PubMed Health⌕ Search

Biomedical subjects

B L Davidson

Publications and source records attributed to B L Davidson.

At least 73 records · Page 4Linked to original sources
PubMed1998

The importance of TGF-beta in murine visceral leishmaniasis.

IFN-gamma is critical for the cure of leishmaniasis in humans and mice. BALB/c mice are genetically susceptible to infection with the visceralizing species of Leishmania, L. chagasi. We have evidence that a soluble factor(s) inhibits IFN-gamma production by cultured liver granuloma cells from BALB/c mice during L. chagasi infection. In contrast, liver granulomas from C3H.HeJ mice, which are genetically resistant to L. chagasi infection, produce abundant IFN-gamma. According to ELISAs and neutralization studies, there was not evidence that the Th2-type cytokines IL-10 or IL-4 contributed to IFN-gamma suppression. However, both Ab neutralization and immunohistochemistry showed that granuloma-derived TGF-beta was, at least in part, responsible for inhibiting IFN-gamma release by CD4+ cells in BALB/c liver granuloma cultures. Consistently, TGF-beta levels were high in liver granulomas from susceptible BALB/c mice but low in resistant C3H mice or in BALB/c mice that were immunized against L. chagasi disease. Administration of recombinant adenovirus expressing TGF-beta (AdV-TGFbeta) but not IL-10 (AdV-IL10) caused genetically resistant C3H mice to become significantly more susceptible to L. chagasi infection. In contrast, either AdV-TGFbeta or AdV-IL10 could abrogate the protective immune response achieved by immunization of BALB/c mice. We conclude that locally secreted TGF-beta inhibits Th1-associated cure of murine visceral leishmaniasis caused by L. chagasi, independently of Th2-type cytokines.

Adenoviridae↗
PubMed1998

Extensive beta-glucuronidase activity in murine central nervous system after adenovirus-mediated gene transfer to brain.

Mucopolysaccharidosis type VII (MPS VII), caused by beta-glucuronidase deficiency, is a classic lysosomal storage disease. In the central nervous system (CNS), there is widespread pathology with distention of vacuoles in neurons and glia. An approach to therapy for MPS VII would require extensive delivery of enzyme to the CNS and subsequent uptake by the affected cells. In this study we show that intrastriatal injection of recombinant adenovirus encoding beta-glucuronidase (Ad betagluc) to MPS VII or wild-type mice results in focal, intense beta-glucuronidase mRNA expression near the injection site. Further, histochemical staining for enzyme activity showed that beta-glucuronidase activity extended well beyond transduced cells. Activity was detected throughout the ipsilateral striatum as well as in the corpus callosum, ventricles, and bilateral neocortex. Similarly, after injection into the right lateral ventricle or cisterna magna, enzyme activity was present in the ependymal cells of the ventricles, in the subarachnoid spaces, and also in the underlying cortex (150-500 microm from ependyma). The distribution of enzyme was most extensive 21 days after gene transfer to normal mouse brain, with more than 50% of the hemisphere positive for beta-glucuronidase activity. Eighty-four days after adenovirus injection a substantial level of enzyme expression remained (>40% of hemisphere positive for beta-glucuronidase activity). Histological sections from striatum of beta-glucuronidase-deficient mice injected with Ad betagluc showed a marked reduction in the number of distended vacuoles in both neurons and glia, as compared with uninjected striatum. Importantly, correction was noted in both hemispheres. Our finding that a relatively small number of transduced cells produce enzyme that reaches a large proportion of the CNS has favorable implications in developing direct gene transfer therapies for lysosomal storage disorders.

Adenoviridae↗
PubMed1998

Progressive muscular dystrophy in alpha-sarcoglycan-deficient mice.

