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PubMed1992

Temporal lymphoreticular changes caused by ts1, a paralytogenic mutant of Moloney murine leukemia virus TB.

Inoculation of newborn FVB/N mice with ts1, a mutant of Moloney murine leukemia virus TB, induced severe thymic atrophy, spongiform polioencephalomyelopathy, and fatal posterior paralysis of the affected mice 35-40 days after inoculation. During the early course of infection viral replication was found in the spleen and, more importantly, within the thymus. Of these organs, the thymus was affected most severely by ts1-infection. Thymic weights of infected mice decreased markedly during disease progression, culminating in severe atrophy at the time of paralysis. During the first 10 days after inoculation, the virus replicated within the endothelial lining of splenic and thymic capillaries and was released albuminally into the basement membrane before spreading outwardly into perithelial, epithelial, and reticuloendothelial cells. Within these cells there was productive viral replication and subsequent dissemination of the virus to the thymic T cell population. Early infection (up to 10 days after inoculation) of the thymus induced an increase in thymocytic mitosis, followed by a progressive increase in thymocytic death between 15 and 35 days after inoculation. Thymuses from paralyzed mice killed 30-39 days after inoculation, demonstrated pronounced involution, characterized by loss of lobular architecture, effacement of the cortex and medulla, severe depletion of thymocytes, and partial or complete loss of Hassall's corpuscles. Immunohistochemistry for viral antigens showed positive labeling of splenic megakaryocytes, reticuloendothelial cells, and thymocytes in mitosis, and reticulo-epithelial-endothelial cells of the thymus. The thymic phase of viral replication appeared to be crucial for development of neurological lesions and posterior paralysis.

Animals↗
PubMed1991

Further characterization of ts1-8, a mutant of herpes simplex virus type 1.

Our initial characterization of a herpes simplex virus type 1, temperature sensitive host shutoff mutant, called ts1-8, revealed that it has a low plaquing efficiency and exhibits a defect in the shutoff of host polypeptide synthesis and host DNA replication at the nonpermissive temperature of 39.5 degrees C. Using intratypic marker rescue experiments the ts plaquing mutation was mapped to a 557 bp region. Sequence analysis and complementation studies revealed that the low plaquing efficiency phenotype is due to a mutation in the glycoprotein B gene converting Pro-357 to Ser. This novel tsgB mutation is located in a conserved region of gB and it is distinct from the delayed host shutoff mutation (dhs).

Amino Acid Sequence↗
PubMed1999

Stability and immunoreactivity of the monoclonal anticytokeratin antibody TS1 after different degrees of iodination.

The immunoreactivity, stability and in vivo kinetics of an anticytokeratin 8 monoclonal antibody, TS1, were investigated following different degrees of labeling with 125I (0.2, 1 and 2-3 125I/TS1 MAb). By testing with ELISA, it was demonstrated that a high degree of iodination, i.e. > 2 125I/TS1, caused a rapid decrease in immunoreactivity to almost zero within 10 days. Furthermore, a complete degradation to low molecular weight fragments and free iodine was seen, as shown by SDS PAGE and autoradiography. The differently labeled radionuclide conjugates were injected into nude mice inoculated with HeLa Hep2 cells and tumor doses (estimated by MIRD formalism), tumor:non-tumor dose ratios, % I.D./gram tissue, Gy/MBq and in vivo kinetics of the differently labeled MAbs were determined. Despite the in vitro instability of the highest iodinated radionuclide conjugate, it was possible to deliver high doses to the tumors if the conjugate was injected into the animal immediately after completion of the iodination procedure. Increases from 1.4 Gy to 15.2 Gy delivered tumor dose were obtained with a tenfold increase in the specific activity, without alterations in the tumor:non-tumor tissue dose ratios. There is room for significant improvements in efficacy at radioimmunotherapy, which can be gained by optimizing the degree of iodination. For therapeutical applications a high degree of iodination may be an advantage.

Animals↗
PubMed2000

Synthesis of virus-specific high-mobility DNA after temperature upshift of SC-1 cells chronically infected with moloney murine leukemia virus mutant ts1.

