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S D Miller

Publications and source records attributed to S D Miller.

At least 91 records · Page 5Linked to original sources
PubMed1996

Corneal infection with herpes simplex virus type 1 leads to autoimmune responses in rats.

Lewis rats were infected by corneal scarification with HSV type 1 type strain F virus. The animals showed symptoms of infection and inflammatory infiltrates of the eye but little mortality. After one month, immune responses to viral and autoantigens were examined. It was shown that lymph node cells proliferated to the myelin antigen, proteolipoprotein, and the HSV antigen, glycoprotein D, but showed depressed responses to antigens of the eye, specifically corneal and retinal antigens. Splenic cells showed small but significant responses to antigens of the eye, indicating immune deviation similar to that previously demonstrated in ACAID, where antigen had been injected into the anterior chamber of the eye.

Animals↗
PubMed1996

Inhibition of relapsing experimental autoimmune encephalomyelitis in SJL mice by feeding the immunodominant PLP139-151 peptide.

Peripheral antigen-specific tolerance can be induced by feeding protein antigens. The mechanism has been described as either clonal anergy/deletion or induction of antigen-specific regulatory cells that produce transforming growth factor-beta (TGF-beta). These two mechanisms have been linked to the magnitude and frequency of the dose of antigen fed; a single high dose induces anergy/deletion, whereas multiple low doses of antigen induce TGF-beta-secreting regulatory cells. In the present study, we investigated the mechanisms of feeding soluble peptides of proteolipid protein (PLP) for prevention of experimental autoimmune encephalomyelitis (EAE) induced by either intact PLP or the immunodominant PLP139-151 peptide. Feeding PLP139-151 prevented acute and relapsing EAE induced by either PLP139-151 or intact PLP. PLP139-151 feeding induced anergy in the T helper 1 (Th1) population as measured by an inhibition of both proliferation and interferon-gamma (IFN-gamma) production. Interleukin-4 (IL-4) production was increased, but increased TGF-beta production was not observed. Importantly, PLP139-151 feeding induced anergy in peripheral and central nervous system (CNS)-in-filtrating T cells. Feeding of the subdominant PLP epitope (PLP178-191) failed to inhibit EAE induced by PLP139-151; therefore, oral tolerance was not due to induction of bystander suppression. These results demonstrate that both acute and relapsing paralysis in EAE can be prevented by feeding the immunodominant peptide of PLP.

Administration, Oral↗
PubMed1996

Prevention and treatment of relapsing autoimmune encephalomyelitis with myelin peptide-coupled splenocytes.

Injection of antigen cross-linked accessory cells has proven to be an efficient and highly selective approach for inducing epitope-specific peripheral tolerance. This approach has been used successfully to inhibit induction of experimental autoimmune encephalomyelitis (EAE) and to dissect the relative dominance of component encephalitogenic determinants that contribute to both acute and relapsing EAE. In this study, we evaluated the tolerogenic effect of the dominant encephalitogenic epitope for SJL/J mice, residues 139-151 of myelin proteolipid protein (PLP), on the induction and relapses of EAE induced actively with PLP139-151/CFA. Our results demonstrate the powerful protective effect of treating mice before induction of EASE with PLP139-151-conjugated splenocytes (SPL) on the incidence and severity of both the initial episode and the first relapse of EAE. Moreover, treatment of mice on the first day of onset of clinical signs of EAE reduced the severity of the first relapse, apparently by reducing T cell recognition of PLP139-151, although no significant therapeutic effect was observed during the initial treated clinical episode. These data demonstrate the utility of using neuroantigen-coupled accessory cells to prevent and treat relapsing EAE.

Amino Acid Sequence↗
PubMed1996

CTLA-4: a negative regulator of autoimmune disease.

CTLA-4, a CD28 homologue expressed on activated T cells, binds with high affinity to the CD28 ligands, B7-1 (CD80) and B7-2 (CD86). This study was designed to examine the role of CTLA-4 in regulating autoimmune disease. Murine relapsing-remitting experimental autoimmune encephalomyelitis (R-EAE) is a demyelinating disease mediated by PLP139-151-specific CD4+ T cells in SJL/J mice. Anti-CTLA-4 mAbs (or their F(ab) fragments) enhanced in vitro proliferation and pro-inflammatory cytokine production by PLP139-151-primed lymph node cells. Addition of either reagent to in vitro activation cultures potentiated the ability of T cells to adoptively transfer disease to naive recipients. In vivo administration of anti-CTLA-4 mAb to recipients of PLP139-151-specific T cells resulted in accelerated and exacerbated disease. Finally, anti-CTLA-4 treatment of mice during disease remission resulted in the exacerbation of relapses. Collectively, these results suggest that CTLA-4 mediates the downregulation of ongoing immune responses and plays a major role in regulating autoimmunity.