Limb-girdle muscular dystrophy type 2D (LGMD 2D) is an autosomal recessive disorder caused by mutations in the alpha-sarcoglycan gene. To determine how alpha-sarcoglycan deficiency leads to muscle fiber degeneration, we generated and analyzed alpha-sarcoglycan- deficient mice. Sgca-null mice developed progressive muscular dystrophy and, in contrast to other animal models for muscular dystrophy, showed ongoing muscle necrosis with age, a hallmark of the human disease. Sgca-null mice also revealed loss of sarcolemmal integrity, elevated serum levels of muscle enzymes, increased muscle masses, and changes in the generation of absolute force. Molecular analysis of Sgca-null mice demonstrated that the absence of alpha-sarcoglycan resulted in the complete loss of the sarcoglycan complex, sarcospan, and a disruption of alpha-dystroglycan association with membranes. In contrast, no change in the expression of epsilon-sarcoglycan (alpha-sarcoglycan homologue) was observed. Recombinant alpha-sarcoglycan adenovirus injection into Sgca-deficient muscles restored the sarcoglycan complex and sarcospan to the membrane. We propose that the sarcoglycan-sarcospan complex is requisite for stable association of alpha-dystroglycan with the sarcolemma. The Sgca-deficient mice will be a valuable model for elucidating the pathogenesis of sarcoglycan deficient limb-girdle muscular dystrophies and for the development of therapeutic strategies for this disease.

Amino Acid Sequence↗
PubMed1998

Superior cytotoxicity with ganciclovir compared with acyclovir and 1-beta-D-arabinofuranosylthymine in herpes simplex virus-thymidine kinase-expressing cells: a novel paradigm for cell killing.

Enzyme-prodrug therapy using ganciclovir and herpes simplex virus-thymidine kinase (HSV-TK) has demonstrated excellent antitumor activity in many different types of malignant cells. Previously, we noted that ganciclovir was substantially more cytotoxic than other HSV-TK substrates. Therefore, we embarked on a study to determine the basis for the superior cytotoxicity of ganciclovir. In U251tk human glioblastoma cells that stably express HSV-TK, ganciclovir elicited a >4 log cell kill instead of the < or =1.5 log cell kill mediated by two other HSV-TK substrates, 1-beta-D-arabinofuranosylthymine (araT) and acyclovir. Study of the metabolism of these drugs demonstrated that acyclovir was poorly phosphorylated to its active triphosphate with DNA incorporation below the limit of detection, which may explain the < 1 log cell kill in these cells. Lower levels of ganciclovir triphosphate accumulated compared with araT triphosphate (araTTP) under conditions that induced < or =1 log cell kill (67 versus 1235 pmol/10(7) cells, respectively), and the half-life for the triphosphate of ganciclovir was shorter than that of araT (terminal half-lives of 15 and 41 h, respectively). Incorporation of ganciclovir monophosphate into DNA was less than that of araT monophosphate, and both analogues were retained in DNA for > or =48 h. Thus, the superior cytotoxicity of ganciclovir was not due to enhanced metabolism to active forms. Highly cytotoxic concentrations of ganciclovir produced only weak inhibition of DNA synthesis. This allowed cells to proceed through S and G2-M phases during and after drug exposure, resulting in a doubling of cell number by 48 h after drug washout. As they attempted to progress through the cell cycle a second time, ganciclovir-treated cells accumulated in early S-phase and remained there until cell death, suggesting that ganciclovir incorporation in the DNA template was important for cytotoxicity. In contrast, strong inhibition of DNA synthesis by araTTP prevented cells from traversing the cell cycle for at least 12 h after drug washout, when the active metabolite was largely degraded araT-treated cells were unable to divide for at least 72 h after drug exposure, at which point the surviving cells displayed a normal cell cycle distribution pattern. Based on the results presented here, we propose a novel paradigm in which the ability of ganciclovir to incorporate into DNA without inhibiting progression through S-phase, combined with high cytotoxicity for incorporated ganciclovir monophosphate, produces multilog cytotoxicity.

Acyclovir↗
PubMed1998

Effects of keratinocyte and hepatocyte growth factor in vivo: implications for retrovirus-mediated gene transfer to liver.

We have previously shown that intravenous administration of keratinocyte growth factor (KGF) induces hepatocyte proliferation, allowing for efficient and noninvasive in vivo gene transfer with high-titer retroviral vectors in mice. The distinctive periportal distribution of transduced cells led us to investigate the ability of virus-sized particles to perfuse the liver adequately after growth factor treatment. We found that perfusion was adequate, and that transduction was limited to the periportal region because only those cells were stimulated to divide. Cells in this region also showed increased expression of Ram-1, the receptor for the murine Moloney leukemia virus (MoMLV) amphotropic envelope, after KGF treatment. In further studies we found that recombinant hepatocyte growth factor (HGF) induces a different population of hepatocytes to divide and upregulate Ram-1. The differential pattern of induction suggested that combining KGF and HGF would improve gene transfer efficiency further. Indeed, simultaneous delivery of both growth factors leads to an overall increase in the number of proliferating cells. Importantly, when coupled with MoMLV delivery, efficiency of gene transfer increased. These results confirm the utility of growth factors for noninvasive hepatic gene transfer in mice, and demonstrate how experiments to define the mechanism of transduction can be taken advantage of to develop improved gene transfer protocols.

