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PubMed1984

A role for macrophages in suppressor cell induction.

A mechanism responsible for the induction of NP-specific first order (inducer) suppressor cells (TS1) is described. TS1 cells are induced by i.v. administration of hapten-coupled splenic cells. Their activity is assessed by the adoptive transfer of NP-specific suppression during the afferent phase of the contact sensitivity response. NP-coupled firmly adherent, FcR+, I-A-bearing macrophages induce TS1. The antigen-presenting cells required for TS1 induction lack the Thy-1 and Lyt-1 markers, and are resistant to 500 R irradiation and to cyclophosphamide treatment. NP-coupled dendritic cells fail to induce TS1 activity. The induction of TS1 cells is genetically restricted by genes that map in the I-J region of the H-2 complex. The NP-coupled antigen-presenting cells must share at least one I-J allele with the TS1 donor for effective induction of TS1 activity. To minimize allogeneic effects in these studies, the activity of the TS1 population was assessed by adoptive transfer into syngeneic recipients. The present results are compared with the mechanisms required for the induction of second and third order suppressor cells.

Animals↗
PubMed1997

Dosimetry of fractionated experimental radioimmunotargeting with idiotypic and anti-idiotypic anticytokeratin antibodies.

BACKGROUND: Repeated injections of iodine-125 (125I)-labeled tumor targeting anticytokeratin monoclonal antibody (TS1) and a nonlabeled antiidiotypic monoclonal antibody against TS1 (alphaTS1) were compared with a single injection of the radiolabeled TS1 in experimental radioimmunotargeting. Anti-TS1 was used to remove nontargeting TS1. METHODS: Nude mice were inoculated with HeLa Hep2 cells. The animals in Group A received a single injection of 13 MBq 125I-labeled TS1. The animals in Group B received four injections of 125I-labeled TS1 (8-13 MBq) followed by alphaTS1 24 hours later, at 2-week intervals. The mean absorbed doses were calculated according to the Medical Internal Radiation Dose Committee criteria based on repetitive radioimmunoscintigraphies during an observation period of 59 days. RESULTS: A 11 gray (Gy) mean dose to the tumor and 2 Gy to the whole body was achieved in Group A. Mean peak tumor uptake of 5% of the injected dose (ID), corresponding to 14% ID/g, was observed on Day 17 after a single injection of the labeled monoclonal antibody. A mean peak tumor uptake of the same order of magnitude was seen in Group B. An absolute increase in the tumor uptake was observed in Group B during the entire observation period. The mean absorbed dose to the tumors was 11 Gy at the end of the observation period, whereas the whole body dose was only 2.5 Gy in Group B. Autoradiography of the tumors at the end of the observation period confirmed an intensive heterogeneous accumulation of activity in the entire tumor. CONCLUSIONS: The fractionated strategy can contribute to a significant accumulation of radiolabeled TS1 in the tumors. Furthermore, the use of alphaTS1 makes it possible to increase the tumor-to-nontumor dose ratio and maintain a prolonged high activity accumulation in the tumor.

Animals↗
PubMed2001

Sensitivity to diethylether anesthesia of fruit flies primarily depends on the genotypes of the sodium channel gene rather than the states of the membranes and the mechanisms might be different from heat-induced paralysis.

The para locus of Drosophila melanogaster encodes the alpha subunit of a voltage-sensitive sodium channel. Many of the mutants develop paralysis at the high temperature (37 degrees C) and are hypersensitive to diethylether anesthesia. We examined whether the two aspects of the phenotype are mediated by a same mechanism that involves the sodium channel molecule by investigating properties of the three para alleles (para(hd838), para(ts1) and para(ts3)). Larvae of the all para strains showed almost normal sensitivities to diethylether anesthesia while adult flies of them showed hypersensitivities to that in the following manner: para(hd838)<==para(ts1)<para(ts3)<Canton-S. Larvae of the two para strains showed hypersensitivities to heat-induced paralysis in the following manner: para(ts1)=para(ts3)<para(hd838)=Canton-S, while adult flies of the all para strains showed hypersensitivities to that in the following manner: para(ts1)=para(ts3)<para(hd838)<Canton-S. The distinct phenotype of para(hd838) from para(ts1) or para(ts3) observed in the larval and adult heat-induced paralysis, would be the reflection of the difference of the mutation sites between in para(hd838) and para(ts1) or para(ts3). In addition, because the rank of sensitivity in the adult anesthesia and heat-induced paralysis were reversed between para(hd838) and para(ts1) or para(ts3), the mechanisms of diethylether anesthesia and heat-induced paralysis are not the same. There would be the anesthesia-specific mechanisms because the sensitivity to anesthesia became more remarkable in para(hd838) than in para(ts1) or para(ts3). para(hd838) has an insertion of P-element, one of a transposable element, in the second intron of the para sodium channel gene. Excision of the P-element from the para locus of the para(hd838) conferred the flies the wild-typic phenotype and reduction of the para gene in para(hd838) dramatically enhanced the hypersensitivity to anesthesia, suggesting that the phenotype of the strain was caused exclusively by the mutation of the para locus. The susceptibility to anesthesia also depends on the temperature at which the flies were assayed, not at which they were cultured, but the dependence on the assay temperature was smaller than that on the genotype. By these findings we could assure that the sensitivity to diethylether anesthesia of para(hd838) primarily depends on the genotypes of the sodium channel gene rather than other reasons such as the fluidity of the membranes.