Abatacept↗
PubMed1996

Flow cytometric and functional analyses of central nervous system-infiltrating cells in SJL/J mice with Theiler's virus-induced demyelinating disease. Evidence for a CD4+ T cell-mediated pathology.

Theiler's murine encephalomyelitis viruses (TMEVs) are endemic enteric pathogens of mice that cause immune-mediated, chronic, progressive, central nervous system (CNS) demyelinating disease in susceptible strains. Analysis of T cell phenotype and functional state from TMEV-infected SJL/J mice by flow cytometry reveals that 13.5 to 25% of the CD4+ T cells in the CNS express high affinity IL-2R, a marker of recent T cell activation, whereas splenic levels of CD4+IL-2R+ T cells generally range between 2 and 8.5%. In contrast, very few CD8+ T cells (<1-2%) from either site express IL-2R. From days 20 to 119 postinfection, the percentage of CD4+IL-2R+ T cells increases gradually in the CNS, but varies little in the spleen. CD4+ T cells isolated from the spinal cord of infected mice proliferate in vitro in response to viral Ag. Similar T cell phenotypes were found in experimental autoimmune encephalomyelitis, an established model of CD4+ T cell-mediated demyelination. In addition, most CD4+ and CD8+ T cells in CNS isolates from TMEV-infected mice are CD44+, indicating that prior activation may be required to traffic through and/or be retained in the CNS. Finally, TCR V beta region usage as well as IL-2R expression by individual V beta region subsets are heterogeneous in both the CNS and spleen. These results are consistent with a model in which a polyclonal population of TMEV-specific, CD4+ Th1 cells plays a major effector role in the demyelinating process.

Animals↗
PubMed1996

Adoptively transferred CD8+ T lymphocytes provide protection against TMEV-induced demyelinating disease in BALB/c mice.

On intracerebral infection with the BeAn strain of Theiler's murine encephalomyelitis virus (TMEV), certain mouse strains develop a chronic demyelinating disease similar both clinically and pathologically to human multiple sclerosis. Other strains remain resistant. We previously established that differential susceptibility to this demyelinating disease exists among BALB/c substrains, with BALB/cAnNCr mice being susceptible while BALB/cByJ mice are resistant. BALB/cByJ mice are rendered susceptible to TMEV-induced demyelination on exposure to low dose gamma-irradiation before TMEV infection. BALB/cAnNCr and irradiated, infected BALB/cByJ animals are protected against TMEV-induced demyelination by the transfer of a splenic population from TMEV-infected BALB/cByJ donors. Resistance to demyelination appears to be mediated by a CD8+ radiosensitive population, which is induced on infection with TMEV and which must act early to establish resistance to TMEV-induced demyelination.

Animals↗
PubMed1996

Differential expression of DNA polymerase alpha in normal and transformed human fibroblasts.

The expression of DNA polymerase alpha (pol alpha) was studied in human fibroblast lines W138 (fetal lung) and GM3529 (skin, established from a 66 yr old donor), and their Simian virus 40 (SV40) large tumor antigen (TAg)-transformed corollaries, 2RA and 2-1 respectively. Both SV40-transformed and pSV3.neo (SV40-derived plasmid)-transformed cells express TAg, a virally encoded protein not expressed by the normal parent cell lines. Northern blot hybridization studies showed increased recovery of pol alpha mRNA from transformed cells compared with normal cells. This increase was correlated with increased pol alpha mRNA transcription as determined by nuclear run-on assays. Northern blot analyses also showed an increase in the instability of translationally active pol alpha mRNA in transformed cells. The results suggest that TAg, in addition to its dsDNA binding, pol alpha binding, retinoblastoma protein binding and helicase activities, may be involved either directly or indirectly in regulation of the steady state mRNA levels of pol alpha at the transcriptional level in both fetal and aged donor-derived transformed fibroblasts.

Aged↗
PubMed1996

Epitope spreading.