Premature termination products of reverse transcription that consist physically of viral minus-sense single-stranded DNA that is shorter than one long terminal repeat and partial DNA duplexes are dramatically increased in the central nervous system (CNS) of FVB/N mice that are infected by ts1, a temperature-sensitive mutant of Moloney murine leukemia virus. Due to their migration in agarose gels, these incomplete physical forms of DNA have been designated high-mobility (HM) DNA. In non-CNS tissues, the level of HM DNA is either low or not detectable. In order to determine the conditions that are necessary for the synthesis of HM DNA in vivo, we have characterized the physical forms of HM DNA that were synthesized in vitro in chronically infected SC-1 cells after temperature upshift. At the permissive temperature of 34 degrees C, the chronically infected SC-1 cells did not synthesize HM DNA. After temperature upshift of the cultured cells from 34 to 37 degrees C, the chronically infected SC-1 cells developed extremely high levels of HM DNA. Following temperature downshift of the cultured cells from 37 to 34 degrees C, a decrease in the level of HM DNA and an increase in the level of unintegrated linear proviral DNA occurred simultaneously. These results suggested that the accumulation of HM DNA both in vitro and in vivo may be the result of superinfection.

Animals↗
PubMed1999

Epitope specificity of the monoclonal anticytokeratin antibody TS1.

Due to their abundance in epithelial cells and deposition in necrotic regions intratumorally, cytokeratins (CKs) have been established as valuable targets for both radioimmunolocalization and radioimmunotherapy. The target epitope for the monoclonal anti-CK8 antibody, TS1, used for both experimental radioimmunolocalization and radioimmunotherapy, was determined by means of synthesis of 96 overlapping peptides that covered the entire CK8 molecule. A highly conserved peptide sequence, spanning amino acids (aa) 343-357 and covering the discontinuous epitope in the helical 2B domain, was identified. The epitope retains its helical structure, as shown with circular dichroism spectroscopy, although the length of the peptide (ie., >20 aa) is crucial for maintenance of immunoreactivity. To determine which aa residues are crucial for binding to the monoclonal antibody, alanine scanning was performed on a 26-mer covering aa 340-365, with the sequence QRGELAIKDANAKLSELEAALQRAKQ. The 26 modified peptides were evaluated using ELISA and BIAcore technology. The uniqueness of this epitope has been established by data base sequence comparisons.

Amino Acid Sequence↗
PubMed2003

[Automatic erythrocytometry in a robotized microscope MEKOS-Ts1].

Measurements of the form and size of erythrocytes are needed in the diagnosis of a number of diseases. However, such measurements, if made manually, are a labor-consuming and often inaccurate method, which ensures the determination of a very limited number of parameters. Hardware/software unit MEKOS-C1 enables an automated examination of blood smear, thus speeding up significantly the analysis and ensuring a more complete and accurate information. The possibilities of unit MEKOS-C1 were evaluated for the diagnosis of ovalocytosis. Blood smears of 19 patients from the Russian Pediatric Clinical Hospital, including 8 patients with inherited ovalocytosis, 1 patient with spherocytic ovalocytosis and 10 patients without the disease, were made use of Erythrocytes were isolated in the images of preparations and the contour of each cell was approximated by ellipse. The ratio between ellipse semi-axes served as a measure of erythrocytes' ovality. The mean ratio of semi-axes (RS) and the index of ovalocytosis (IO), i.e. a ratio of the mean maximum diameter to the mean minimal diameter, were calculated for each smear. Manual IO measurements were made in all preparations as a control. Since an additional error can enter the result because of the irregular smear nature and impossibility to standardize completely the technology of smear preparation, the data, obtained from two different smear parts and from parallel preparations, were compared. The reliability, stability and good reproducibility of the automated measurement results were demonstrated. The mean erythrocytes' RS correlated well with IO, obtained manually, and did not virtually differ from RS, measured in the automated manner. The mean RS value of erythrocytes, obtained from patients with inherited ovalocytosis, significantly differed from the control values, which is indicative of a high information density of the discussed parameter. Therefore, RS, when measured automatically, is a reliable and convenient characteristic of erythrocytes' ovality under the conditions of using the ordinary technique of smear preparation.