Journal Article↗
PubMed1991

Increased endocytosis in the Saccharomyces cerevisiae fragile mutant VY1160.

The VY1160 mutant is characterized by cell lysis in hypotonic solutions and generally increased permeability to substances for which Saccharomyces cerevisiae cells are not permeable. Two mutations, srb1 and ts1, have been identified in VY1160 mutant, and previous studies (Kozhina et al., 1979) have shown srb1 to be responsible for cell lysis. We now present evidence that the ts1 mutation leads to increased endocytosis in VY1160 cells. The internalization of lucifer yellow carbohydrazide in VY1160 cells is time-, temperature- and energy-dependent and consistent with a fluid-phase mechanism of endocytosis. The rate of steady-state accumulation of the dye at 37 degrees C is 145 ng/micrograms DNA per h for VY1160 mutant and 23 ng/micrograms DNA per h for S288C parental strain. Studies with isogenic strains having either the srb1 or the ts1 mutation, or SRB1 TS1 wild-type alleles have shown that only ts1 strains possess increased endocytosis. Quantitation of endocytosis in cells grown at 24 degrees C and shifted at 38 degrees C shows that ts1 strains, but not srb1 and wild-type strains, increase ten-fold the internalization of lucifer yellow 2 h after the shift at 38 degrees C. The analysis of ts1 x wild-type crosses provides evidence that the temperature-sensitive phenotype segregates together with the enhanced endocytosis. It is concluded that the increased endocytosis might explain the generally increased permeability of VY1160 mutant cells.

Adsorption↗
PubMed1987

Physical mapping of two herpes simplex virus type 1 host shutoff loci: rescue of each ts mutation occurs with two unique cloned regions of the viral genome.

Two complementing temperature-sensitive (ts) herpes simplex virus type 1 (HSV-1) mutants, PAA1rts1 and ts199, were defective in viral DNA synthesis and in the shutoff of cellular macromolecular synthesis at 39.5 degrees C, the nonpermissive temperature. PAA1sts1 and PAA1rts1+ recombinants and PAA1rts1+ revertants were used to examine the contributions of the PAA1r mutation and the ts1 mutation of PAA1rts1 in affecting the levels of viral and cellular DNA synthesized at 34 and 39.5 degrees C. The results of this study suggests an interaction between the viral DNA polymerase and the ts1+ gene product during HSV-1 DNA replication and possibly in the inhibition of host DNA synthesis by HSV-1. Physical mapping of the ts mutations present in ts199 and the PAA1sts1 recombinant ts1-8 were performed by intratypic marker rescue experiments. Surprisingly, both the ts1-8 and ts199 mutations were rescued by two cloned fragments: ts1-8 by BglII-K (map coordinates 0.095 to 0.163) and BglII-I (map coordinates 0.314 to 0.417), while ts199 was rescued by BglII-K and BglII-O (map coordinates 0.163 to 0.197). In more refined mapping experiments, the regions between coordinates 0.347 to 0.378 and 0.126 to 0.163 were able to rescue the ts1-8 mutation. Southern hybridization analysis confirmed that the fragments that rescued ts1-8 and those that rescued ts199 had homology, as predicted by the physical mapping results.

Animals↗
PubMed1991

Murine retroviral neurovirulence correlates with an enhanced ability ofvirus to infect selectively, replicate in, and activate resident microglial cells.

