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PubMed2004

Frequency distribution of thiopurine S-methyltransferase alleles in a polish population.

Thiopurine S-methyltransferase (TPMT) is an enzyme that catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine, 6-thioguanine, and azathioprine. TPMT activity exhibits an interindividual variability mainly a result of genetic polymorphism. Patients with intermediate or deficient TPMT activity are at risk for toxicity after receiving standard doses of thiopurine drugs. It has previously been reported that 3 variant alleles:TPMT*2, *3A, and *3C are responsible for over 95% cases of lower enzyme activity. The purpose of this study was to determine the frequency of TPMT variant alleles in a Polish population. DNA samples were obtained from 358 unrelated healthy Polish subjects of white origin, and TPMT genetic polymorphism was determined using PCR-RFLP and allele-specific PCR methods. The results showed that allelic frequencies were 0.4% for TPMT*2, 2.7% for TPMT*3A, and 0.1% for TPMT*3C, respectively. A TPMT*3B allele was not found in the studied population. The general pattern of TPMT allele disposition in the Polish population is similar to those determined for other white populations, but the frequency of total variant alleles is lower than in other European populations studied to date.

Adolescent↗
PubMedDate not supplied

Rapid progression of hip subluxation in cerebral palsy after selective posterior rhizotomy.

Rapid progression of hip subluxation was noted in the year after selective dorsal rhizotomy in seven hips (six patients). The hips that subluxed progressed from a lateral extrusion index averaging 25% preoperatively as compared with 50% after rhizotomy. Although preexistent hip dysplasia was a predisposing factor, hips with an intermediate degree of preoperative lateral extrusion (12-25%) had variable results. Ongoing and more frequent evaluation of hip stability is necessary after dorsal rhizotomy.

Adolescent↗
PubMed2005

Conservation genetics and population history of the threatened European mink Mustela lutreola, with an emphasis on the west European population.

In species of great conservation concern, special attention must be paid to their phylogeography, in particular the origin of animals for captive breeding and reintroduction. The endangered European mink lives now in at least three well-separated populations in northeast, southeast and west Europe. Our aim is to assess the genetic structure of these populations to identify 'distinct population segments' (DPS) and advise captive breeding programmes. First, the mtDNA control region was completely sequenced in 176 minks and 10 polecats. The analysis revealed that the western population is characterized by a single mtDNA haplotype that is closely related to those in eastern regions but nevertheless, not found there to date. The northeast European animals are much more variable (pi = 0.012, h = 0.939), with the southeast samples intermediate (pi = 0.0012, h = 0.469). Second, 155 European mink were genotyped using six microsatellites. The latter display the same trends of genetic diversity among regions as mtDNA [gene diversity and allelic richness highest in northeast Europe (H(E) = 0.539, R(S) = 3.76), lowest in west Europe (H(E) = 0.379, R(S) = 2.12)], and provide evidences that the southeast and possibly the west populations have undergone a recent bottleneck. Our results indicate that the western population derives from a few animals which recently colonized this region, possibly after a human introduction. Microsatellite data also reveal that isolation by distance occurs in the western population, causing some inbreeding because related individuals mate. As genetic data indicate that the three populations have not undergone independent evolutionary histories for long (no phylogeographical structure), they should not be considered as distinct DPS. In conclusion, the captive breeding programme should use animals from different parts of the species' present distribution area.

Animals↗
PubMed1994

Glucocorticosteroid resistance in humans. Elucidation of the molecular mechanisms and implications for pathophysiology.

Familial glucocorticoid resistance (FGR) is a rare hereditary disorder characterized by hypercortisolism and the absence of stigmata of Cushing's syndrome. The inability of glucocorticoids to exert their effects on target tissues is compensated for by increases in circulating corticotropin (ACTH) and cortisol, the former causing excess secretion of both adrenal androgens and adrenal steroid-biosynthesis intermediates with salt-retaining activity. There is considerable variability in the clinical presentations of FGR ranging from asymptomatic, to isolated chronic fatigue and to hypertension with or without hypokalemic alkalosis or to hyperandrogenism, or both. In women, hyperandrogenism can result in acne, hirsutism, menstrual irregularities, oligoanovulation, and infertility; in men it may lead to infertility and in children to precocious puberty. The reported molecular defects in FGR, such as point mutations and a microdeletion of the glucocorticoid receptor (GR) gene, cause partial resistance by, respectively, compromising the function of the GR or decreasing its intracellular concentration in glucocorticoid target tissues. Complete glucocorticoid resistance is believed to be incompatible with life in humans. Hence, the glucocorticoid resistance cases reported have been partial and of variable degree. The extreme variability in the clinical manifestations of the disorder can, additionally, be explained by differing sensitivity of target tissues to mineralocorticoids or androgens or both, and perhaps by different biochemical defects of the glucocorticoid receptor, causing selective resistance of certain glucocorticoid responses in specific tissues. Isolated tissue-resistance from a somatic mutation of the GR in a corticotropinoma from a patient with Nelson's syndrome was also found, suggesting that this may be a mechanism of tumorigenesis. There is additional evidence that defects of GR function can appear surreptitiously in a variety of clinical conditions, suggesting that glucocorticoid resistance in humans may be involved in the pathogenesis and/or clinical picture of a plethora of disease states, of which FGR is the archetype.