Adolescent↗
PubMed1993

Identification of a new cell adhesion motif in two homologous peptides from the COOH-terminal cell binding domain of human thrombospondin.

Thrombospondin-1 (TS1) contains at least four domains that support cell attachment. The COOH-terminal cell binding domain (CBD) was first identified with a monoclonal antibody against TS1 that blocked secretion-dependent platelet aggregation. Subsequently, this domain of TS1 has been found to bind a number of normal and transformed cells. We have localized attachment sites for human melanoma cells (G361) within the CBD to two noncontiguous 30-residue peptides designated C4 and C7 (Kosfeld, M. D., and Frazier, W. A. (1991) J. Biol. Chem. 267, 16230-16236). Here we report studies to define the active sequences within C4 and C7. An octapeptide, RFYVVMWK (4N1-1), from C4 and a pentapeptide, IRVVM (7N3-1), from C7 were found to support attachment of G361 melanomas, K562 erythroleukemia cells, HT1080 fibrosarcomas, C32 amelanotic melanomas, and endothelial cells. These peptides also inhibit the adhesion of cells to the recombinant CBD of TS1. The hexapeptide RFYVVM (4N1-2) also inhibits cell attachment. The inhibitory effect of combinations of C4- and C7-derived peptides is synergistic. The sequences 4N1-1 and 7N3-1 of TS1 share homology with two cell adhesive peptides from laminin (LM), LMF9 and LMPA22-2, respectively. These TS1 and LM peptides are interchangeable in inhibiting the adhesion of G361 cells to LM or TS1, suggesting a possible sharing of receptors by LM and TS1. K562 cells, however, bound only to TS1, and this binding was inhibited preferentially by the TS1 CBD peptides, indicating a receptor specific for TS1 which does not recognize LM. The active TS1 peptides are highly conserved among five species and four isoforms of TS1. Homologs of the TS1 peptides are found in tenascin, a matrix protein that shares several properties with TS1 and in factor VIII, alpha 2-macroglobulin, and von Willebrand factor.

Amino Acid Sequence↗
PubMed1995

Differential effect of rapamycin and cyclosporin A in proliferation in a murine T cell line expressing either intermediate or high affinity receptor for IL-2.

It has been reported that rapamycin (rap), cyclosporin A (CsA) and FK506 have immunosuppressive effect during the activation process of murine T cells. These drugs were investigated for their suppressive effect on a murine T cell line expressing intermediate (TS1 beta) or high (TS1 alpha beta) affinity IL-2R. Rap and CsA strongly inhibit the IL-2-dependent proliferation of TS1 alpha beta cells while they minimally affect the IL-2-mediated proliferation of TS1 beta cells. FK506 does not have any effect on the IL-2-driven proliferation of either TS1 beta or TS1 alpha beta cells. Simultaneous addition of Rap and CsA or Rap and FK506 inhibit the IL-2-mediated proliferation of TS1 beta and TS1 alpha beta cells and therefore FK506 does not revert the inhibition mediated by Rap in TS1 alpha beta cells. Neither Rap nor CsA affect IL-2R expression and internalization in TS1 alpha beta cells. CsA and Rap strongly inhibit the appearance of DNA binding activity of NF-AT and to a lesser extent NF-kappa B. Rap inhibits IL-2-stimulated phosphatidylinositol 3 (PI3) kinase activity in TS1 alpha beta cells. In TS1 beta cells, Rap activates PI3 kinase on its own, inhibiting the IL-2-stimulated PI3 kinase to a lesser extent. These results suggest that PI3 kinase is a target for Rap action. Our results strongly suggest that we have Rap and CsA sensitive and resistant activation pathways operating in TS1 beta and TS1 alpha beta cells.

Base Sequence↗
PubMed1992

Murine leukemia virus induced central nervous system diseases.

