receptors expressed on microglia are functional as demonstrated by the ability of nanomolar concentrations of substance P to initiate activation of the transcriptional activator, NF-kappaB. Given the weight of evidence supporting the role of substance P--substance P receptor interactions in the initiation of optimal proinflammatory responses by myeloid cells, the demonstration of authentic and functional NK-1 receptors in microglia identifies this neuropeptide as a potentially important contributor to CNS inflammatory responses during disease states.

Animals↗
PubMed2002

The role of CTLA-4 in induction and maintenance of peripheral T cell tolerance.

T cell receptor engagement and the B7-CD28 / CTLA-4 signaling pathways play critical roles in T cell activation and regulation. CD28 engagement results in T cell activation, differentiation and survival while CTLA-4 signals block IL-2 production, cell cycle progression and T cell differentiation. We explored the role of CTLA-4 in peripheral tolerance induced by intravenous administration of ethylene carbodiimide-fixed, antigen-coupled splenocytes in the PLP139 - 151-induced relapsing experimental autoimmune encephalomyelitis system. Tolerance induction with PLP139 - 151-coupled splenocytes correlates with low B7 expression on the fixed antigen-presenting cells, conditions that would favor CTLA-4-mediated inhibition. Administration of CTLA-4Ig or anti-CTLA-4 concomitant with the 'tolerogenic' stimulus, however, failed to reverse tolerance induction. In contrast, blocking CTLA-4 at the time of secondary 'immunogenic' encounter with antigen reversed the tolerant state. These findings indicate that CTLA-4 is required to maintain the unresponsive state of the tolerized T cells upon antigenic stimulation under inflammatory conditions and, therefore, have important implications for therapeutic regulation of autoimmune disease.

Abatacept↗
PubMed2002

CD40/CD40L interaction is essential for the induction of EAE in the absence of CD28-mediated co-stimulation.

CD28 provides a co-stimulatory signal critical for optimal T cell activation. We and others have shown that the B7/CD28 co-stimulatory pathway is a major regulatory pathway for the control of immune responses. Experimentally induced models of autoimmunity have been shown to be prevented or reduced in intensity in mice deficient for CD28. Here, we show that EAE and accompanying neuroantigen-specific immune responses are drastically reduced in the absence of CD28. However, we go on to show that EAE can be induced in CD28-deficient mice following two immunizations. After re-immunization, CD28-deficient mice develop severe EAE with myelin-specific responses equal to those of wildtype controls, and extensive demyelination in the spinal cord. Treatment of CD28-deficient mice with anti-CD40L at the time of immunization significantly reduced DTH responses and prevented the development of EAE following two immunizations, indicating a critical role for CD40/CD40L signaling in the absence of CD28. Taken together, our results indicate that CD28-mediated co-stimulation does not regulate immunological anergy. Instead, CD28 appears to adjust the threshold for activation and expansion of autoreactive cells.

Animals↗
PubMed2002

Myelin-specific tolerance attenuates the progression of a virus-induced demyelinating disease: implications for the treatment of MS.

Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), a multiple sclerosis (MS) model, is a central nervous system (CNS) demyelinating disease characterized by early peripheral T cell responses to virus epitopes which spreads to myelin epitopes during chronic disease. We show that CD4(+) T cells isolated from the spinal cords of chronically infected SJL mice proliferate and secrete pro-inflammatory cytokines upon in vitro challenge with both TMEV epitopes and proteolipid protein (PLP(139-151)). Importantly, myelin-specific tolerance induced by intravenous administration of MP4, a fusion of the myelin proteins myelin basic protein (MBP) and PLP, to SJL mice with ongoing TMEV-IDD attenuated disease progression and resulted in significantly less demyelination and decreased inflammatory cell infiltration in the CNS. Paradoxically, peptide-specific splenic T cell proliferative and IFN-gamma responses were enhanced in the tolerized mice. Collectively, these results indicate that myelin-specific T cell responses contribute to chronic disease progression in this virus-induced model of MS, and suggest caution in the use of antigen-specific tolerance for treatment of ongoing autoimmune disease.

Amino Acid Sequence↗
PubMed2002

Transient anti-CD154-mediated immunotherapy of ongoing relapsing experimental autoimmune encephalomyelitis induces long-term inhibition of disease relapses.

Relapsing experimental autoimmune encephalomyelitis (R-EAE) is a Th1-mediated central nervous system (CNS) autoimmune disease with pathology similar to that of relapsing-remitting multiple sclerosis. Among recent therapeutic approaches to prevent or treat relapsing disease is the strategic blockade of the CD154-CD40 ligand pair interactions. We have previously shown that CD154 blockade at the peak of acute disease can, in the short term, inhibit spontaneous disease relapse and this is at least partly associated with the inhibition of T cell effector function and blockade of inflammatory cell recruitment to and/or retention in the CNS. However, little is understood about the long-term effects of CD154 blockade in the inhibition of immune responses to encephalitogenic antigens. Here we demonstrate that transient anti-CD154 blockade of CD154-CD40 interactions at the peak of acute phase of R-EAE resulted in significant long-term inhibition (by >80%) of clinical relapses and that clinical disease in those mice that did relapse was reduced in duration and severity compared to control antibody-treated mice. Additionally, we show that this strategy permanently inhibits DTH responses of T cells specific for relapse-associated encephalitogenic epitopes. Thus, transient CD154 blockade during ongoing disease has a long-term therapeutic efficacy in preventing disease relapses.

