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Biomedical subjects

D E Scott

Publications and source records attributed to D E Scott.

At least 37 records · Page 2Linked to original sources
PubMed1995

Retinoid treatment of experimental allergic encephalomyelitis. IL-4 production correlates with improved disease course.

Experimental allergic encephalomyelitis (EAE) is an autoimmune disease characterized by central nervous system inflammation and demyelination. Retinoids regulate cell differentiation and growth by binding to and activating retinoic acid receptors, which seem to be nuclear transcription factors. The effect of retinoids on chronic relapsing EAE produced by the transfer of myelin basic protein (MBP)-specific lymph node cells (LNC) was studied. All-trans-retinoic acid (tRA) inhibited the proliferation of MBP-specific LNC in vitro. However, the capacity of these cells to transfer EAE was markedly reduced by concentrations of tRA that only mildly inhibited T cell proliferation. The presence of tRA during in vitro MBP-specific LNC activation resulted in a considerable increase in IL-4 mRNA, whereas mRNA for IL-2, TNF-alpha, and IFN-gamma was decreased. Increased IL-4 also was detected in culture supernatants. However, the presence of a neutralizing Ab to IL-4 (11B11) during MBP-specific LNC activation in vitro did not reverse the inhibition of encephalitogenicity caused by tRA. The administration of retinoids in vivo resulted in an improved clinical course, even when given after disease onset. These findings suggest that T cell activation in the presence of tRA results in the development of T cells of the Th2 phenotype, which, in turn, might be responsible for the decrease in the encephalitogenicity of MBP-specific T cells. The modulation by retinoids of an immune response dominated by Th1-like T cells to one in which the protective cytokines of Th2-like cells predominate may have potential relevance for human demyelinating diseases such as multiple sclerosis.

Animals↗
PubMed1995

Neural regeneration and neuronal migration following injury. I. The endocrine hypothalamus and neurohypophyseal system.

Central to this investigation are several basic hypotheses that are designed to test the role of nitric oxide (NO) in the complex process of central regeneration and plasticity in a well established model system of the mammalian brain. We have employed histochemical techniques at the light and ultrastructural level coupled with correlative scanning electron microscopy, immunoelectron microscopy, and in situ hybridization in order to determine the functional significance of the increased expression of nitric oxide synthase (NOS) in neurons of the supraoptic (SON) and paraventricular (PVN) nuclei which accompanies regeneration of their axotomized neurites following hypophysectomy. The aim of this investigation was to determine the potential role and temporal up-regulation of NOS in this basic regenerative process and to establish the ultrastructural and neuroanatomical correlates during critical periods of regeneration and regrowth of SON and PVN axons following hypophysectomy in the endocrine hypothalamus of the rat. Our data support the hypothesis that NO may serve as a second messenger molecule that may act in some fashion to govern not only the process of central regeneration and regrowth of magnocellular (SON/PVN) axons into the median eminence, neural stem, and neural lobe (the neurohypophyseal system) but may also influence the regeneration of neurites into new neuroanatomical domains such as the adjacent lumen of the third cerebral ventricle. We have demonstrated a distinct temporal relationship between injury (axotomy) of SON/PVN axons and the establishment of new neurovascular zones following hypophysectomy with the up-regulation of NOS. This up-regulation appears to correlate well with successful regeneration in the mammalian neurohypophyseal system. We have also successfully inhibited axonal regeneration with the use of nitroarginine, a competitive antagonist of NO. NOS up-regulation attendant to regeneration of SON and PVN axons may have inestimable clinical implications, particularly with respect to closed head injury and cerebral contusion that involves the mechanical shearing of the infundibular stalk. In addition, this investigation has reaffirmed that large numbers of bona fide neurons migrate and emerge upon the floor of the adjacent third cerebral ventricle shortly following hypophysectomy (within 2 weeks). The origin and mechanisms of neuronal migration and plasticity following hypophysectomy are the subject of interpretation and discussion in this investigation.

Amino Acid Oxidoreductases↗
PubMed1995

Distinct roles for B7-1 (CD-80) and B7-2 (CD-86) in the initiation of experimental allergic encephalomyelitis.