To determine the biologic basis of ts1 MoMuLV neurovirulence in vivo, newborn CFW/D mice were inoculated with neurovirulent ts1 MoMuLV and nonneurovirulent wt MoMuLV and the temporal response to virus infection in the central nervous system (CNS), spleen, and thymus was studied comparatively. Experimental procedures included single and double labeling in situ immunohistochemistry with selective morphometric analyses, and steady state immunoblotting of viral proteins. Cellular targets for virus infection were identical for both ts1 and wt MoMuLV and consisted sequentially of 1) splenic megakaryocytes, 2) splenic and thymic lymphocytes, 3) CNS capillary endothelial cells, and 4) CNS pericytes and microglia. Resident microglial cells served as the major reservor and amplifier of virus infection in the CNS of ts1 MoMuLV-infected mice; a similar but much less significant role was played by microglia in wt MoMuLV-infected mice. The genesis and progression of severe spongiform lesions in ts1 MoMuLV-infected mice were both temporally and spatially correlated with amplified virus infection of microglia, and hyperplasia and hypertrophy of both virus-infected and nonvirus-infected microglial cells. Direct virus infection of neurons was never observed. The development of clinical neurologic disease and spongiform lesions in ts1 MoMuLV-infected mice correlated with the accumulation of both viral gag and env gene products in the CNS; there was no selective accumulation of env precursor polyprotein Pr80env. When compared to wt MoMuLV-infected mice, the neurovirulence of ts1 MoMuLV-infected mice occurred by an enhanced ability to replicate in the CNS and to infect and activate more microglia, rather than by a fundamental change in cellular tropism or topography of virus infection.

Animals↗
PubMed1985

Characterization of the accessory cells involved in suppressor T cell induction.

The ability of UV-treated splenic adherent cells (SAC) to induce T cell-mediated immunity and suppressor T cells was analyzed in the 4-hydroxy-3-nitrophenyl acetyl (NP) system. UV irradiation of 0.88 KJ/m2 decreased the capacity of NP-coupled SAC to induce delayed-type hypersensitivity (DTH) responses by about 50%. The ability of uncoupled UV-treated SAC to induce allogeneic DTH response was also imparied, indicating that UV-treated SAC are inefficient at inducing DTH in these systems. TS1 induction by UV-treated NP-SAC was evaluated TS1 induction by UV-treated NP-SAC was evaluated by using adherent cells that were subjected to the same dose of UV irradiation that impaired DTH induction. Intravenous administration of 10(3) or 10(4) UV-treated NP-coupled SAC induced TS1 cells with the same efficiency as non-UV-irradiated cells. The TS1 cells induced in this fashion were antigen specific. Furthermore, to establish that the antigen was not reprocessed by the host, I-J-mismatched, UV-treated NP-SAC were unable to induce TS1 cells. The population of antigen-presenting cells responsible for TS1 induction appear to express both I-A and I-J determinants. TS2 induction by UV-treated accessory cells was also analyzed. TSF1 inducer suppressor factor was pulsed onto graded numbers of either normal or UV-treated adherent cells. The same levels of antigen-specific suppression were induced with normal and UV-treated cells. Finally, TS3 induction by UV-treated NP-SAC was analyzed. UV-treated and normal NP-SAC (3 X 10(3] induced antigen-specific suppression of NP DTH responses. I-J-mismatched, UV-treated NP-SAC failed to induce suppression, suggesting that the hapten was not reprocessed by the host under these experimental conditions. The accessory cell population responsible for TS3 induction appears to express both I-A and I-J determinants. Thus, there are at least two functional distinctions between the antigen-presenting cells that induce immunity vs those that induce suppressor cells. First, UV treatment selectively impairs the antigen-presenting cells, which activate the positive limb of the immune response. Second, I-J determinants appear to be specifically associated with the SAC, which induce suppressor T cells. Although these criteria can be used to distinguish the accessory cells involved in suppressor cell pathways from those controlling helper T cell induction, there were no discernible phenotypic differences among the accessory cells that induce the TS1, TS2, and TS3 subsets.

Animals↗
PubMed2001

Conditional modification of behavior in Drosophila by targeted expression of a temperature-sensitive shibire allele in defined neurons.

