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At least 19 recordsLinked to original sources

PubMed1999

Enhanced permeability of insulin across the rat intestinal membrane by various absorption enhancers: their intestinal mucosal toxicity and absorption-enhancing mechanism of n-lauryl-beta-D-maltopyranoside.

We have examined the in-vitro permeability characteristics of insulin in the presence of various absorption enhancers across rat intestinal membranes and have assessed the intestinal toxicity of the enhancers using an in-vitro Ussing chamber method. The absorption enhancing mechanism of n-lauryl-beta-D-maltopyranoside was studied also. The permeability of insulin across the intestinal membranes was low in the absence of absorption enhancers. However, the permeability was improved in the presence of enhancers such as sodium glycocholate and sodium deoxycholate in the jejunum, and sodium glycocholate, sodium deoxycholate, n-lauryl-beta-D-maltopyranoside, sodium caprate and ethylenediaminetetraacetic acid (EDTA) in the colon. Overall, the absorption enhancing effects were greater on the colonic membrane than on the jejunal membrane. The intestinal membrane toxicity of these enhancers was characterized using the release of cytosolic lactate dehydrogenase from the colonic membrane. A marked increase in the release of lactate dehydrogenase was observed in the presence of sodium deoxycholate and EDTA. The release of lactate dehydrogenase in the presence of these absorption enhancers was similar to that seen with sodium dodecyl sulphate (SDS), used as a positive control, indicating high toxicity of these enhancers to the intestinal membrane. In contrast, sodium glycocholate and sodium caprate caused minor releases of lactate dehydrogenase, similar to control levels, suggesting low toxicity. In addition, the amount of lactate dehydrogenase in the presence of n-lauryl-beta-D-maltopyranoside was much less than that seen with sodium deoxycholate, EDTA and SDS. Therefore, sodium glycocholate, sodium caprate and n-lauryl-beta-D-maltopyranoside are useful absorption enhancers due to their high absorption enhancing effects and low intestinal toxicity. To investigate the absorption enhancing mechanisms of n-lauryl-beta-D-maltopyranoside, the transepithelial electrical resistance (TEER), voltage clamp experiments and the circular dichroism spectra were studied. n-Lauryl-beta-D-maltopyranoside decreased the TEER values in a dose-dependent manner, suggesting that the enhancer may open the tight junctions of the epithelium, thereby increasing the permeability of insulin via a paracellular pathway. This speculation was supported by the findings that 20 mM n-lauryl-beta-D-maltopyranoside produced a greater increase in the paracellular flux rate than in the transcellular flux rate by the voltage clamp studies. Evaluating the circular dichroism spectra we found that insulin oligomers were not dissociated to monomers by the addition of n-lauryl-beta-D-maltopyranoside, but dissociation did occur with the addition of sodium glycocholate. Thus, the dissociation of insulin was not a major factor in the absorption enhancing effect of n-lauryl-beta-D-maltopyranoside. These findings provide basic information to select the optimal enhancer for the intestinal delivery of peptide and protein drugs including insulin.

Algorithms↗

PubMed1994

Selective synergy of immunoglobulin enhancer elements in B-cell development: a characteristic of kappa light chain enhancers, but not heavy chain enhancers.

We have examined the interactions of the enhancers of the kappa immunoglobulin light chain gene as well as the interactions of the intron, mu, and 3' alpha enhancers of the heavy chain locus in mouse. We have observed that each of the kappa enhancers is very weak in comparison with the heavy chain intron enhancer. The mouse heavy chain 3' alpha enhancer is relatively weak as well. However, two kappa enhancers together synergistically activate transcription of a luciferase reporter gene to a level that is roughly equivalent to the heavy chain mu enhancer. Additionally, dimerization of either kappa enhancer results in synergistic increases in transcription. This property of synergism appears to be confined to the enhancers of the kappa locus, as addition of the 3' alpha E to mu E containing constructs increases transcription only modestly, and neither heavy chain enhancer synergizes when dimerized. We have gone on to characterize some of the minimal requirements for synergism between the kappa enhancers and find that the KB and E2 sites are required, but not the E3 site. The implications of these results for the coordinate regulation of the heavy and light chain transcription are discussed.

Animals↗

PubMedDate not supplied

Detection and characterization of focal liver lesions using superparamagnetic iron oxide-enhanced magnetic resonance imaging: comparison between ferumoxides-enhanced T1-weighted imaging and delayed-phase gadolinium-enhanced T1-weighted imaging.