The activation and differentiation of T cells require both antigen/MHC recognition and costimulatory signals. The present studies examined the role of B7-1 (CD80) and B7-2 (CD86) costimulation in the prototypic autoimmune disorder, experimental allergic encephalomyelitis (EAE). In adoptively transferred EAE, in vitro activation of myelin basic protein (MBP)-specific lymph node cells was inhibited by the combination of anti-CD80 plus anti-CD86, but not individually. However, in actively induced disease, one injection of anti-CD80 significantly reduced disease, while anti-CD86 exacerbated disease. Interestingly, one injection of CTLA-4Ig suppressed disease, while multiple injections resulted in enhanced disease. Thus, the costimulation provided by B7-1 molecules appears to be important for the development of encephalitogenic T cells. The enhanced disease caused by multiple injections of CTLA-4Ig or a single injection of anti-CD86 suggests an inhibitory function for CD86 interaction with its counterreceptors CD28 and CTLA-4 in EAE. Alternatively, these results are consistent with an essential timing requirement for the coordinated interaction of B7 and CD28 family receptors, and that disruption of this critical timing can have opposing results on the outcome of an immune response.

Animals↗
PubMed1994

Cytokine-induced immune deviation as a therapy for inflammatory autoimmune disease.

The properties and outcome of an immune response are best predicted by the lymphokine phenotype of the responding T cells. Cytokines produced by CD4+ T helper type 1 (Th1) T cells mediate delayed type hypersensitivity (DTH) and inflammatory responses, whereas cytokines produced by Th2 T cells mediate helper T cell functions for antibody production. To determine whether induction of Th2-like cells would modulate an inflammatory response, interleukin 4 (IL-4) was administered to animals with experimental allergic encephalomyelitis (EAE), a prototypic autoimmune disease produced by Th1-like T cells specific for myelin basic protein (MBP). IL-4 treatment resulted in amelioration of clinical disease, the induction of MBP-specific Th2 cells, diminished demyelination, and inhibition of the synthesis of inflammatory cytokines in the central nervous system (CNS). Modulation of an immune response from one dominated by excessive activity of Th1-like T cells to one dominated by the protective cytokines produced by Th2-like T cells may have applicability to the therapy of certain human autoimmune diseases.

Animals↗
PubMed1994

Superantigen modulation of experimental allergic encephalomyelitis: activation of anergy determines outcome.

Experimental allergic encephalomyelitis (EAE) is an autoimmune disease that can be induced by the adoptive transfer of CD4, myelin basic protein (MBP)-specific T cells. Superantigens activate T cells expressing appropriate TCR V genes. In this study, MBP-specific T cells activated in vitro with a superantigen, staphylococcal enterotoxin B (SEB), could adoptively transfer a severe form of EAE in (PLxSJL)F1 mice, but did not transfer disease in PL/J or SJL/J mice. SEB treatment of donor mice anergized MBP-specific T cells using V beta 8 in (PLxSJL)F1 mice, because subsequent in vitro activation with SEB resulted in a marked decrease in proliferation to SEB and inability to transfer EAE. However, donor cells from (PLxSJL)F1 mice immunized with MBP/CFA that had been exposed to SEB in vivo before MBP stimulation in vitro still produced EAE in recipient mice. To confirm that non-V beta 8 T cells could transfer disease, donor mice were treated with antibody that eliminated V beta 8 T cells; MBP-activated T cells from these mice could still transfer EAE. Finally, EAE induced by SEB-activated T cells was substantially reduced in mice receiving anti-V beta 8 therapy in vivo. The ability of superantigens to activate encephalitogenic T cells may have relevance to human diseases such as multiple sclerosis.

Animals↗
PubMed1993

Studies of T cell deletion and T cell anergy following in vivo administration of SEB to normal and lupus-prone mice.

This study examines the responses of lupus-prone NZB, (NZB x NZW) F1, BXSB, MRL-lpr/lpr and control mice (H-2 and Mls matched) to in vivo administration of the superantigen staphylococcal enterotoxin B (SEB). Two weeks after i.v. administration of 500 micrograms SEB, CD4+V beta 8+ lymph node T cells were deleted equivalently by lupus-prone and control mice. However, IE+ strains deleted a greater proportion (47% to 77%) of their CD4+V beta 8+ cells than did IE- strains (24% to 27%). CD8+V beta 8+ cells were deleted less than CD4+V beta 8+ cells by injection of 500 micrograms SEB. IE- strains failed to delete CD8+V beta 8+ cells, whereas six of seven IE+ strains deleted > 25% of their CD8+V beta 8+ cells. IE+ MRL-lpr/lpr mice showed some impairment in deletion: they failed to delete CD8+V beta 8+ cells at all doses of SEB and had reduced deletion of CD4+V beta 8+ cells at low doses of in vivo SEB (10 and 50 micrograms). Peripheral expansion of the intrathymically deleted V beta 7 TCR family was not observed in lupus-prone mice 2 wk after 500 micrograms in vivo SEB. In vitro restimulation with SEB of mice previously injected with 500 micrograms SEB demonstrated anergy in T cells from all strains, including the IE- and MRL-lpr/lpr. This result contrasts with previous reports of tolerance defects in lupus-prone strains using B cell read-out assays as measures of tolerance. The present study demonstrates that there is no global defect in peripheral T cell deletion or anergy in lupus-prone mice to the superantigen SEB. Although additional Ag would need to be studied, these experiments raise the possibility that some reported tolerance defects in lupus-prone strains may reflect excessive B cell responses to relatively normal T cell signals.