Behavior is a manifestation of temporally and spatially defined neuronal activities. To understand how behavior is controlled by the nervous system, it is important to identify the neuronal substrates responsible for these activities, and to elucidate how they are integrated into a functional circuit. I introduce a novel and general method to conditionally perturb anatomically defined neurons in intact Drosophila. In this method, a temperature-sensitive allele of shibire (shi(ts1)) is overexpressed in neuronal subsets using the GAL4/UAS system. Because the shi gene product is essential for synaptic vesicle recycling, and shi(ts1) is semidominant, a simple temperature shift should lead to fast and reversible effects on synaptic transmission of shi(ts1) expressing neurons. When shi(ts1) expression was directed to cholinergic neurons, adult flies showed a dramatic response to the restrictive temperature, becoming motionless within 2 min at 30 degrees C. This temperature-induced paralysis was reversible. After being shifted back to the permissive temperature, they readily regained their activity and started to walk in 1 min. When shi(ts1) was expressed in photoreceptor cells, adults and larvae exhibited temperature-dependent blindness. These observations show that the GAL4/UAS system can be used to express shi(ts1) in a specific subset of neurons to cause temperature-dependent changes in behavior. Because this method allows perturbation of the neuronal activities rapidly and reversibly in a spatially and temporally restricted manner, it will be useful to study the functional significance of particular neuronal subsets in the behavior of intact animals.

Alleles↗
PubMed1993

Rudimentary thymus of SCID mouse plays an important role in the development of retrovirus-induced neurologic disorders.

The role of the thymus in neurologic disorders induced by the murine retrovirus, ts1, a neuropathogenic and lymphocytopathic mutant of the Moloney murine leukemia virus-TB, was examined using severe combined immune deficiency (SCID) mice. Athymic nude mice are resistant to ts1-induced neurologic disease. All SCID mice inoculated neonatally with ts1 developed neurologic disorders similar to those of inoculated BALB/c mice, albeit after a longer latency period. In some experiments, instead of inoculating ts1 directly, purified thymocytes, CD4+, or CD8+ T cells from ts1-infected BALB/c mice were transferred to neonatal H-2 compatible SCID mice. We found that SCID mice that received infected thymocytes developed the disease faster than those that received infected CD4+ T cells. SCID mice that received infected CD8+ T cells did not develop any disease. Thus, the (rudimentary) thymus of SCID mouse plays a key role in ts1-induced neurologic disease. In addition, flow cytometric analysis of the reconstituted SCID mice showed that CD8+ T cells migrate and preferentially colonize the thymus while CD4+ T cells were found in the spleen and to a lesser extent in the thymus. However, the significance of this organ specific movements of transferred cells in relation to the virus infection remains unclear. In view of the involvement of the thymus and the CD4+ T cells in human immunodeficiency virus infection, which also infects the central nervous system (CNS) in most cases, our findings in this murine model may help us better understand how the thymus may contribute to the damage of the CNS in retrovirus infections.

Animals↗
PubMed1996

Long-term cultivation and productive infection of primary thymocyte cultures by a thymocytopathic murine retrovirus.

ts1, a mutant of MoMuLV, selectively kills T cells and neurons in the infected host resulting in neuroimmunodegeneration. In the infected thymus there is an early increase in mitosis of thymocytes followed by rapid death, suggesting that thymocyte death may be induced by viral mitogenic activation. Studies on thymocytes obtained from ts1-infected mice indicated that the ts1-induced depletion of thymocytes is mediated through activation-induced death by apoptosis. To further investigate the interaction between ts1 and thymocytes, we have established long-term primary murine thymocyte cultures by placing the thymocytes together with thymic remnants in culture medium containing IL-2 and IL-7. These thymocytes retained their immature phenotype and we susceptible to infection by ts1 and its parental wild-type MoMuLV. ts1-infected thymocytes proliferated initially at accelerated rate but subsequently produced more infectious virus and died much faster than control or MoMuLV-infected thymocytes. These in vitro studies to some extent reflect our in vivo studies reported previously.

Animals↗
PubMed2002

Conditional disruption of synaptic transmission induces male-male courtship behavior in Drosophila.