Epitope (determinant) spreading is the development of immune responses to endogenous epitopes secondary to the release of self antigens during a chronic autoimmune or inflammatory response. The past year has seen considerable advances in our understanding of the contribution of epitope spreading to the chronic pathogenesis of experimental T-cell-mediated and antibody-mediated autoimmune diseases. Most significantly, conclusive functional evidence for a major role for epitope spreading in the chronic pathogenesis of murine relapsing-remitting experimental autoimmune encephalomyelitis, a CD4+ T-cell-mediated model of multiple sclerosis, was forthcoming.

Animals↗
PubMed1996

Primary subtaler arthrodesis for the treatment of comminuted calcaneal fractures.

We retrospectively evaluated the results of primary subtalar arthrodesis for the treatment of severely comminuted calcaneal fractures. Of 108 patients with 112 calcaneal fractures treated at our institution between 1989 and 1992, 16 (15%) underwent primary subtalar arthrodesis through an extensile lateral approach. The calcaneal height and width were restored with standard fixation techniques and then arthrodesis was performed with bone graft and fixation by 7.0-mm cannulated cancellous screws. Fourteen patients (12 males and 2 females; mean age, 40 years) were available for examination at a mean time of 26 months (range, 12-54 months) after surgery. Arthrodesis, evidenced by radiographic bony bridging across the arthrodesis site, was present in all patients between 8 and 12 weeks. Minor wound complications occurred in three patients. Of the 12 patients employed before the injury, 11 returned to their original occupations at a mean time of 8.8 months after injury (range, 1 month to 3 years). The mean AOFAS 100-point clinical rating scale score, evaluating pain, function, and alignment, was 72.4 points (range, 48-88 points). We conclude that primary subtalar arthrodesis is indicated as part of the management of comminuted displaced articular calcaneal fractures, yielding results that allowed 11 of 12 formerly employed patients to return to work.

Adult↗
PubMed1996

Ankle arthrodesis: results after the miniarthrotomy technique.

Of 34 ankle fusions (34 patients) performed at our institution between June 1992 and June 1993, 15 utilized a miniarthrotomy technique. This technique involves two 1.5-cm incisions, one medial and one anterolateral, through which the ankle joint cartilage and synovium are debrided. Subchondral bone resection is completed with a high-speed cutting tool, creating a "slurry" that is saved for local bone graft. The ankle is then appropriately positioned (5 degrees of valgus, 0 degree of dorsiflexion, and neutral rotation), cannulated screws are inserted, the position is checked fluoroscopically, and the wound is closed. The patient receives a short leg cast at 2 weeks and a walking cast at 3 to 5 weeks until there is radiographic and clinical evidence of solid arthrodesis. In our 15 patients, follow-up ranged from 12 to 19 months after surgery and arthrodesis was radiographically evident at a mean of 6.0 weeks (range, 3-15 weeks). Complications were limited to a transient synovitis in 7/15 patients, which lasted approximately 3 weeks and was possibly related to the bone slurry. Although ankle joints with marked malalignment require a more extensive open arthrodesis procedure, this miniarthrotomy technique offers decreased soft-tissue insult, decreased bone stripping, easy application, and rapid healing time for the treatment of severe degenerative changes of the ankle with minimal deformity.

Adult↗
PubMed1996

Ultrasound in the diagnosis of posterior tibial tendon pathology.

We retrospectively evaluated the effectiveness of ultrasonography as a diagnostic tool for investigating pathology in the posterior tibial tendon by comparing the preoperative ultrasonograms for 17 patients with their recorded surgical findings. In all cases, the surgical findings confirmed the ultrasonographic diagnoses: 3 inflammations, 4 partial tears, and 10 ruptures. Interestingly, two ruptures had been undiagnosed by magnetic resonance imaging. Ultrasonography, which seems to be a reliable means of visualizing the extent of pathology of the symptomatic posterior tibial tendon, may be a valuable tool in surgical planning.

Adult↗
PubMed1996

The miniarthrotomy technique of ankle arthrodesis: a cadaver study of operative vascular compromise and early clinical results.

We present a two-part study of the miniarthrotomy ankle fusion technique for minimally deformed joints: a laboratory investigation of ankle vascularity and a clinical review of the early results. In the laboratory portion, five pairs of cadaver legs were injected with radiographic dye, after which arthrodesis was performed via either the open technique (one leg of each pair) or the miniarthrotomy technique (the contralateral leg of each pair). Two legs in the open arthrodesis group had disruption of the peroneal arterial circulation, but no disruption was identified in the miniarthrotomy group. In the clinical portion of the study, we reviewed the results of 32 patients who had undergone ankle fusion via the miniarthrotomy technique. One patient had a nonunion and two patients had delayed union. The average time to union for the 31 patients was 8 weeks (range: 6 to 22). These results compare favorably to the arthroscopically assisted method of fusion and offers another choice for arthrodesis of minimally deformed ankles. We concluded that with minimal disruption, there is less likelihood of arterial injury and devascularization, which may indirectly have a positive effect on the rate of ankle arthrodesis.