Adrenocorticotropic Hormone↗
PubMed1989

The effect of loading on position sense at the proximal interphalangeal joint of the human index finger.

1. Proprioceptive acuity was tested at the proximal interphalangeal joint of the index finger of normal subjects. 2. Examination of the ability of the subjects to match finger positions (position matching procedure) revealed that digital nerve block (DNB) of the finger resulted in characteristic alignment errors at the extremes in all subjects. 3. When one finger (target finger) is positioned close to full extension, all subjects hyperextended the anaesthetized matching finger, whilst target finger positioning towards full flexion resulted in hyperflexion of the matching finger. At intermediate positions the pattern of matching errors was more variable but tended to be consistent for a given subject. 4. When the matching finger was isotonically loaded into flexion, there was little change in matching performance for most subjects. However, when the matching finger was anaesthetized, such loading now produced clear alteration in performance in all subjects. This indicates that muscle receptors contribute to proprioceptive sensations at this joint, but require other afferent sources to optimally resolve position when the finger is loaded. 5. Two other test procedures (angle reproduction and assigned positions) were assessed and compared with the results obtained by the position matching technique. Although alterations in proprioceptive performance during DNB could be detected with these procedures, they tended to be less sensitive than the position matching procedure.

Adult↗
PubMed2001

Freshwater forcing of abrupt climate change during the last glaciation.

Large millennial-scale fluctuations of the southern margin of the North American Laurentide Ice Sheet occurred during the last deglaciation, when the margin was located between about 43 degrees and 49 degrees N. Fluctuations of the ice margin triggered episodic increases in the flux of freshwater to the North Atlantic by rerouting continental runoff from the Mississippi River drainage to the Hudson or St. Lawrence Rivers. We found that periods of increased freshwater flow to the North Atlantic occurred at the same time as reductions in the formation of North Atlantic Deep Water, thus providing a mechanism for observed climate variability that may be generally characteristic of times of intermediate global ice volume.

Journal Article↗
PubMed2006

Rubidium-rich asymptotic giant branch stars.

A long-debated issue concerning the nucleosynthesis of neutron-rich elements in asymptotic giant branch (AGB) stars is the identification of the neutron source. We report intermediate-mass (4 to 8 solar masses) AGB stars in our Galaxy that are rubidium-rich as a result of overproduction of the long-lived radioactive isotope (87)Rb, as predicted theoretically 40 years ago. This finding represents direct observational evidence that the (22)Ne(alpha,n)(25)Mg reaction must be the dominant neutron source in these stars. These stars challenge our understanding of the late stages of the evolution of intermediate-mass stars and would have promoted a highly variable Rb/Sr environment in the early solar nebula.

Journal Article↗
PubMed1967

Transferrin polymorphism and population differences in the genetic variability of chimpanzees.

Genetic divergencies between chimpanzee populations, not only.between Pan panicus and Pan troglodytes but also between different groups of the latter, are revealed by typing of transferrin. In particular, differences in the incidence of polymorphic transferrins occur between the groups formed by subdividing a large captive chimpanzee colony of heterogeneous geographic origins into racial types solely on the basis of morphological traits. Genetic variability is extremely high in one of these groups, intermediate in another, and relatively low in a third, with the pattern of changing frequencies of allelic genes at the T(f) locus following the pattern of geographic distribution of the actual conspecific populations or races for which the groups are named.

Animals↗
PubMed2005

Spring ligament complex: MR imaging-anatomic correlation and findings in asymptomatic subjects.