Animals↗
PubMed1998

Superoxide production in vascular smooth muscle contributes to oxidative stress and impaired relaxation in atherosclerosis.

The endothelium is a source of reactive oxygen species in short-term models of hypercholesterolemia and atherosclerosis. We examined a chronic model of atherosclerosis for increased vascular production of superoxide (O2-.) and determined whether endothelial overexpression of superoxide dismutase (SOD) would improve endothelium-dependent relaxation. Superoxide generation was 3 times higher in isolated aortas from Watanabe heritable hyperlipidemic (WHHL) rabbits (2 to 4 years old) compared with aortas from New Zealand White (NZ) rabbits (43+/-10 versus 14+/-2 relative light units x min(-1) x mm(-2), n=9, P<0.05). After in vitro transduction with adenovirus containing the gene for CuZn-SOD (AdCMVCuZn-SOD) or extracellular SOD (AdCMVEC-SOD), endothelial O2-. levels in WHHL aortas were significantly reduced. Gene transfer of SOD to WHHL aortas, however, failed to improve the impaired relaxation to acetylcholine or calcium ionophore. By use of the oxidative fluorescent dye hydroethidine, an in situ assay indicated markedly increased generation of O2-. throughout the wall of WHHL aorta, especially within layers of smooth muscle. This finding was confirmed by demonstrating increased O2-. levels in smooth muscle cells cultured from WHHL aorta. We conclude that elevated O2-. levels in atherosclerotic vessels are not confined to the endothelium but occur throughout the vascular wall, including smooth muscle cells. Reduction in endothelial O2-. levels is not sufficient to improve endothelium-dependent relaxation. Generation of reactive oxygen species within the media may contribute to vasomotor dysfunction in atherosclerosis.

Animals↗
PubMed1998

Reproducible and efficient murine CNS gene delivery using a microprocessor-controlled injector.

To develop a reproducible gene transfer method for the murine CNS we evaluated delivery of various gene vehicles using mechanical or manual stereotaxic intracranial inoculation. A microprocessor controlled microsyringe pump (The World Precision Instruments/UltraMicroPump) programmable for volume, rate and syringe size and designed to dispense nanoliter and picoliter volumes was compared to a standard manual deliver method. Gene transfer efficiency of two viral vectors, two synthetic cationic lipid molecules, and naked DNA were evaluated in mice injected unilaterally in two brain regions. Animals received 1 microl over 10 min. of either HSVlac (1 x 10(5) b.f.u), AdLac (1 x 10(5) p.f.u), Tfx-10 or Tfx-20 (2.6 microg DNA in 2.0 microl Tfx; 1:1 charge ratio of DNA to liposome), or naked DNA (HSVlac plasmid, 10 microg/microl). After 4 days, animals from each group were perfused and tissue prepared for X-gal histochemical detection of beta-galactosidase expression. Blue cells were observed in the HSV, Adenovirus, and Tfx-20 groups only at the injection site in animals injected using the UMP. Animals injected manually exhibited fewer blue cells and positive cells were not restricted to the injection site. To quantify expression, tissue punches harvested from the injection sites as well as other brain regions were analyzed using a chemiluminescent reporter assay to detect beta-galactosidase (Galacto-Light). These data indicated increased activity in all animals injected with a lacZ containing vector via the UMP as compared to manual delivery: A 41% increase in the expression levels of beta-gal in HSVlac infected animals (p = 0.0029); a 29% increase in Adlac infected animals (p = 0.01); a 56% increase in Tfx-10 transduced animals (p = 0.04); a 24% increase in Tfx-20 transduced animals (p = 0.01); and a 69% increase in naked DNA gene transfer (p = 0.05). Total beta-galactosidase activity was greatest in HSVlac infected mice followed by Adlac > Tfx-20 > Tfx-10 = naked DNA.

Adenoviridae↗
PubMed1998

Gene transfer to rodent brain with recombinant adenoviral vectors: effects of infusion parameters, infectious titer, and virus concentration on transduction volume.