It is reported here that male-male courtship behavior is evoked instantaneously in the fruit fly Drosophila by conditional disruption of synaptic transmission. A temperature-sensitive allele of the Drosophila dynamin gene shibire (shi(ts1)) was expressed by using the GAL4/UAS system to disrupt synaptic transmission from GAL4-positive neurons in a temperature-dependent manner. An enhancer-trap GAL4 line C309 directing shi(ts1) expression in central and peripheral neurons (C309/UAS-shi(ts1)) initiated stereotypical precopulatory behavior toward other mature males immediately after a temperature shift from the permissive to restrictive temperature. At the restrictive temperature, C309/UAS-shi(ts1) males formed "courtship chains" and exhibited abnormally high levels of head-to-head interactions. The temperature-induced male-male courtship is attributable not to an increase in sexual attractiveness but to an increase in sexual activity of C309/UAS-shi(ts1) males. Interestingly, the temperature-induced increase in sexual activity is specific toward male partners, because C309/UAS-shi(ts1) males courted receptive virgin females less vigorously and copulated less efficiently after shifted to the restrictive temperature. Among the GAL4-positive neurons in C309, conditional disruption of certain cholinergic neurons but not the mushroom body intrinsic neurons plays a critical role in the induction of male-male courtship. These neurons may be involved in inhibitory systems that normally suppress aberrant male-male courtship. The presented strategy that can induce behavioral abnormalities by disrupting synaptic transmission in an acute and noninvasive manner will allow further exploration as to how distinct neuronal groups control sexual orientation and other aspects of reproductive behavior in Drosophila.

Alleles↗
PubMed2005

Up-regulation of astrocyte cyclooxygenase-2, CCAAT/enhancer-binding protein-homology protein, glucose-related protein 78, eukaryotic initiation factor 2 alpha, and c-Jun N-terminal kinase by a neurovirulent murine retrovirus.

In susceptible strains of mice, infection with the mutant retrovirus MoMuLV-ts1 causes a neurodegeneration and immunodeficiency syndrome that resembles human human immunodeficiency virus-acquired immunodeficiency syndrome (HIV-AIDS). In this study the authors show increased expression of cyclooxygenase-2 (COX-2) in the brainstem tissues of ts1-infected mice. Up-regulated central nervous system (CNS) levels of this enzyme are associated with HIV-associated dementia and other inflammatory and neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. In brainstem sections, the authors find that astrocytes surrounding spongiform lesions contain increased amounts of immunoreactive COX-2. COX-2 is also up-regulated in cultured ts1-infected cells from the C1 astrocytic cell line, and activation of c-Jun N-terminal kinase, or JNK, pathway. Markers of endoplasmic reticulum (ER) stress, specifically the CCAAT/enhancer-binding protein (CHOP), the glucose-related protein 78 (GRP78), and phosphorylated eukaryotic initiation factor 2 alpha (eIF2 alpha), were also up-regulated in ts1-infected C1 astrocytes. Up-regulation of COX-2 and the above ER signaling factors was reversed by treatment of the infected cells with curcumin which specifically inhibits the JNK/c-Jun pathway. These findings indicate that the JNK/c-Jun pathway is most likely responsible for COX-2 expression induced by ts1 in astrocytes, and that ts1 infection in astrocytes may lead to up-regulation of both inflammatory and ER stress pathways in the central nervous system. Because COX-2 inhibitors are now widely used to treat inflammatory conditions in animals and humans, this finding suggests that these drugs may be useful for therapeutic intervention in neurodegenerative syndromes as well.

Animals↗
PubMed2003

Vulnerability of allografts to rejection by MHC class II-restricted T-cell receptor transgenic mice.

BACKGROUND: Examination of the in vivo activation and function of CD4+ T cells in response to allografts may advance our understanding of the rejection process. We analyzed the capacity of transgenic class II-restricted CD4 T cells to reject skin, cardiac, and islet transplants. METHODS: TS1 mice possess a high frequency of CD4+ T cells specific for the immunodominant epitope of the viral hemagglutinin (HA) protein. We analyzed the kinetics of rejection of skin, heart, and islet grafts by naïve and sensitized TS1 mice and by adoptively transferred TS1 lymphocytes. RESULTS: Rejection of heart transplants was more rapid than skin grafts (mean survival time, 12.9 vs. 26.6 days), and islet grafts survived indefinitely in TS1 mice. These findings may be partly attributable to the supranormal frequency of HA-reactive cells in TS1 mice. In support of this, we found that adoptive transfer of 5 x 10(5) TS1 lymphocytes to Balb/c hosts effected consistent rejection of HA-bearing skin transplants, whereas a significantly greater number (3 x 10(6)) was required for heart transplant rejection. The in vivo proliferative response of HA-specific T cells to heart and skin was found to be robust and predominantly localized to the draining lymph nodes. CONCLUSION: We developed a model of allograft rejection in which the responding T cells and relevant graft antigen are specifically defined. Adoptive transfer of carboxy-fluorescein succinimidyl ester-labeled transgenic T cells allowed us to visualize a robust proliferative response in vivo to heart and skin allografts, which in both cases was localized to regional lymph nodes.