Animals↗
PubMed2002

Epitope spreading and molecular mimicry as triggers of autoimmunity in the Theiler's virus-induced demyelinating disease model of multiple sclerosis.

The pathogenesis of multiple sclerosis (MS), a human demyelinating disease of the central nervous system (CNS), is currently unknown. It is widely thought that MS is an autoimmune disease which is supported by animal studies showing that myelin-specific CD4+ T cells can induce similar clinical disease in mice as observed in MS. However, the mechanism(s) of activation of these autoreactive CD4+ T cells are unknown. Although genetic susceptibility is important, other factors may be involved. Viral infections have long thought to be involved in the pathogenesis of MS although there exists little or no direct evidence implicating a role for a specific virus in MS pathogenesis. This review will discuss two models of virus-induced CNS autoimmunity, molecular mimicry and epitope spreading. These two mechanisms of activation of autoreactive T cells are presented in the context of MS.

Animals↗
PubMed2002

Epitope spreading in immune-mediated diseases: implications for immunotherapy.

Evidence continues to accumulate supporting the hypothesis that tissue damage during an immune response can lead to the priming of self-reactive T and/or B lymphocytes, regardless of the specificity of the initial insult. This review will focus primarily on epitope spreading at the T-cell level. Understanding the cellular and molecular basis of epitope spreading in various chronic immune-mediated human diseases and their animal models is crucial to understanding the pathogenesis of these diseases and to the ultimate goal of designing antigen-specific treatments.

Animals↗
PubMed2002

Normal Th1 development following long-term therapeutic blockade of CD154-CD40 in experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is a Th1-mediated demyelinating disease of the CNS with similarities to multiple sclerosis. We and others have shown that a short-term course of anti-CD154 mAb treatment to block CD154-CD40 interactions can be used to prevent or even treat ongoing PLP139-151-induced relapsing EAE. However, little is known of the long-term effects of CD154 blockade on the development of antigen-specific T cell function. Here, we show that short-term treatment with anti-CD154 at the time of PLP139-151/CFA immunization inhibits clinical disease for up to 100 days after immunization. At this point, comparable numbers of Th1 cells are observed in anti-CD154 and control Ig-treated mice, as assessed by antigen-specific ELISPOT assays. Thus, the long-term Th1/Th2 balance is largely unaffected. Inflammatory responses are diminished in anti-CD154-treated mice, as indicated by reduced in vivo delayed-type hypersensitivity and reduced levels of splenic IFN-gamma secretion in vitro. However, upon adoptive transfer of T cells isolated from the spleens of anti-CD154-treated mice, these cells contributed as effectively to clinical disease as those obtained from control-treated mice. Thus, anti-CD154 therapy leads to long-term therapeutic efficacy without exerting a long-term influence on Th1 development.

Amino Acid Sequence↗
PubMed2002

Theiler's virus-mediated autoimmunity: local presentation of CNS antigens and epitope spreading.

Theiler's murine encephalomyelitis virus (TMEV), a natural mouse pathogen, is a neurotropic picornavirus that induces a chronic, CD4+ T cell-mediated demyelinating disease with a clinical course and histopathology similar to those of chronic-progressive multiple sclerosis. Upon infection, TMEV-specific CD4+ T cells target persistent viral antigens in the CNS and initiate myelin damage. Later in the disease, myelin-specific CD4+ T cells are primed by epitope spreading, and these autoimmune T cells contribute to the pathogenesis of the chronic-progressive disease. This review focuses upon aspects of the initiation of a virally induced CD4+ T cell-mediated autoimmune response. First, the steps involved in the hierarchical activation of non-cross-reactive myelin-specific T cells in the SJL/J mouse after CNS infection with TMEV and the role of these autoreactive T cells in chronic myelin damage are discussed. Second, the process of epitope spreading and the role of CNS antigen presenting cells in the temporal presentation of self-antigens is considered. Finally, we will discuss aspects of T cell activation and antigen presentation, and how they can impact autoimmune disease.

Animals↗
PubMedDate not supplied

Targeting the TCR: T-cell receptor and peptide-specific tolerance-based strategies for restoring self-tolerance in CNS autoimmune disease.

A principal theme in autoimmunity is the breakdown of central tolerance resulting in the persistence and eventual activation of autoreactive T cells. Because CD4(+) T cells are key contributors to the underlying pathogenic mechanisms responsible for the onset and progression of most autoimmune diseases, they are a logical target for therapeutic interventions. One technique for restoring self-tolerance is to exploit the endogenous regulatory mechanisms that govern CD4(+) T-cell activation. In this review, we discuss promising techniques with the common goal of inducing antigen (Ag)-specific tolerance. Emphasis is given to the use of non-mitogenic anti-CD3 and peptide-specific tolerance strategies that specifically target the T-cell receptor (TCR) in the absence of costimulatory signals. These approaches produce a TCR signal of insufficient strength to cause CD4(+) T-cell activation and instead induce functional T-cell anergy or deletion while avoiding generalized long-term immunosuppression.

Animals↗
PubMedDate not supplied

Corneal transplantation in Alaska Natives (excerpts). 1975.

Since the time of the first corneal transplant in Alaska by Dr. Milo Fritz in 1958, great strides have been made in the field of corneal transplantation surgery. The introduction of fine 10-0 nylon sutures, the operating microscope, microsurgical instrumentation, and recently developed corneal preservation techniques has improved the prognosis in transplantation for all types of corneal disease, including PKC scarring. Our own experience at ANMC suggests that we should expect 80-90% of transplants performed for PKC to remain clear.

Alaska↗