Animals↗
PubMed1993

Increased expression of nitric oxide synthase in hypothalamic neuronal regeneration.

This investigation deals with the histochemical and scanning electron microscopic (SEM) correlates that depict regeneration of the neurohypophyseal system that may be nitric oxide dependent following hypophysectomy in the rodent hypothalamus. NOS histochemistry and correlative SEM were employed to establish the rates of regrowth and appearance of NOS-positive supraoptic (SON) and paraventricular (PVN) neurites and their cell bodies following hypophysectomy. NOS activity increased significantly in SON and PVN neuronal perikarya and regenerating axons by 2 weeks. NOS-positive neurites were observed to regrow into the adjacent median eminence and insinuate into the lumen of the third cerebral ventricle. By 4 weeks posthypophysectomy, NOS staining of SON and PVN neurons and their regrown neurites had returned to normal control levels. Despite this fact, large complexes of apparent magnocellular neurites remained upon the floor of the third cerebral ventricle as observed with SEM. These observations support the hypothesis that NO may play a fundamental role in the process of regeneration, plasticity, and retargeting of SON and PVN axons following injury.

Amino Acid Oxidoreductases↗
PubMed1993

Transplantation of the mammalian pineal gland: studies of survival, revascularization, reinnervation, and recovery of function.

The survival, revascularization, reinnervation, and recovery of function of transplanted rat pineal glands were studied following grafting into four different locations in pinealectomized rats. Pineal grafts were well vascularized by fenestrated capillaries. Pinealocytes in the grafts maintained high-metabolic activity. More nerve fibers and terminals were observed in the grafts within the anterior chamber of the eye than in the third cerebral ventricle and the pineal region (in situ transplantation). No fibers or terminals were found in grafts placed beneath the renal capsule. Nighttime serum melatonin levels increased significantly in pinealectomized rats with transplants into either the third cerebral ventricle or the anterior eye chamber. This increase might reflect graft reinnervation. Yet day-night differences in serum melatonin were observed only in host rats receiving transplants in the anterior eye chamber. In conclusion, pinealocytes survived transplantation into different locations and exhibited ultrastructural features indicative of active secretory processes; however, day-night differences in serum melatonin are only restored following transplants into the anterior eye chamber. Reinnervation of the grafts by the host superior cervical ganglion is necessary for this restoration.

Animals↗
PubMed1992

Studies of bone marrow progenitor cells in lupus-prone mice. I. NZB marrow cells demonstrate increased growth in Whitlock-Witte culture and increased splenic colony-forming unit activity in the Thy-1-, lineage- population.

Previous studies have demonstrated that NZB marrow can transfer features of autoimmunity. Therefore, we undertook a study of NZB marrow to determine whether it demonstrated any phenotypic abnormalities. In Whitlock-Witte cultures, NZB marrow cells generated nonadherent cells at low seeding densities, densities at which marrow from other strains did not generate nonadherent cells. In contrast, NZB marrow grew less well than controls in Dexter cultures. Inasmuch as the latter favor growth of granulocyte-macrophage precursors and the former B cells, these results suggest a possible skewing of NZB marrow cells toward lymphocyte production. Unfractionated marrow cells from NZB mice were found to produce 10-fold more splenic colonies in lethally irradiated recipients than marrow cells from control mice. This result was independent of the genotype of the recipient. When the progenitor Thy-1lo, Lin- marrow subpopulation was studied, NZB mice did not differ substantially from controls regarding splenic CFU. Therefore, Thy-1-, Lin- marrow cells were studied as a possible source of the excess splenic CFU in NZB mice. Indeed, the NZB Thy-1-, Lin- population contained 30-fold more splenic CFU than did the Thy-1-, Lin- population from control mice. These results suggest that NZB mice have unusual marrow progenitor cells; such cells may play a role in their autoimmune disease.