BACKGROUND: Double contrast magnetic resonance (MR) imaging using superparamagnetic iron oxide (SPIO) and gadolinium (Gd) is performed to detect and characterize focal liver lesions. However, this technique is a costly and lengthy process. The purpose of this study was to determine the usefulness of SPIO-enhanced MR imaging including SPIO-enhanced T1-weighted imaging in diagnosing focal liver lesions. METHODS: Eighty-four focal liver lesions were examined with a 1.5-T MR unit. Transverse precontrast T1- and T2-weighted images and SPIO (ferumoxides)-enhanced T1- and T2-weighted images were obtained, followed by Gd-enhanced T1 -weighted imaging. The Gd set (i.e., precontrast T1- and T2-weighted and delayed-phase gadolinium-enhanced T1-weighted images) and ferumoxides set (i.e., precontrast T1- and ferumoxides-enhanced T1- and T2-weighted images) were reviewed by two independent readers. RESULTS: More lesions were detected from the ferumoxides set than from the Gd set. Ferumoxides-enhanced T1-weighted imaging showed enhancement patterns of the lesions similar to those of delayed-phase Gd-enhanced T1-weighted imaging. The diagnoses of hepatic metastasis and cyst by the ferumoxides set were similar to those by the Gd set. However, a dynamic study may be inevitable for the diagnosis of hepatocellular carcinoma and hemangioma. CONCLUSION: The ferumoxides set was useful for the detection of focal hepatic lesions. Ferumoxides-enhanced T1-weighted imaging may replace delayed-phase gadolinium-enhanced T1-weighted imaging in the diagnosis of hepatic metastasis and cysts.

Carcinoma, Hepatocellular↗

PubMed1984

An SV40 "enhancer trap" incorporates exogenous enhancers or generates enhancers from its own sequences.

We have transfected monkey CV-1 cells with non-infectious, linear SV40 DNA, lacking the 72 bp repeat enhancer region. Infectious virus was recovered from this "enhancer trap" upon cotransfection with enhancer DNA segments from various viruses, notably a truncated polyoma enhancer that was integrated as a dimer. Cotransfection of the "enhancer trap" with fragmented DNA of mouse, monkey, or human origin yielded no recombinant virus with integrated cellular sequences, with one possible exception. In some transfection experiments without added viral enhancer DNA, SV40 variants were generated that have a segment of their flanking "late" DNA duplicated to substitute for the deleted 72 bp repeat. In one variant, an 88 bp duplication creates a strong enhancer from this nonenhancing DNA region. Both the polyoma enhancer fragment and the spontaneously created enhancers lack the alternating purines-pyrimidines or "CACA box" suggested to be characteristic for enhancer elements and show only limited homology to the "GTGG(AAATTT)G box."

Animals↗

PubMed1989

Mapping of functional regions of murine retrovirus long terminal repeat enhancers: enhancer domains interact and are not independent in their contributions to enhancer activity.

We have used deletion and recombinant long terminal repeat (LTR) mutants to examine enhancer activity differences between LTRs of the nonpathogenic Akv and the thymus lymphomagenic MCF13 murine retroviruses. Deletion mutant analysis revealed that major control regions for MCF13 and Akv LTR enhancer activity were similar but not identical. For both LTRs, major control regions were distinctly different in a murine T-cell and a fibroblast cell line. Recombinant enhancer analysis showed that LTRs could be divided into three regions capable of altering the level of enhancer activity through cooperative or antagonistic interaction. The contribution of each region to enhancer activity was dependent on its context with respect to the other regions. LTR enhancer function in different cell types appears to be the result of the interaction of enhancer modular elements.

AKR murine leukemia virus↗

PubMedDate not supplied

Surface-enhanced Raman scattering and surface-enhanced resonance Raman scattering excitation profiles of Ag-2,2'-bipyridine surface complexes and of [Ru(bpy)3]2+ on Ag colloidal surfaces: manifestations of the charge-transfer resonance contributions to the overall surface enhancement of Raman scattering.