The ts1 mutant of Moloney murine leukemia virus TB (MoMuLV-TB) causes a degenerative neurologic and immunologic disease in mice characterized by development of spongiform encephalomyelopathy that results in hind-limb paralysis, marked thymic atrophy associated with immunodeficiency, and generalized body wasting. T cells, particularly CD4+ helper T cells, play a key role in the pathogenesis of the disease induced by ts1. Therefore, ts1 is unique among the described murine retroviruses in its ability to afflict both the central nervous system (CNS) and the T-cell compartment of the immune system in the same host. This particular ability to cause degenerative diseases involving both the CNS and immune system is shared by the lentiviruses responsible for development of the acquired immunodeficiency syndromes of humans and macaques. Our goal has been to elucidate the specific cellular and molecular mechanisms that underlie this neuro- and immunopathogenicity of ts1. We have previously reported that the primary neuropathogenic determinant of ts1 maps to a single amino acid substitution, Val-25-Ile, in the precursor envelope protein gPr80env. Further, at the restrictive temperature, the Val-25-Ile substitution did not prevent oligomerization of the gPr80env proteins; however, the structure of the oligomer was incompetent for transport from the ER to the Golgi. These findings suggest that the cytopathic effect of ts1 in neural cells might be due to accumulation of the gPr80env oligomers in the ER. Since glial cells are targets of ts1 infection in vivo, primary astrocytic cultures were established and the cytopathic effect of ts1 and MoMuLV-TB on these cells assessed. Both viruses replicate well in astrocytes and their replication is cytopathic, albeit to different degrees. The ts1 mutant appears to produce greater cell killing than the wild-type virus. Furthermore, it was found that the rate of processing of gPr80env of ts1 in astrocytes is slower than that of MoMuLV-TB. Therefore, the inefficient transport and processing of gPr80env of ts1 appears to correlate with its cytopathic effect in these cells. Electron microscopic studies of the ts1-infected astrocytes revealed large numbers of aberrant particles in the ER. The in vitro cytopathic effect of ts1 on astrocytes may reflect what happens in vivo. An indirect mechanism of neuronal-cell killing by ts1 is proposed.

Animals↗
PubMed1997

Experimental radioimmunotargeting combining nonlabeled, iodine-125-labeled, and anti-idiotypic anticytokeratin monoclonal antibodies: a dosimetric evaluation.

BACKGROUND: Preinjection of a nonlabeled tumor targeting anticytokeratin monoclonal antibody (TS1) and postinjection of an anti-idiotypic anticytokeratin monoclonal antibody (alphaTS1) were evaluated separately and in combination to investigate their effects on the accumulation of iodine-125 (125I)-labeled TS1 in experimental radioimmunotargeting. TS1 targets deposited extracellular cytokeratin 8 from necrotic tumor cells. METHODS: Nude mice were inoculated with HeLa Hep 2 cells. Four different groups were followed with 504 repetitive quantitative radioimmunoscintigraphic recordings during a 78-day observation period. The absorbed doses were calculated according to criteria of the Medical International Radiation Dose Committee. RESULTS: As much as 2% of the injected dose (ID) of 125I-labeled TS1 accumulated in the tumor, and the peak tumor uptake was recorded as late as Day 30 after the injection of 125I-labeled TS1. Anti-TS1 caused a rapid decrease in the whole body activity. The highest tumor-to-nontumor activity ratios were obtained when a pre-injection of nonlabeled TS1 was combined with a postinjection of alphaTS1. The mean absorbed dose in tumor per unit activity administered was 0.44 gray/megabecquerel (Gy/MBq) and in nontumor tissues 0.15 Gy/MBq after a single injection of 125I-TS1. The efficacy was 0.34 Gy/MBq in tumor and 0.1 Gy/MBq in nontumor tissues after a combination of preinjection of nonlabeled TS1 and postinjection of nonlabeled alphaTS1. This indicates a 20% increase in tumor doses compared with a single injection of labeled TS1. CONCLUSIONS: This study confirms an extensive accumulation of TS1 in the tumor, with peak values as late as 30 days after injection of labeled TS1. Furthermore, both preinjection of nonlabeled TS1 and postinjection of alphaTS1 can improve radioimmunotargeting.

Animals↗
PubMed1990

Relationships between antigen-specific helper and inducer suppressor T cell hybridomas.