Adoptive Transfer↗
PubMed1993

The application of immunotargeting into cancer chemotherapy with carboplatin: in vitro and in vivo studies.

Anti-tumor effects of the following 2 cis-diammin (1, 1-cyclobutandicarboxylato) platin II (carboplatin, Bristol-Myers-Squibb) conjugates were evaluated through both in vitro and in vivo experiments: (1) carboplatin coupled with anti-cytokeratin monoclonal antibody (MAb), TS1 via carboxymethyl dextran (carboplatin-carboxymethyl dextran-TS1), and (2) carboplatin-carboxymethyl dextran-avidin targeted to biotinylated TS1. Using 1-ethyl-3(3-dimethylaminopropyl)-carbodiimide and N-hydroxysuccinimide, carboplatin was conjugated to carboxymethyl dextran, TS1, or avidin, at high molar ratios. The staining positivity of carboplatin-carboxymethyl dextran-TS1 in indirect immunofluorescence was almost identical to that of the original MAb. The average dose of carboplatin given in each treatment was about 60% of a clinical dose. Regarding cytotoxicity, the free drug showed the strongest effect and the best dose-dependency in cell lines: HeLa and ZR-75-1. An in vivo study giving carboplatin-MAb conjugates or free drug to HeLa tumor bearing nude rats proved that the efficacy of carboplatin-carboxymethyl dextran-TS1 in HeLa tumor was not greater than that of the free carboplatin.

Animals↗
PubMed1983

Biological and structural studies with an adenovirus type 2 temperature-sensitive mutant defective for uncoating.

We compared some of the biological and structural features of an adenovirus type 2 temperature-sensitive mutant (ts1) defective for maturation cleavages and uncoating with wild-type (WT) virus. The cleavage defect caused ts1 to produce virions at 39 degrees that contained five precursor proteins (pTP, 11K, PVI, PVII, PVIII). Coinfection of cells with such ts1 virions and a variety of mutants or WT virus not only failed to complement ts1 but actually depressed the infection by the second virus. The uncoating defect could only be overcome by multiplicity-dependent leakiness. The structure of the ts1 virion was compared with that of WT virus by iodination with chloramine-T, chloroglycoluril and lactoperoxidase, by cross-linking, and by digestion with proteases. Aside from the presence of precursor proteins and the greater stability of ts1 virions, no other differences were found that could account for the uncoating defect. Therefore, we postulate that this defect was caused by the greater stability imparted to the virion by precursor proteins PVI, PVII and PVIII.

Adenoviruses, Human↗
PubMed1990

Murine retroviral-induced spongiform neuronal degeneration parallels resident microglial cell infection: ultrastructural findings.

Ts1 Moloney murine leukemia virus (MoMuLV) is a neurovirulent retrovirus that causes a progressive, noninflammatory, spongiform, neurodegenerative disease in mice. The temporal localization of cellular targets for virus replication and the genesis of ultrastructural spongiform changes in the central nervous system (CNS) of CFW/D mice inoculated at birth with neurovirulent ts1 MoMuLV and nonneurovirulent wild type (wt) MoMuLV were studied comparatively by transmission electron microscopy. Cellular targets for both ts1 and wt MoMuLV infection were sequentially (a) splenic megakaryocytes, (b) CNS intravascular platelets and capillary endothelia, and (c) resident CNS pericytes and microglia. When compared with wt MoMuLV-infected mice, ts1 MoMuLV-infected mice had amplified localization of virus to microglia with disease progression that paralleled the development of spongiform changes both temporally and spatially. Virus infection of neurons was never observed. Spongiform lesions originated from the dilated cytocavitary system of proximal neuronal processes (predominantly dendrites) and from vacuolated myelin sheaths of distal axons. As the disease progressed, the severity of the spongiform lesions in ts1 MoMuLV-infected mice increased rapidly and was associated with increased number of virions and virus-infected cells. Lesions in wt MoMuLV-infected mice were not severe and regressed terminally with apparent clearance of virus from the CNS. These studies indicated that murine retroviral-induced spongiform lesions originated from both neuronal and oligodendroglial degeneration; splenic megakaryocytes, platelets, and cell-free viremia contributed to systemic dissemination of virus to the CNS; microglia were the major cell target and reservoir for virus infection in the CNS; and the neurovirulence of ts1 MoMuLV occurred by enhanced replication rather than by a fundamental change in cellular tropism. The identification of microglia as the major CNS cell target for virus infection and the absence of productive virus infection of neurons suggested an indirect mechanism for murine retroviral-induced neuronal dysfunction.