Excitation profiles of SERS (surface-enhanced Raman scattering) and/or SERRS (surface-enhanced resonance Raman scattering) spectral bands of two forms of a Ag-bpy (bpy = 2,2'-bipyridine) surface complex and of [Ru(bpy)3]2+ on Ag nanoparticle (hydrosol) surfaces were determined from the spectra excited in the 458-600 nm region and are reported together with the FT-SERS spectra of the Ag-bpy surface complex and FT Raman spectra of [Ru(bpy)3] Cl2. Seven of the observed 11 fundamentals as well as their first overtones and combination bands are selectively enhanced in SERS of the Ag-bpy surface complex formed in the Ag colloid/HCl/bpy system. The profiles of these bands show a common maximum at approximately 540 nm. The selectively enhanced bands of the Ag-bpy surface complex have nearly the same wavenumbers as those enhanced in the SERRS and resonance Raman spectra of [Ru(bpy)3]2+ upon excitation close to the 453 nm maximum of its MLCT absorption band. Moreover, the intensity patterns of the bpy vibrations of the two species match both in resonance (541 nm excitation for Ag-bpy, 458 nm for [Ru(bpy)3]2+) and in off-resonance (458 and 1064 nm for Ag-bpy, 1064 nm for [Ru(bpy)3]2+). The distinct band shapes of the excitation profiles of the selectively enhanced vibrational modes of the Ag-bpy surface complex, as well as the observation of overtones and combination bands in the SERS spectra upon excitation into this "band", are interpreted in terms of a charge-transfer resonance contribution to the overall SERS enhancement. In view of the near-coincidence of the vibrational modes coupled to the resonant electronic transition of Ag-bpy with those coupled to the MLCT transition of [Ru(bpy)3]2+, the resonant electronic transition is tentatively assigned to a Ag metal to bpy (pi*) CT transition.

Journal Article↗

PubMed2005

Contrast-enhanced sonography with SonoVue: enhancement patterns of benign focal liver lesions and correlation with dynamic gadobenate dimeglumine-enhanced MRI.

OBJECTIVE: Contrast-enhanced real-time low-mechanical-index sonography is a new diagnostic technique for the assessment of macro- and microcirculation. The purpose of our article is to describe contrast-enhancement patterns of different benign focal liver lesions using the second-generation contrast agent SonoVue and to compare these findings with those of gadobenate dimeglumine-enhanced MRI. CONCLUSION: SonoVue-enhanced real-time low-mechanical-index sonography provides specific contrast-enhancement patterns of different benign focal liver lesions, allowing accurate characterization. Findings on SonoVue-enhanced sonography correlate well with those obtained on gadobenate dimeglumine-enhanced MRI.

Adult↗

PubMed2000

Activation of c-myc promoter P1 by immunoglobulin kappa gene enhancers in Burkitt lymphoma: functional characterization of the intron enhancer motifs kappaB, E box 1 and E box 2, and of the 3' enhancer motif PU.

Deregulated expression of the proto-oncogene c- myc in Burkitt lymphoma (BL) cells carrying a t(2;8) translocation is mediated by a synergistic interaction of the translocated immunoglobulin (Ig) kappa gene intron (kappaEi) and 3' (kappaE3') enhancers and characterized by a strong activation of the promoter P1. We have investigated the functional role of distinct kappa enhancer sequence motifs in P1 activation on both mini-chromosomes and reporter gene constructs. Stable and transient transfections of BL cells revealed critical roles of the kappaEi and kappaE3' elements kappaB and PU, respectively. Joint mutation of kappaB and PU completely abolished P1 activity, implying that an interaction of kappaB- and PU-binding factors is essential for the enhancer synergism. Mutation of the E box 1 and E box 2 motifs markedly decreased P1 activity in transient but not in stable transfection experiments. Co-expression of the NF-kappaB subunit p65(RelA) and Sp1, an essential factor for P1 transcription, in Drosophila melanogaster SL2 cells synergistically enhanced promoter activity. Our results support a model which proposes cross-talk between promoter and enhancer binding factors as the basic mechanism for kappa enhancer-mediated c- myc activation in BL cells.

Animals↗

PubMed1995

Brain metastases--comparison of gadodiamide injection-enhanced MR imaging at standard and high dose, contrast-enhanced CT and non-contrast-enhanced MR imaging.