Ts1, or inducer suppressor T cells, share many phenotypic and functional characteristics with helper/inducer subset of T cells. In order to evaluate the relationship between these cell types, we made a series of new Ts1 hybridomas by the fusion of Ts1 cells with the functionally TCR alpha/beta-negative BW thymoma (BW 1100). Three Ts1 hybridomas (CKB-Ts1-38, CKB-Ts1-53, and CKB-Ts1-81) were established that express TCR and produce Ag-specific suppressor factors constitutively, thus making it possible to study the nature and specificity of Ag receptors, MHC restriction, and lymphokine production by the Ts1 hybridomas. Results presented in this report demonstrate that all the Ts1 hybridomas described here express CD3-associated TCR-alpha beta. These three Ts1 hybridomas recognize Ag (NP-KLH) specifically in a growth inhibition assay and this recognition is restricted by IE molecules. Two of the hybridomas also produce IL-2 or IL-2 and IL-4 upon Ag-specific activation. Thus, by these three criteria the Ts1 hybridomas appear indistinguishable from Th cells. These three Ts1 hybridomas, however, release suppressor factors (TsF1) in the supernatant that suppress both in vivo DTH and in vitro PFC responses in an Ag-specific manner. Like the TsF1 factors characterized previously, the suppression mediated by these factors are Igh restricted and lack H-2 restriction. These factors mediate suppression when given in the induction phase but not during the effector phase of the immune response. The TsF1 factors are absorbed by Ag (NP-BSA), and anti-TCR affinity columns and the suppressor activity can be recovered by elution. The data are consistent with the interpretation that Ts1 inducer-suppressor T cells are related to Th cells; the feature that distinguishes these cells is the ability to produce Ag-binding factors that specifically suppress immune responses.

Animals↗
PubMed1995

Thrombospondin 1 expression in transformed endothelial cells restores a normal phenotype and suppresses their tumorigenesis.

Murine endothelial cells are readily transformed in a single step by the polyomavirus oncogene encoding middle-sized tumor antigen. These cells (bEND.3) form tumors (hemangiomas) in mice which are lethal in newborn animals. The bEND.3 cells rapidly proliferate in culture and express little or no thrombospondin 1 (TS1). To determine the role of TS1 in regulation of endothelial cell phenotype, we stably transfected bEND.3 cells with a human TS1 expression vector. The cells expressing human TS1 were readily identified by their altered morphology and exhibited a slower growth rate and lower saturation density than the parental bEND.3 cells. The TS1-expressing cells also formed aligned cords of cells instead of clumps or cysts in Matrigel. Moreover, while the bEND.3 cells formed large tumors in nude mice within 48 hr, the TS1-expressing cells failed to form tumors even after 1 month. The TS1-transfected cells expressed transforming growth factor beta mRNA and bioactivity at levels similar to those of the parental or vector-transfected bEND.3 cells, indicating that the effects of TS1 expression are not due to the activation of transforming growth factor beta by TS1. TS1 expression resulted in a > 100-fold decrease in net fibrinolytic (urokinase-type plasminogen activator, uPA) activity due to more plasminogen-activator inhibitor 1 and less uPA secretion. TS1 thus appears to be an important regulator of endothelial cell phenotype required for maintaining the quiescent, differentiated state.

Animals↗
PubMed1995

Proline 137 is critical for adenovirus protease encapsidation and activation but not enzyme activity.

Infection with the adenovirus type 2 ts1 mutant at the nonpermissive temperature resulted in the production of noninfectious virions. This has been ascribed to the P137L mutation in the virus-encoded cysteine protease which causes a defect in protease activity. Here we have examined the ts1 defect in detail as a means of learning more about the viral protease. The ts1 protease accumulated in the nucleus normally and was found associated with incomplete particles as was the case with wt. This enzyme was active in both wt and ts1 incomplete particles produced at 39 degrees (ts1-39 TCs), provided they were dissociated with 4 M urea. While the wt protease was packaged into complete particles, the ts1-39 particles were totally devoid of protease. This defect was nearly completely corrected by addition of the 11-residue activating peptide PVIc (GVQSLKRRRCF) to the medium late in infection. Rescue of ts1 occurred via restoration of enzyme activity and packaging of the ts1 enzyme into complete virions. Recombinant ts1 enzyme was not temperature sensitive. The P137L mutation responsible for the ts1 defect appeared therefore to be an in vivo phenotype involving apparently linked events of protease packaging and activation mediated by the PVI protein.