Initial studies examining intraparenchymal injection of recombinant viral vectors in rodent brain have demonstrated a limited region of gene transfer. We examined, independently, different infusion parameters to determine if the volume of cells transduced acutely could be increased. Varying the rate of infusion from 0.3 to 3 microliters/min at constant time and virus dose did not improve the volume of brain transduced, with the lowest rate of infusion demonstrating the least amount of gene transfer. However, transduction volume did increase with increasing particle concentrations of virus, although the improvements were modest from 3 to 9 x 10(9) total particles infused. Infusion of virus under conditions of hypertonicity resulted in modest improvements in the final transduced volume. These studies suggest that most changes in infusion parameters will have small effects on the initial transduction volume in rodent brain.

Adenoviridae↗
PubMed1998

Behavioral and cellular protection of rat dopaminergic neurons by an adenoviral vector encoding glial cell line-derived neurotrophic factor.

Previously, we observed that an adenoviral (Ad) vector encoding human glial cell line-derived neurotrophic factor (GDNF), injected near the rat substantia nigra (SN), protects SN dopaminergic (DA) neuronal soma from 6-hydroxydopamine (6-OHDA)-induced degeneration. In the present study, the effects of Ad GDNF injected into the striatum, the site of DA nerve terminals, were assessed in the same lesion model. So that effects on cell survival could be assessed without relying on DA phenotypic markers, fluorogold (FG) was infused bilaterally into striatae to retrogradely label DA neurons. Ad GDNF or control treatment (Ad mGDNF, encoding a deletion mutant GDNF, Ad lacZ, vehicle, or no injection) was injected unilaterally into the striatum near one FG site. Progressive degeneration of DA neurons was initiated 7 days later by unilateral injection of 6-OHDA at this FG site. At 42 days after 6-OHDA, Ad GDNF prevented the death of 40% of susceptible DA neurons that projected to the lesion site. Ad GDNF prevented the development of behavioral asymmetries which depend on striatal dopamine, including limb use asymmetries during spontaneous movements along vertical surfaces and amphetamine-induced rotation. Both behavioral asymmetries were exhibited by control-treated, lesioned rats. Interestingly, these behavioral protections occurred in the absence of an increase in the density of DA nerve fibers in the striatum of Ad GDNF-treated rats. ELISA measurements of transgene proteins showed that nanogram quantities of GDNF and lacZ transgene were present in the striatum for 7 weeks, and picogram quantities of GDNF in the SN due to retrograde transport of vector and/or transgene protein. These studies demonstrate that Ad GDNF can sustain increased levels of biosynthesized GDNF in the terminal region of DA neurons for at least 7 weeks and that this GDNF slows the degeneration of DA neurons and prevents the appearance of dopamine dependent motor asymmetries in a rat model of Parkinson's disease (PD). GDNF gene therapy targeted to the striatum, a more surgically accessible site than the SN, may be clinically applicable to humans with PD.

Adenoviridae↗
PubMed1998

Replication-deficient adenovirus vector transfer of gfp reporter gene into supraoptic nucleus and subfornical organ neurons.

The present studies used defined cells of the subfornical organ (SFO) and supraoptic nuclei (SON) as model systems to demonstrate the efficacy of replication-deficient adenovirus (Ad) encoding green fluorescent protein (GFP) for gene transfer. The studies investigated the effects of both direct transfection of the SON and indirect transfection (i.e., via retrograde transport) of SFO neurons. The SON of rats were injected with Ad (2 x 10(6) pfu) and sacrificed 1-7 days later for cell culture of the SON and of the SFO. In the SON, GFP fluorescence was visualized in both neuronal and nonneuronal cells while only neurons in the SFO expressed GFP. Successful in vitro transfection of cultured cells from the SON and SFO was also achieved with Ad (2 x 10(6) to 2 x 10(8) pfu). The expression of GFP in in vitro transfected cells was higher in nonneuronal (approximately 28% in SON and SFO) than neuronal (approximately 4% in SON and 10% in SFO) cells. The expression of GFP was time and viral concentration related. No apparent alterations in cellular morphology of transfected cells were detected and electrophysiological characterization of transfected cells was similar between GFP-expressing and nonexpressing neurons. We conclude that (1) GFP is an effective marker for gene transfer in living SON and SFO cells, (2) Ad infects both neuronal and nonneuronal cells, (3) Ad is taken up by axonal projections from the SON and retrogradely transported to the SFO where it is expressed at detectable levels, and (4) Ad does not adversely affect neuronal viability. These results demonstrate the feasibility of using adenoviral vectors to deliver genes to the SFO-SON axis.