The aim was to compare the abilities of contrast-enhanced CT, non-contrast-enhanced MR imaging and contrast-enhanced MR imaging using standard (0.1 mmol/kg b.w.) and high (0.3 mmol/kg b.w.) doses of Gadodiamide injection to detect brain metastases (i.e. blood-brain barrier damage). Sixteen patients with at least 2 metastases found by CT were evaluated by MR imaging using non-contrast-enhanced spin-echo, T1-weighted, T2-weighted sequences, and contrast-enhanced spin-echo T1-weighted sequences at 2 dose levels. Gadodiamide injection was first given at the dose of 0.1 mmol/kg b.w. After imaging, another 0.2 mmol/kg b.w. was given, yielding a cumulative dose of 0.3 mmol/kg b.w. No contrast media-related adverse events were recorded. The images were evaluated openly by one and blindly by 2 investigators and the number of metastases, size, delineation (open study) and diagnostic certainty (blind study) of each individual metastasis noted. High-dose MR imaging showed significantly more and smaller metastases than any other examination, and gave a higher diagnostic certainty. All high-dose images were superior to those with the standard dose MR imaging when compared blindly in pairs. We conclude that spin-echo MR imaging with a high dose of Gadodiamide injection is an efficient way to improve the detection of brain metastases, in particular of small ones.

Adult↗

PubMedDate not supplied

Enhancement pattern of hepatocellular carcinoma: comparison of real-time contrast-enhanced ultrasound and contrast-enhanced computed tomography.

We compared the enhancement pattern of 98 hepatocellular carcinoma nodules in 92 patients on contrast-enhanced ultrasound (CEUS) and contrast-enhanced computed tomography (CECT). Contrast-enhanced ultrasound was performed with SonoVue and a low mechanical index method. In arterial phase, 98 nodules were hyperenhancing on CEUS and 94 on CECT. In portal phase, 82 nodules were hypoenhancing on CEUS and 83 on CECT. Peripheral thin-rim-like enhancement was exhibited in 30 nodules on CEUS and 31 on CECT. Intratumoral vessels were visualized in 94 nodules on CEUS and 36 on CECT.

Adult↗

PubMed1994

Interferon-gamma enhances monocyte cytotoxicity via enhanced reactive oxygen intermediate production. Absence of an effect on macrophage cytotoxicity is due to failure to enhance reactive nitrogen intermediate production.

Interferon-gamma (IFN-gamma) enhanced the cytotoxic capability of freshly isolated human blood monocytes but failed to enhance the tumoricidal competence of monocyte-derived macrophages. Treatment of monocytes with IFN-gamma (100 U/ml) caused a significant increase (P < 0.001) in lucigenin-dependent chemiluminescence and O2- production stimulated by N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) during the first few days in culture but IFN-gamma was unable to prevent the decline to negligible levels of chemiluminescence and O2- production which occurred during the later days in vitro. Culture of monocytes in the presence of IFN-gamma had no effect on phorbol 12-myristate 13-acetate (PMA)-stimulated O2- production. However, IFN-gamma decreased PMA-stimulated lucigenin-dependent chemiluminescence during the first 24 hr in vitro but then significantly enhanced (P < 0.001) chemiluminescence after 2-4 days in culture. IFN-gamma was unable to prevent the eventual decline to undetectable levels in PMA-stimulated chemiluminescence during the later days in vitro. Nitrite production by macrophages was unaffected by IFN-gamma treatment. It is concluded therefore, that IFN-gamma enhanced the cytotoxicity of freshly isolated human blood monocytes by increasing reactive oxygen intermediate generation but was unable to enhance the tumoricidal competence of macrophages as reactive nitrogen intermediate production was unaffected.

Acridines↗

PubMed1990

Protein recognition sites in polyomavirus enhancer: formation of a novel site for NF-1 factor in an enhancer mutant and characterization of a site in the enhancer D domain.

Polyomavirus mutants selected for modified host range exhibit DNA sequence alterations in the regulatory region, which consist mainly of duplications and/or deletions. Single base pair mutations have also been observed, which create or abolish DNA sequence motifs recognized by DNA-binding regulatory factors. The present work deals with the molecular characterization of a Polyoma mutant (PyNB11/1), selected for its high efficiency of growth in neuroblastoma cells. The enhancer region of PyNB11/1 displays a 91 bp tandem duplication harbouring a novel DNA sequence motif created at the boundary of the duplicated fragment. This motif is absent in the wild-type enhancer and is specifically recognized by a nuclear factor that belongs to the NF-1 family of transcription factors. We also report the characterization of an as yet unidentified DNA sequence motif in the D domain of the viral enhancer, that represents the binding site for a nuclear factor that is ubiquitous and comparably abundant in several murine cell types.

Animals↗

PubMed1994

Bladder tumor staging: comparison of contrast-enhanced CT, T1- and T2-weighted MR imaging, dynamic gadolinium-enhanced imaging, and late gadolinium-enhanced imaging.