Adenoviridae↗
PubMed2006

Impact of effector cell differentiation on CD4+ T cells that evade negative selection by a self-peptide.

We have used a transgenic mouse system to examine how differing reactivities of TCRs expressed by naive versus effector cells can shape the functional potential of autoreactive CD4+ T cells. Transgenic mice expressing TCRs that exhibit either high (TS1) or low [TS1(SW)] reactivity toward the I-Ed-restricted determinant S1 from the influenza virus PR8 hemagglutinin (HA) were mated with transgenic mice expressing HA under the control of different promoters. HACII mice express HA driven by an MHC class II promoter, and both the TS1 and TS1(SW) TCRs underwent substantial deletion in this background. HA104 mice express HA driven by an SV40 promoter, and the highly reactive TS1 TCR was substantially deleted. By contrast, the less reactive TS1(SW) TCR underwent little or no deletion in TS1(SW) x HA104 mice, although CD5 up-regulation indicated that they had interacted with the S1 self-peptide. In adoptive transfer studies, naive CD4+ T cells expressing the TS1(SW) TCR failed to proliferate in response to the S1 peptide in HA104 mice, and were inefficient at providing help for HA-specific antibody responses. However, effector CD4+ T cells generated from TS1(SW) x HA104 mice acquired the ability to proliferate in response to the S1 peptide in HA104 mice, and were as efficient as CD4+ T cells expressing the high reactivity TS1 TCR in helping HA-specific antibody responses. Collectively, these studies demonstrate a basis by which CD4+ T cells expressing TCRs with low reactivity toward self-peptides can evade negative selection and acquire enhanced autoreactivity following activation by a cross-reactive antigen.

Animals↗
PubMed1985

Effects of first-order Cryptococcus-specific T-suppressor cells on induction of cells responsible for delayed-type hypersensitivity.

Cell-mediated immunity is an important aspect of host resistance against Cryptococcus neoformans. Using a CBA/J murine model, we demonstrated that injection of cryptococcal antigen (CneF) at dosages sufficient to stimulate the antigenemia observed in cryptococcosis patients induces specific T-cell-mediated suppression of the cryptococcal delayed-type hypersensitivity response. The purpose of this study was to establish whether Lyt 1+, first-order T-suppressor (Ts1) cells block the induction of T cells responsible for delayed-type hypersensitivity (TDH cells) or whether they function by inducing Lyt 2+, efferent suppressor (Ts2) cells. In one set of experiments, suppression was observed when Ts1 cells were adoptively transferred to recipient animals the day before, the day of, or the day after immunization; however, when Ts1 cells were transferred after TDH cells were present, no suppression occurred. In other experiments, putative TDH cells from lymph nodes (LN) or spleens were adoptively transferred from mice after immunization or after a suppressive dose of CneF or adoptive transfer of Ts1 cells and immunization. Delayed-type hypersensitivity could not be transferred with LN or spleen cells from mice receiving the suppressive dose of CneF or the Ts1 cells, even when the LN or spleen cells were treated with anti-Lyt 2.1 antibody and complement to remove any Ts2 cells. Delayed-type hypersensitivity was readily transferred with LN or spleen cells from immunized mice whether the cells were or were not treated with anti-Lyt 2 and complement. Furthermore, the cells in the tolerized LN cell pools responsible for suppression of TDH cell induction were Lyt 1+ 2-, I-J+ cells, which is the phenotype of the Ts1 cells. Taken together, these data indicate that Ts1 cells inhibit the induction of TDH cells. This finding, coupled with the previous demonstration that Ts1 cells or a Ts1 cell-derived soluble factor (TsF1) induces Ts2 cells, establishes that the cryptococcal Ts1 cells are bifunctional in the suppressive pathway.