Adult↗
PubMed1995

Myelin antigen-coupled splenocytes suppress experimental autoimmune encephalomyelitis in Lewis rats through a partially reversible anergy mechanism.

Mechanisms of adult tolerance induced by injecting myelin Ag/ECDI (ethyl carbodiimide)-coupled splenocytes (Ag-SPL) were evaluated in Lewis rat experimental autoimmune encephalomyelitis (EAE). Rats could be tolerized against the major encephalitogenic epitope of guinea pig basic protein (Gp-BP), residues 72-89, using either S72-89-SPL or crude spinal cord homogenate (SCH)-SPL. In contrast to lymph node responses that were not affected significantly, the proliferation responses of blood T cells were markedly inhibited at the peak of EAE and during the recovery period to both Gp-BP and S72-89, but not to purified protein derivative (PPD), demonstrating Ag-specific tolerance. Tolerance induction reduced the number of infiltrating spinal cord (SC) cells, especially recruited CD45RC+ cells, as well as SC proliferation responses to S72-89 throughout the course of EAE. In contrast, SC response to PPD was increased at onset of EAE, but later during recovery the PPD response was also decreased compared with control rats. Tolerance induced by S72-89-SPL in blood and SC T cells could be reversed by incubation in IL-2, in accordance with an anergy model. BP-specific T cells preincubated in vitro with Gp-BP-SPL were rendered unresponsive to Gp-BP or S72-89, compared with the same T cells preincubated with histone (Hist)-SPL that remained Ag responsive. Consistent with an anergy model, preincubation with BP-SPL+IL-2 partially prevented tolerance induction to BP. T cells tolerized in vitro to BP-SPL induced milder EAE with delayed onset compared with control-tolerized T cells that produced lethal disease. These results demonstrate the efficacy of myelin Ag-coupled SPL in preventing EAE by selective tolerization of encephalitogenic T cells through a partially reversible anergy-induction mechanism.

Amino Acid Sequence↗
PubMed1995

An important role for the chemokine macrophage inflammatory protein-1 alpha in the pathogenesis of the T cell-mediated autoimmune disease, experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is a CD4+ T cell-mediated, inflammatory demyelinating disease of the central nervous system (CNS) that serves as a model for the human demyelinating disease, multiple sclerosis. A critical event in the pathogenesis of EAE is the entry of both Ag-specific T lymphocytes and Ag-nonspecific mononuclear cells into the CNS. In the present report we investigated the role of two C-C chemokines (macrophage inflammatory protein-1 alpha (MIP-1 alpha) and monocyte chemotactic protein-1) and a C-x-C chemokine (MIP-2) in the pathogenesis of EAE. Production in the CNS of MIP-1 alpha, but not that of MIP-2, a rodent homologue of IL-8, or monocyte chemotactic protein-1, correlated with development of severe clinical disease. Administration of anti-MIP-1 alpha, but not that of anti-monocyte chemotactic protein-1, prevented the development of both acute and relapsing paralytic disease as well as infiltration of mononuclear cells into the CNS initiated by the transfer of neuroantigen peptide-activated T cells. Ab therapy could also be used to ameliorate the severity of ongoing clinical disease. Anti-MIP-1 alpha did not affect the activation of encepahlitogenic T cells as measured by cytokine secretion, surface marker expression, and ability to adoptively transfer EAE. These results demonstrate that MIP-1 alpha plays an important role in directing the chemoattraction of mononuclear inflammatory cells in the T cell-mediated autoimmune disease, EAE.

Animals↗
PubMed1995

Neuroantigen-specific Th2 cells are inefficient suppressors of experimental autoimmune encephalomyelitis induced by effector Th1 cells.