Animals↗
PubMed1985

Dextran augments delayed-type hypersensitivity by interrupting one limb of the suppressor cascade.

We have studied the immunomodulatory effect of dextran on the development of delayed-type contact hypersensitivity to a hapten in mice. Administration of an optimal dose of dextran 2 hours before applying picryl chloride to abdominal skin caused a twofold rise in the level of hapten-specific DTH. A study of the kinetics of development of DTH under the influence of dextran showed that comparable levels of response could be seen 2 days earlier in treated than in untreated mice, i.e., on the third day in contrast to the fifth day after sensitization. The peak of the responses, while greater in dextran-treated mice than in normal controls, remained the same at 5 days. Adoptive transfer studies revealed that comparable levels of DTH were conferred upon recipient mice by half the number of splenic cells from dextran-treated mice than that required from normal sensitized mice. Because several suppressor mechanisms are known to down-regulate DTH, we have studied dextran's effect on the neutralization of these systems as a possible explanation for its enhancing capabilities. Detailed examination was made of dextran's effect on the two suppressor T cells, Ts1 and Ts3, that act in tandem as well as its effect on the Ts1 and macrophage that work in combination. Both systems depress the efferent limb of DTH. We have found that dextran blocks the Ts1-macrophage pathway that controls DTH. Ts1 was found to arise normally in mice pretreated with dextran. Furthermore, Ts1 from dextran-treated mice produced TsF1 normally. However, we have found that dextran interferes with the production of macrophage suppressor factor (M phi-SF). Interference was partial when dextran was introduced during the interval in which macrophages were being armed with TsF1, and it was complete when dextran was put with pre-armed macrophages before they were triggered with antigen for production of M phi-SF. On the other hand, the Ts1-Ts3 limb of suppression remained unaffected by exposure to the immunomodulator. We found Ts3 arose normally in hapten-sensitized mice that had been pretreated with dextran. In addition, Ts3 became armed with TsF1 in vitro in the presence of dextran since the cells functioned properly to suppress mature DTH effector cells. Finally, TsF3 was able to act in vitro upon DTH effector cells despite the presence of dextran.(ABSTRACT TRUNCATED AT 400 WORDS)

Adjuvants, Immunologic↗
PubMed2006

Origin of rotational barriers of the N-N bond in hydrazine: NBO analysis.

Hydrazine passes through two transition states, TS1 (phi = 0 degrees ) and TS2 (phi = 180 degrees ), in the course of internal rotation around its N-N bond. The origin of the corresponding rotational barriers in hydrazine has been extensively studied by experimental and theoretical methods. Here, we used natural bond orbital (NBO) analysis and energy decomposition of rotational barrier energy (DeltaE(barrier)) to understand the origin of the torsional potential energy profile of this molecule. DeltaE(barrier) was dissected into structural (DeltaE(struc)), steric exchange (DeltaE(steric)), and hyperconjugative (DeltaE(deloc)) energy contributions. In both transition states, the major barrier-forming contribution is DeltaE(deloc). The TS2 barrier is lowered by pyramidalization of nitrogen atoms through lowering DeltaE(struc), not by N-N bond lengthening through lowering DeltaE(steric). Higher pyramidality of nitrogen atoms of TS2 than that of TS1 explains well why the N-N bond of TS2 is longer than that of TS1. Finally, the steric repulsion between nitrogen lone pairs does not determine the rotational barrier; nuclear-nuclear Coulombic repulsion between outer H/H atoms in TS1 plays an important role in increasing DeltaE(struc). Taken together, we explain the reason for the different TS1 and TS2 barriers. We show that NBO analysis is a useful tool for understanding structures and potential energy surfaces of compounds containing the N-N bond.

Electrons↗