Animals↗
PubMed2006

Retrovirus-induced oxidative stress with neuroimmunodegeneration is suppressed by antioxidant treatment with a refined monosodium alpha-luminol (Galavit).

Oxidative stress is involved in many human neuroimmunodegenerative diseases, including human immunodeficiency virus disease/AIDS. The retrovirus ts1, a mutant of Moloney murine leukemia virus, causes oxidative stress and progressive neuro- and immunopathology in mice infected soon after birth. These pathological changes include spongiform neurodegeneration, astrogliosis, thymic atrophy, and T-cell depletion. Astrocytes and thymocytes are directly infected and killed by ts1. Neurons are not infected, but they also die, most likely as an indirect result of local glial infection. Cytopathic effects of ts1 infection in cultured astrocytes are associated with accumulation of the viral envelope precursor protein gPr80env in the endoplasmic reticulum (ER), which triggers ER stress and oxidative stress. We have reported (i) that activation of the Nrf2 transcription factor and upregulation of antioxidative defenses occurs in astrocytes infected with ts1 in vitro and (ii) that some ts1-infected astrocytes survive infection by mobilization of these pathways. Here, we show that treatment with a refined monosodium alpha-luminol (Galavit; GVT) suppresses oxidative stress and Nrf2 activation in cultured ts1-infected astrocytes. GVT treatment also inhibits the development of spongiform encephalopathy and gliosis in the central nervous system (CNS) in ts1-infected mice, preserves normal cytoarchitecture in the thymus, and delays paralysis, thymic atrophy, wasting, and death. GVT treatment of infected mice reduces ts1-induced oxidative stress, cell death, and pathogenesis in both the CNS and thymus of treated animals. These studies suggest that oxidative stress mediates ts1-induced neurodegeneration and T-cell loss.

Active Transport, Cell Nucleus↗
PubMed1983

Hapten-specific responses to the phenyltrimethylamino hapten. IV. Occurrence of mechanistically distinct idiotypic suppressor T cells before the appearance of anti-idiotypic suppressor T cells induced by the monovalent antigen L-tyrosine-p-azophenyltrimethylammonium.

We have previously shown that a single i.p. injection of the monovalent synthetic antigen, L-tyrosine-p-azophenyltrimethylammonium [tyr(TMA)] in complete Freund's adjuvant induces an anti-idiotypic T suppressor cell (Ts2) population that can be detected 6 wk later by its ability to shut down delayed-type hypersensitivity (DTH) specific for the TMA hapten. In this paper we present evidence that 2 wk after tyr(TMA) administration, a subset of Ts, termed Ts1, appears that is both functionally and phenotypically distinct from the late appearing Ts2 population. The early occurring Ts1 act only at the induction phase of the DTH response and can also suppress this response intrinsically. This latter point is in marked contrast to our previous observation that the tyr(TMA)-induced anti-idiotypic Ts2 fail to function intrinsically and can only be detected upon adoptive transfer into naive mice. Ts1 bear idiotypic receptors and are Ly-1+,2- in contrast to the anti-idiotypic Ly-1-,2+ Ts2 population. In addition, unlike the Ts2 population, Ts1 are comparatively nylon wool-adherent. Adsorption of Ts1 on either antigen- or idiotype-coated petri dishes indicate that the suppressor activity can be transferred only by antigen-binding cells. Cellfree factors prepared from spleens containing the Ts1 population can suppress DTH only if administered at the induction phase of the response, in contrast to the factors derived from the Ts2 population that act both at induction as well as effector phases, suggesting that Ts1 and Ts2 can function via soluble mediators. Finally, we show that when Ts1-bearing mice are primed and boosted for anti-TMA antibody formation, the resulting response was overall reduced with respect to the idiotype-positive and negative plaque-forming cells that differs from the Ts2-bearing hosts wherein the idiotypic component is preferentially suppressed. The appearance of Ts1 before the detection of Ts2 in the same experimental animals is discussed with reference to a normal physiologic sequence of events involved in suppressor pathways.

Animals↗