We have identified a method of polarizing polyclonal populations of activated T helper cells toward either the Th1 or Th2 phenotype using different short-term in vitro culture conditions. Since the Ag used was an encephalitogenic peptide for SJL/J mice, the pathogenic potential of these cell populations was tested in an adoptive transfer model of experimental autoimmune encephalomyelitis (EAE). Th1 cells reproducibly caused severe EAE, whereas highly polarized Th2 cells did not. Furthermore, highly polarized Th2 cells did not suppress EAE caused by Th1 cells. The anti-inflammatory cytokines made by Th2 cells may simply fail to inhibit tissue destruction mediated by differentiated Th1 cells at the effector phase of the disease. It is also possible that highly polarized Th2 cells may be inefficient at crossing the blood-brain barrier, which may limit their suppressive potential. In contrast, incompletely skewed T cell populations that produced high levels of both Th1 and Th2 cytokines were consistently only weakly encephalitogenic. Therefore, disease inhibition by Th2 cytokines may best be accomplished by intervention at earlier points preceding development of differentiated Th1 cells.

Animals↗
PubMed1995

Treatment with bacterial LPS renders genetically resistant C57BL/6 mice susceptible to Theiler's virus-induced demyelinating disease.

Theiler's murine encephalomyelitis virus (TMEV) induces a demyelinating disease in susceptible strains, which clinically and histopathologically resembles human multiple sclerosis. Since bacterial LPS produced by Gram-negative bacteria is known to potentiate an immune response and trigger resident central nervous system cells to produce various inflammatory cytokines, we examined the ability of LPS to affect resistance to TMEV-induced demyelinating disease (TMEV-IDD). Intraperitoneal injection of LPS, concomitant with intracerebral of genetically resistant C57BL/6 mice with TMEV, resulted in clinical symptoms in approximately 50% of the group. The increase in susceptibility following LPS treatment correlated with the enhanced levels of TMEV-specific delayed-type hypersensitivity and T cell proliferative responses. Similar treatment with LPS, however, did not accelerate the clinical course of susceptible (SJL/J) or intermediately susceptible (C3H) mice. The LPS-treated C57BL/6 mice displayed an increased viral persistence in the central nervous system when compared with nontreated control mice. Intraperitoneal administration of IL-1 beta could mimic the LPS effect in C57BL/6 mice, suggesting that the increase in susceptibility to TMEV-IDD may function via IL-1 produced following LPS stimulation.

Adjuvants, Immunologic↗
PubMed1995

Two models of multiple sclerosis: experimental allergic encephalomyelitis (EAE) and Theiler's murine encephalomyelitis virus (TMEV) infection. A pathological and immunological comparison.

Theiler's murine encephalomyelitis virus (TMEV) infection and experimental allergic encephalomyelitis (EAE) are considered among the best models of human multiple sclerosis (MS). In both models, clinical disease is characterized by paralysis, while pathological changes consist of inflammatory demyelination. In both models there is a genetic influence on susceptibility/resistance to the development of disease. This has been thoroughly studied in TMEV infection, and it has been found to depend on both major histocompatibility complex (MHC) and non-MHC genes. At least four genes have been so far identified. Because of this genetic influence, some strains of mice are more susceptible to both clinical and pathological changes than others, and susceptibility appears to best correlate with the ability of a certain murine strain to develop a delayed-type hypersensitivity (DTH) response to viral antigens. We have also observed that even among mice which are equally susceptible clinically, striking differences may be seen under pathological examination. These consist of different gradients of severity of inflammation, particularly in regards to the macrophage component. There is an inverse relationship between the number of macrophages, and their length of stay in the CNS, and the ability of mice to remyelinate their lesions. The most severe lesions are in SJL/J mice, and remyelination in this strain is extremely poor. The least severe lesions in terms of macrophage invasion are in strains such as NZW and RIIIS/J, and these are able to remyelinate lesions very successfully. Murine chronic relapsing EAE (CR-EAE) shows pathological changes in many ways similar to those in TMEV-infected SJL/J mice, although less severe in terms of degrees of macrophage infiltration and tissue destruction. Mice with CR-EAE have a correspondingly limited ability to remyelinate their lesions. In both models the pathology appears to be mediated through a DTH response. However, while in EAE the DTH response is clearly against neuroantigens, the response in TMEV infection is against the virus itself. The end result in both models would be that of myelin destruction through a lymphotoxin-cytokine-mediated mechanism. The importance of the DTH response in both models is well illustrated by the effects of tolerance induction in EAE and TMEV infection to neuroantigens and virus, respectively. These are important models of human MS, since the current hypothesis is that a viral infection early in life, on the appropriate genetic background, may trigger a secondary misdirected immune response which could be directed either against myelin antigens and/or possible persistent virus(es).

Animals↗