PURPOSE: To evaluate the accuracy of contrast material-enhanced computed tomography (CT), unenhanced T1- and T2-weighted magnetic resonance (MR) imaging, and dynamic gadolinium-enhanced spoiled gradient-echo MR imaging in the staging of bladder cancer. MATERIALS AND METHODS: Thirty-six patients with histologically proved bladder cancer were prospectively examined with CT and MR imaging before tumor resection. Images were evaluated in a blinded fashion. RESULTS: All methods depicted tumors comparably well. Staging was correct in 16 of 29 patients (55%) with CT and 27 of 36 patients (75%) overall with MR imaging. Overstaging was the most common error, and both CT and MR imaging were more accurate for higher-staged tumors. CONCLUSION: CT and MR imaging perform well in the detection of tumors but are less accurate in staging. Dynamic gadolinium-enhanced MR imaging is better than other techniques, but the difference is not statistically significant.

Carcinoma, Transitional Cell↗

PubMed2003

Alpha beta T-cell development is not affected by inversion of TCR beta gene enhancer sequences: polar enhancement of gene expression regardless of enhancer orientation.

V(D)J recombination and expression of the T-cell receptor beta (TCRbeta) gene are required for the development of the alphabeta T lymphocyte lineage. These processes depend on a transcriptional enhancer (Ebeta) which acts preferentially on adjacent upstream sequences, and has little impact on the 5' distal and 3' proximal regions of the TCRbeta locus. Using knock-in mice, we show that alphabeta T-cell differentiation and TCRbeta gene recombination and expression are not sensitive to the orientation of Ebeta sequences. We discuss the implication of these results regarding the mode of enhancer function at this locus during T lymphocyte development.

Animals↗

PubMed2001

Multifocal inflammatory pseudotumor of the liver: dynamic gadolinium-enhanced, ferumoxides-enhanced, and mangafodipir trisodium-enhanced MR imaging findings.

The MRI characteristics of a multifocal inflammatory pseudotumor of the liver are described. Emphasis is placed on the appearances following intravenous administration of both non-specific and liver-specific MR contrast agents. On post-gadolinium gradient-echo (GE) images an early, intense, and peripheral enhancement was followed by a homogeneous, complete, and persistent enhancement. Lesions showed no uptake following administration of ferumoxides particles nor mangafodipir trisodium, respectively. During follow-up, a peripheral hyperintense rim appeared on precontrast T1-weighted images, a feature not previously described.

Adult↗

PubMed2006

Excellent absorption enhancing characteristics of NO donors for improving the intestinal absorption of poorly absorbable compound compared with conventional absorption enhancers.

The characteristics of NO donors, NOC5 [3-(2-hydroxy-1-(1-methylethyl-2-nitrosohydrazino)-1-propanamine), NOC12 [N-ethyl-2-(1-ethyl-2-hydroxy-2-nitrosohydrazino)-ethanamine] and SNAP [S-nitroso-N-acetyl-DL-penicillamine] as absorption enhancers for poorly absorbable drugs were examined in rats using an in situ closed loop method. They were compared with a group of conventional absorption enhancers including sodium glycocholate (NaGC), sodium caprate (NaCap), sodium salicylate (NaSal) and n-dodecyl-beta-D-maltopyranoside (LM). 5(6)-carboxyfluorescein (CF) was used as a model drug to investigate effectiveness, site-dependency, and concentration-dependency of the tested enhancers. Overall, the NO donors can improve the intestinal absorption of CF at low concentration (5 mM), whereas higher concentration was required for the conventional absorption enhancers to elicit the absorption enhancing effect. In the small intestine, SNAP was the most effective absorption enhancers, although its concentration (5 mM) was lower than the conventional absorption enhancers (20 mM). On the other hand, LM and NaCap as well as the three NO donors were effective to improve the colonic absorption of CF. In the regional difference in the absorption enhancing effects, the NO donors showed significant effects in all intestinal regions, whereas we observed a regional difference in the absorption enhancing effect of the other conventional absorption enhancers. In the conventional enhancers, the absorption enhancing effects were generally greater in the large intestine than those in the small intestine. LM and NaCap were ineffective in the jejunum, although they were effective for improving the absorption of CF in the colon. NaSal was ineffective in both the jejunum and the colon. The absorption enhancement produced by NO donors was greatly affected by increasing the enhancer concentration from 3 to 5 mM, but only a slight increase was obtained when the concentration was raised to 10 mM. Similar results were obtained for the other enhancers over the range of 10 to 20 mM, but the absorption enhancing effects of these enhancers were almost saturated above these concentrations. These results suggest that NO donors possess excellent effectiveness as absorption enhancers for poorly absorbable drugs compared with the conventional enhancers. They can enhance intestinal absorption of CF from all intestinal regions and they are effective at very low concentrations.