PURPOSE: To use magnetic resonance (MR) imaging to assess the anatomy of the spring ligament complex (SLC) in cadaveric feet and to prospectively evaluate the MR imaging depiction of this complex in asymptomatic subjects. MATERIALS AND METHODS: Cadaveric feet were obtained and used according to institutional guidelines and with institutional approval and consent from the donors (before death) or the appropriate family members. Healthy volunteers were examined, with institutional review board approval and informed consent from each volunteer. MR imaging findings of the SLC in five cadaveric feet were analyzed and correlated with the findings in dissected foot specimens. Then, the MR imaging findings in the feet of 78 asymptomatic subjects were analyzed. For all three parts of the SLC, visibility, optimal imaging plane, and signal intensity characteristics were analyzed. The thicknesses of all SLC parts were measured. The measurements obtained in men and women were compared by using the Mann-Whitney U test, and Pearson correlation coefficients for associations between ligament thickness and subject age and sex were calculated. RESULTS: In the cadaveric feet, MR imaging enabled differentiation of all three parts of the SLC. The superomedial calcaneonavicular ligament (CNL) was visible in all; the medioplantar oblique CNL, in 60; and the inferoplantar longitudinal CNL, in 71 volunteers. The superomedial CNL had a mean thickness of 3.2 mm, was best seen on transverse oblique or coronal MR images, and had mainly intermediate signal intensity on T1-weighted images and low signal intensity on T2-weighted images. The medioplantar oblique CNL had a mean thickness of 2.8 mm, was best seen on transverse oblique MR images, and had mainly a typical striated appearance on T1- and T2-weighted images. The inferoplantar longitudinal CNL was the thickest (mean thickness, 4.0 mm), was best seen on coronal MR images, and had mainly intermediate signal intensity on T1-weighted images and variable signal intensity on T2-weighted images. Women had significantly thinner superomedial (mean thickness, 3.3 vs 3.5 mm; P = .015, Mann-Whitney U test) and inferoplantar longitudinal (mean thickness, 3.8 vs 4.2 mm; P = .02) CNLs than men. There was no significant correlation between ligament thickness and subject age. CONCLUSION: The superomedial and inferoplantar longitudinal CNLs are consistently visible portions of the SLC. The medioplantar oblique ligament is thinner, is seen less consistently, and has mainly a characteristic striated MR imaging appearance.

Adult↗
PubMed1998

Model of beta-cell mitochondrial calcium handling and electrical activity. II. Mitochondrial variables.

In the preceding article [Am. J. Physiol. 274 (Cell Physiol. 43): C1158-C1173, 1998], we describe the development of a kinetic model for the interaction of mitochondrial Ca2+ handling and electrical activity in the pancreatic beta-cell. Here we describe further results of those simulations, focusing on mitochondrial variables, the rate of respiration, and fluxes of metabolic intermediates as a function of D-glucose concentration. Our simulations predict relatively smooth increases of O2 consumption, adenine nucleotide transport, oxidative phosphorylation, and ATP production by the tricarboxylic acid cycle as D-glucose concentrations are increased from basal to 20 mM. On the other hand, we find that the active fraction of pyruvate dehydrogenase saturates, due to increases in matrix Ca2+, near the onset of bursting electrical activity and that the NADH/NAD+ ratio in the mitochondria increases by roughly an order of magnitude as glucose concentrations are increased. The mitochondrial ATP/ADP ratio increases by factor of < 2 between the D-glucose threshold for bursting and continuous spiking. According to our simulations, relatively small changes in mitochondrial membrane potential (approximately 1 mV) caused by uptake of Ca2+ are sufficient to alter the cytoplasmic ATP/ADP ratio and influence ATP-sensitive K+ channels in the plasma membrane. In the simulations, these cyclic changes in the mitochondrial membrane potential are due to synchronization of futile cycle of Ca2+ from the cytoplasm through mitochondria via Ca2+ uniporters and Na+/Ca2+ exchange. Our simulations predict steady mitochondrial Ca2+ concentrations on the order of 0.1 microM at low glucose concentrations that become oscillatory with an amplitude on the order of 0.5 microM during bursting. Abrupt increases in mitochondrial Ca2+ concentration > 5 microM may occur during continuous electrical activity.

Adenosine Triphosphate↗
PubMed1978

Neuronal transmission through hippocampal pathways dependent on behavior.