Animals↗
PubMed1992

Collaboration as a strategy for acquired immunodeficiency syndrome prevention.

An eight-session training model used a social interactive framework to combine theoretical and methodological aspects of peer counseling, cross-cultural communication, and transcultural nursing, with a conviction that the participants (volunteers from an ongoing, urban methadone maintenance program) had significant strengths on which to build. The objective was to assist urban, drug dependent black women in taking control of their own lives through collaboration with health care professionals to develop and promote culturally acceptable behavioral alternatives related to reduction of risk for human immunodeficiency virus. The collaborative approach focused on rewards of behavioral change and minimized attention to prevention of negative behaviors, while openly valuing input from the women who are potential health promoters in their own communities. Evaluation of the Peer Counseling Leadership Training Program suggested that the approach facilitated personal risk-reducing behavioral change, improved self esteem, and successfully promoted involvement in community-based prevention efforts.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Strategies for AIDS prevention: leadership training and peer counseling for high-risk African-American women in the drug user community.

A culturally congruent training program to promote HIV risk-reduction behaviors was implemented in a convenient sample of 9 African-American women in an urban methadone treatment program. At each of eight peer counseling and leadership training (PCLT) program sessions, the transmission and prevention of AIDS were discussed while emphasizing enhancement of participants' self-esteem, confidence, and control over high-risk behaviors. The results indicate that support of the women helped develop their sense of purpose and self-worth, reduced sexual and drug use practices associated with risk for HIV and AIDS infection, and promoted assumption of leadership roles and dissemination of accurate AIDS-related information in their communities. It was apparent that knowledge alone does not change behavior if it conflicts with established norms, values, beliefs, and life-styles and that individuals who have a sense of personal control are more willing to explore alternative lower-risk behaviors.

Acquired Immunodeficiency Syndrome↗
PubMed1991

NIH conference. Systemic lupus erythematosus.

Although the cause of systemic lupus erythematosus remains unknown, pathogenic mechanisms are becoming clearer. Both genetic and environmental factors have been implicated in the induction and in the perpetuation of lupus. Implicated environmental triggers include ultraviolet light, chemicals (hydrazines, hair dyes, drugs), some foods, and possibly infectious agents. Lupus is mediated by the immune system. Patients have excess numbers of antibody-forming cells, including those that produce antibodies reactive with self-antigens. Patients also have an increased number of activated T cells, some of which help B cells to produce autoantibodies. A loss of tolerance is a critical immune abnormality in lupus; many of the activated helper T cells may result from a failure in normal tolerance mechanisms. A hematopoietic stem-cell defect could give rise to both B- and T-cell abnormalities. Such a stem-cell abnormality might lead to both a loss of self-tolerance and polyclonal B-cell activation. Antigen-driven, T-cell-dependent expansion of B-cell clones would then give rise to pathogenic autoantibodies, including anti-DNA. We believe that lupus is a syndrome: Patients differ regarding specific inciting factors and immune defects. Some patients have genetically conditioned abnormalities, similar to those found in mice with lupus; others have a combination of genetic and acquired defects. We hope that insights into pathogenesis lead to improved and more individualized therapy.

Animals↗
PubMed1991

Cytokine gene expression after in vivo primary immunization with goat antibody to mouse IgD antibody.

Cytokines are important mediators of effector lymphoid cell function during an immune response, but their expression during an in vivo immune response has not been well documented. We analyzed the kinetics of cytokine gene expression during the course of an in vivo primary immune response to goat antibody to mouse IgD antibody. Total RNA was purified from spleens taken from freshly killed BALB/c mice 1 to 7 days after immunization. The reverse transcriptase polymerase chain reaction was used to evaluate the expression of seven cytokine genes, all of which encode cytokines that are secreted by T cells and are important in T and/or B cell activation and differentiation. These were IFN-gamma, IL-2, IL-4, IL-5, IL-6, IL-9, and IL-10. IL-2 and IL-9 exhibited an early elevated expression at days 2 to 3, and declined as the expression of IL-4, IL-6, IL-10, and IFN-gamma increased. In contrast, IL-5 gene expression showed little change, exhibiting a similar pattern to the housekeeping gene, hypoxanthine-guanine phosphoribosyl transferase. Cell sorting of CD4+ and CD4- cells at day 3 and day 5 after immunization revealed that CD4+ cells were the predominant source of the elevated cytokines (with the exception of IL-6). Our results demonstrate a specific and highly reproducible cytokine gene expression pattern during the course of a primary in vivo immune response that is marked by an absence of a clear-cut Th1/Th2 dichotomy.