Adenoviridae↗
PubMed1998

Tumor reduction in vivo after adenoviral mediated gene transfer of the herpes simplex virus thymidine kinase gene and ganciclovir treatment in human head and neck squamous cell carcinoma.

Gene transfer offers the possibility of novel therapies for head and neck squamous cell carcinoma (HNSCC). To this end, we demonstrate that a replication deficient adenovirus vector (Ad.RSVlacZ) can efficiently transduce foreign genes into human HNSCC cell lines in vitro, and that adenoviral mediated transfer of herpes simplex virus thymidine kinase (Ad.RSVtk) followed by exposure to ganciclovir results in tumor cell killing in vitro and in vivo. Exposure to Ad.RSVlacZ resulted in lacZ expression at multiplicities of infection (MOIs) of 10 and 100 for the cell lines HEp-2 and FaDu, respectively. This increased to 97% (HEp-2) and 49% (FaDu) at an MOI of 10,000. For HEp-2, maximum expression occurred during the first 48 hours after exposure (52% at 24 hours, 48% at 48 hours; MOI 500), then declined by 40% per day. This rapid decline may be caused by dilution of the gene through cell proliferation, because normalizing for the increase in total protein shows that the total number of cells expressing lacZ is stable from days 1 to 4. FaDu and HEp-2 were then transduced by AD.RSVtk and exposed to 20 microM ganciclovir for 24 hours. Significant tumor cell killing, as measured by a colony forming assay, occurred at an MOI of 2 for HEp-2 and 20 for FaDu. At an MOI of 200, 100% of HEp-2 and 97% of FaDu cells were killed. Next, subcutaneous tumor nodules derived from FaDu and HEp-2 were established in the flanks of SCID mice. Direct intratumoral injection of Ad.RSVtk followed by 7 days of ganciclovir therapy resulted in an adenovirus dose dependent reduction of tumor growth, and an actual size reduction of established tumor nodules at the highest does (10(10) plaque forming units). In conclusion, an adenovirus vector can efficiently transduce HNSCC cell lines in vitro. Maximum marker gene expression occurred during the first 48 hours after transduction. Transduction by Ad.RSVtk followed by exposure to ganciclovir resulted in tumor cell killing in vitro and in vivo.

Adenoviridae↗
PubMed1998

Functional rescue of the sarcoglycan complex in the BIO 14.6 hamster using delta-sarcoglycan gene transfer.

Four types of limb-girdle muscular dystrophy (LGMD) are known to be caused by mutations in distinct sarcoglycan genes. The BIO 14.6 hamster is a model for sarcoglycan-deficient LGMD with a deletion in the delta-sarcoglycan (delta-SG) gene. We investigated the function of the sarcoglycan complex and the feasibility of sarcoglycan gene transfer for LGMD using a recombinant delta-SG adenovirus in the BIO 14.6 hamster. We demonstrate extensive long-term expression of delta-sarcoglycan and rescue of the entire sarcoglycan complex, as well as restored stable association of alpha-dystroglycan with the sarcolemma. Importantly, muscle fibers expressing delta-sarcoglycan lack morphological markers of muscular dystrophy and exhibit restored plasma membrane integrity. In summary, the sarcoglycan complex is requisite for the maintenance of sarcolemmal integrity, and primary mutations in individual sarcoglycan components can be corrected in vivo.

Adenoviridae↗
PubMed1998

Effects of macrophage depletion and anti-CD40 ligand on transgene expression and redosing with recombinant adenovirus.