Adjuvants, Pharmaceutic↗

PubMed2001

Detection of renal artery stenosis: prospective comparison of captopril-enhanced Doppler sonography, captopril-enhanced scintigraphy, and MR angiography.

OBJECTIVE: The objective of our study was to compare the value of captopril-enhanced Doppler sonography, captopril-enhanced renal scintigraphy, and gadolinium-enhanced MR angiography for detecting renal artery stenosis. SUBJECTS AND METHODS: Forty-one patients with suspected renovascular hypertension were prospectively examined with captopril-enhanced Doppler sonography, captopril-enhanced renal scintigraphy, gadolinium-enhanced MR angiography, and catheter angiography. The sensitivity and specificity of each technique for detecting renal artery stenosis measuring 50% or greater and 70% or greater were compared using the McNemar test. Positive and negative predictive values were estimated for populations with 5% and 30% prevalence of renal artery stenosis. Kappa values for interobserver agreement were assessed for both gadolinium-enhanced MR angiography and catheter angiography. RESULTS: For detecting renal artery stenosis measuring 50% or greater, the sensitivity of gadolinium-enhanced MR angiography (96.6%) was greater than that of captopril-enhanced Doppler sonography (69%, p = 0.005) and captopril-enhanced renal scintigraphy (41.4%, p = 0.001). No significant difference in specificity was observed among modalities. For renal artery stenosis measuring 50% or greater, positive and negative predictive values were respectively 62% and 86% for captopril-enhanced Doppler sonography, 49% and 76% for captopril-enhanced renal scintigraphy, and 53% and 98% for gadolinium-enhanced MR angiography. Interobserver agreement was high for both gadolinium-enhanced MR angiography (kappa = 0.829) and catheter angiography (kappa = 0.729). CONCLUSION: Gadolinium-enhanced MR angiography is the most accurate noninvasive modality for detecting renal artery stenosis greater than or equal to 50%. The use of captopril-enhanced Doppler sonography in combination with gadolinium-enhanced MR angiography for identifying renal artery stenosis needs to be evaluated with a cost-effectiveness analysis.

Adult↗

PubMed1999

In vitro antibody-dependent enhancement assays are insensitive indicators of in vivo vaccine enhancement of equine infectious anemia virus.

We have previously demonstrated a high propensity for enhancement of virus replication and disease resulting from experimental immunization of ponies with a baculovirus recombinant envelope (rgp90) vaccine from equine infectious anemia virus (EIAV). The current studies were undertaken to examine the correlation between the observed in vivo vaccine enhancement and in vitro assays for antibody-dependent enhancement (ADE) of EIAV replication. Toward this goal an optimized EIAV in vitro enhancement assay was developed using primary equine macrophage cells and used to evaluate the enhancement properties of immune serum taken from rgp90 immunized ponies that displayed various levels of vaccine enhancement after experimental challenge with EIAV. For comparison, we analyzed in parallel immune serum samples from a group of ponies immunized with a viral envelope subunit vaccine (LL-gp) that produced sterile protection from EIAV challenge. The results of these assays demonstrated that the rgp90 immune serum had a greater propensity for in vitro enhancement of EIAV replication than serum from the protected LL-gp immunized ponies; in vitro enhancement levels for the rgp90 immune sera averaged about 1.5, with a maximum enhancement value of about 2.0. While distinguishing between immune serum produced by the rgp90 and LL-gp immunizations, the in vitro enhancement assay failed to reliably correlate with the severity of in vivo enhancement observed among the rgp90 vaccine recipients. Vaccinated ponies that experienced moderate to no disease signs displayed levels of in vitro enhancement similar to those of ponies that experienced severe and fatal enhancement of disease after viral challenge. The observed in vitro enhancement was demonstrated to be dependent on serum immunoglobulin, but independent of complement. These studies demonstrate in the EIAV system that in vitro ADE assays appear to be relatively insensitive indicators of the severity of in vivo enhancement and that relatively low levels of in vitro ADE can be associated with severe to fatal enhancement of virus replication and disease in vivo. These observations suggest that relatively low levels of serum ADE observed in other lentivirus systems, including HIV-1, may have more profound effects on in vivo virus replication and disease than previously recognized.

Animals↗