Animals↗
PubMed1991

No difference in day-night serum melatonin concentration after pineal grafting into the third cerebral ventricle of pinealectomized rats.

Serum melatonin concentration and its day-night difference in pinealectomized, stereotaxically grafted rats with pineal transplants was examined. The nighttime serum melatonin concentration increased significantly only in pinealectomized rats that received two pineal transplants. In neither pinealectomized rats receiving two pineal glands and one cotransplant of superior cervical sympathetic ganglion nor pinealectomized-ganglionectomized rats receiving two pineal transplants was there a demonstrable increased in serum melatonin concentration. Although some pineal transplanted hosts demonstrated increases in serum melatonin concentration, there was no day-night variation in serum melatonin concentration. This may be due to a number of mitigating factors. Pineal grafts may not receive the appropriate functional reinnervation from the host brain due to the location of the transplantation in the cerebral ventricle or due to lack of sufficient time for the growth of invading host neurites.

Analysis of Variance↗
PubMed1990

Anti-CD3 antibody induces rapid expression of cytokine genes in vivo.

Anti-CD3 antibody was administered to mice i.v. and the kinetics of spleen cell cytokine mRNA expression studied by Northern analysis. Untreated mice and mice receiving control antibody had low or undetectable amounts of mRNA for c-fos, c-myc, IL-2, IL-4, and IFN-gamma. After injection of anti-CD3 antibody, substantial increases in all were found. Induction of c-fos was detected at 10 min and of c-myc at 30 min after injection. IL-2, IL-4, and IFN-gamma mRNA were induced by 30 min and reached peak levels at 60 min. Thereafter, IL-2 and IL-4 mRNA declined, whereas IFN-gamma mRNA persisted. The induced cytokine mRNA was not observed in athymic nu/nu mice nor in normal spleen cells from which T cells had been depleted in vitro. The early in vivo induction of IL-4 mRNA contrasts with prior in vitro studies in which IL-4 production was difficult to detect after primary stimulation. To assess the possibility that many T cells had been preprimed in vivo, germfree mice were compared with conventional mice and no differences in cytokine mRNA were found. These data show that T cell-dependent IL message production can be induced rapidly in vivo without prepriming and that the cytokine messages induced after anti-CD3 antibody administration do not suggest a predominance of either Th1 or Th2 type cells.

Animals↗
PubMed1990

Transplantation of the pineal gland in the mammalian third cerebral ventricle.

Fine structural correlates and functional parameters were measured in pinealectomized rats following grafting of the pineal gland into the third cerebral ventricle. Pinealectomy caused a significant decrease in serum melatonin concentration of animals compared to that in normal controls. No significant difference was observed in the serum melatonin concentration between pinealectomized rats and those receiving sham transplantation with fragments of occipital cortex. By 6 weeks nearly 50% of pinealectomized rats receiving pineal transplants demonstrated a significant increase in the serum melatonin concentration in contrast to that of pinealectomized rats and pinealectomized animals receiving sham transplants. Pinealocytes survived and flourished following transplantation from the epithalamic region to the third cerebral ventricle of the hypothalamus in host rats. These cells were found to be arranged individually or in clusters surrounding fenestrated capillaries of the graft. Moreover, these pinealocytes demonstrated ultrastructural features indicative of an active secretory process, including dense-core and clear vesicles as well as vacuoles containing flocculent material. Additional characteristics distinctive of normal control pinealocytes were observed in surviving cells of grafts, such as synaptic ribbons, synaptic ribbon fields, and myeloid bodies. Bundles of unmyelinated axons and apparent adrenergic nerve endings were observed with transmission electron microscopy and immunocystochemistry using antisera against tyrosine hydroxylase (TH). Nerve fibers and terminals were found within perivascular spaces surrounding fenestrated capillaries of viable grafts. These reported observations suggest that a significant population of transplanted pinealocytes recover functional activity (e.g., heightened melatonin secretion) following stereotaxic grafting into the third cerebral ventricles of pinealectomized animals. This apparent recovery of function may be linked directly to reinnervation of the gland by nerve fibers that appear to arise from the underlying median eminence.

Animals↗