The anti-CD40 ligand antibody MR-1, and macrophage-depleting liposomes were tested for their ability as transient immunosuppressive agents to: (1) prolong transgene expression; and (2) permit redosing after recombinant adenovirus infusion of mice. To test for effect on transgene duration, mice were infused with recombinant adenovirus coding for human factor IX (AdFIX), and plasma FIX levels monitored over time. Treatment with either agent significantly prolonged transgene expression. Persistence was accompanied by inhibition of anti-adenovirus (anti-Ad) IgG, and decreased IL-10 and IFN-gamma production from splenic lymphocytes re-exposed to virus particles in vitro. To test for effect on redosing, mice were given a primary infusion of recombinant adenovirus coding for bacterial beta-galactosidase (Ad beta gal), followed by secondary and tertiary infusions of AdFIX on days 24 and 63. Mice that had received MR-1 had low to undetectable anti-Ad on day 24, and efficient transduction occurred. Furthermore, FIX levels endured in these mice, with 40% retention of FIX on day 63, in contrast to rapid loss in naive controls. On day 63, the continuance of negligible anti-Ad levels correlated with successful tertiary transduction. These results suggest that both macrophage depletion and CD40 ligand blockade inhibit immune responses to recombinant adenovirus to slow decline of transgene expression, while only CD40 ligand blockade inhibits anti-Ad antibody generation sufficiently to allow redosing to the liver.

Adenoviridae↗
PubMed1998

Poly (lactic-glycolic) acid copolymer encapsulation of recombinant adenovirus reduces immunogenicity in vivo.

Adenovirus-mediated gene transfer has application to the treatment of diseases of the central nervous system. We demonstrate that a limitation to its use in vivo is an inability to redose to the brain. We show that one factor inhibiting re-dosing is the development of neutralizing anti-adenoviral antibodies. Encapsulation of recombinant adenovirus vectors in poly(lactic/glycolic acid) (PLGA) copolymer enables infection in vitro, in the presence of neutralizing antibodies and results in the release of viable virus for over 100 h. Importantly, encapsulated adenovirus also shows diminished immunogenicity in vivo. Mice immunized with encapsulated recombinant adenoviral vectors show a greater than 45-fold reduction in anti-adenovirus titers relative to non-encapsulated vectors. An extended release formulation of adenovirus that reduces viral immunogenicity and sequesters the viral particle form antibody exposure may improve in vivo efficacy.

Adenoviridae↗
PubMed1998

Attenuation of ischemic inflammatory response in mouse brain using an adenoviral vector to induce overexpression of interleukin-1 receptor antagonist.

It has been demonstrated that administration of an interleukin-1 receptor antagonist protein (IL-1ra) reduces ischemic brain injury; however, the detrimental mechanism initiated by interleukin-1 (IL-1) in ischemic brain injury is unclear. In this study, we used mice that were transfected to overexpress human IL-1ra to elucidate the role of IL-1 in the activation of the inflammatory response after middle cerebral artery occlusion (MCAO). Myeloperoxidase (MPO) activity and immunohistostaining were used as a marker of polymorphonuclear leukocytes (PMNL) infiltration. Adenoviral vector (1 x 10(9) particles) was administered by injection into the right lateral ventricle in mice. Five days later, MCAO was performed on the mice using a suture technique. Permanent MCAO was achieved for 24 hours in the Ad.RSVIL-1ra-transfected. Ad.RSVlacZ-transfected, and saline (control) mice. Myeloperoxidase activity was quantified in each region and localization of MPO was determined by immunohistochemistry. After 2 hours of MCAO, the surface cerebral blood flow was reduced to 13.5% +/- 3.4%, 10.75% +/- 2.6%, and 10.9% +/- 2.6% of baseline in the ischemic hemisphere in Ad.RSVIL-1ra-transfected, Ad.RSVlacZ-transfected, and saline-treated mice, respectively. The MPO activity in the ischemic hemisphere in the Ad.RSVlacZ group was similar to that in the saline control group (cortex: 0.40 +/- 0.22 versus 0.33 +/- 0.11; basal ganglia: 0.46 +/- 0.23 versus 0.49 +/- 0.17; P > 0.05); however, it was significantly reduced in the Ad.RSVIL-1ra group (cortex: 0.18 +/- 0.07; basal ganglia: 0.26 +/- 0.15; P < 0.05). Myeloperoxidase immunohistochemistry showed that the massive accumulation of MPO-positive cells in the ischemic cortex, striatum, and corpus callosum regions was greatly attenuated in Ad.RSVIL-1ra-transfected mice. Our results indicate that Ad.RSVIL-1ra-transfected mice provide a useful tool to study the mechanism of action of IL-1. The MPO activity assay and immunostaining after 24 hours of focal ischemia were significantly reduced in IL-1ra gene-transfected mice, suggesting that IL-1 may play an important role in the activation of inflammatory cells during focal cerebral ischemia.

Adenoviridae↗