1. In chronically prepared, freely moving rats, electrical stimulation was applied to the angular bundle, and responses were recorded extracellularly at a variety of sites in the ipsilateral hippocampal formation. At each recording site the stimulus-response relationship was tested during four different behavioral states. These were slow-wave sleep (SWS), REM sleep ( REM), and also two waking behaviors consisting of the still, alert condition (labeled SAL), and voluntary movement (AW theta). 2. Two varieties of evoked responses were recorded: those due to the synchronous firing of neuronal action potentials (EAPs) and those produced by excitatory synaptic activity (ESPs). The overall pattern of monosynaptic, di-, and trisynaptic responses found was similar in the rat to that found by Andersen et al. (3-5) in cat and rabbit. 3. When the trisynaptic EAP was recorded in CA1, the threshold was similar during all four behavioral states. However, suprathreshold stimuli evoked a greater response during SWS than during the other three states. The trisynaptic ESP was also greater during SWS. 4. Disynaptically, EAPs were recorded in CA3. These were greater in magnitude during SWS than during SAL, but were intermediate in mean amplitude during AWtheta and REM. Response variability was much greater during AWtheta and REM. 5. The monosynaptic EAP recorded in the upper blade of the dentate gyrus (DG) exhibited the same behaviorally correlated properties found disynaptically in CA3. 6. The monosynaptic ESP recorded in the DG, in contrast to the EAP, was greater in magnitude during SAL than during SWS. 7. The primary afferent volley was also recorded at high gain in the DG. The amplitude of this was found to be dependent solely on stimulus intensity and not on behavioral state. 8. The results are interpreted as suggesting that the granule cell membranes in the DG are relatively hyperpolarized during SAL compared with SWS as the result of either tonic excitatory bombardment occurring during SWS or tonic inhibitory bombardment during SAL.

Animals↗
PubMed2005

Apparent diffusion coefficient thresholds do not predict the response to acute stroke thrombolysis.

BACKGROUND AND PURPOSE: Apparent diffusion coefficient (ADC) thresholds for tissue infarction have been identified in acute stroke. IV tissue plasminogen activator (tPA) is associated with tissue salvage. We hypothesized that tPA would lower the ADC threshold for infarction. METHODS: ADC and mean transit time (MTT) maps were generated for 26 patients imaged within 6 hours of stroke onset (12 tPA and 14 conservatively managed controls). MTT maps and day-90 T2-weighted images were coregistered to ADC maps. Relative ADC (rADC) values were calculated for initial diffusion-weighted imaging (DWI) lesions, infarct growth regions (final infarct volume-the acute DWI lesion volume), and hypoperfused salvaged regions (HS; MTT map abnormality-the final infarct volume). When relevant, the DWI lesion was subdivided into DWI reversal and DWI infarct regions. RESULTS: Mean DWI lesion rADC was 0.79 in tPA and 0.74 in untreated patients (P=0.097). Mean rADC in HS and infarct growth regions were similar in tPA patients (0.950 and 0.946) and untreated patients (0.957, P=0.76; 0.970, P=0.08, respectively). The rADC in HS tissue was directly correlated with the time to treatment with tPA (r=0.685; P=0.029). DWI reversal was seen in 67% of tPA-treated patients and in 36% of those conservatively managed (Fisher exact test; P=0.238). In the 13 patients with DWI reversal, the mean rADC in these regions (0.81+/-0.07) was significantly higher than in the acute DWI region that infarcted (0.74+/-0.07; P=0.02), although no absolute thresholds could be identified. CONCLUSIONS: The peri-DWI lesion region contains tissue with intermediate ADC values. The fate of this tissue is variable and cannot be predicted based on the ADC alone. DWI expansion occurs in bioenergetically normal tissue, and this is attenuated by tPA in a time-dependent fashion.

Aged↗
PubMed1995

Differential expression of cathepsins B and D in testis and epididymis of adult rats.

Cathepsins are specific proteases in lysosomes that participate in the degradation of proteins, some of which are derived from endocytosis. In this study we examined the immunocytochemical localization of cathepsin B and D antibodies in cells of rat testis and epididymis, using light and electron microscopic immunocytochemistry. In testis, cathepsin D was immunolocalized over lysosomes of Sertoli cells and Leydig cells and on the acrosome of spermatids. Cathepsin B was found over lysosomes of macrophages. Non-ciliated cells of the efferent ducts revealed intense immunogold labeling over lysosomes with both anti-cathepsin B and D antibodies. In epididymis, cathepsins B and D showed marked variations in expression over the different epithelial cells and regional differences for a given cell type. Anti-cathepsin D antibodies showed intense labeling over lysosomes of principal cells in the corpus and proximal cauda. In contrast, anti-cathepsin B antibodies revealed intensely labeled lysosomes of principal cells of the distal initial segment, intermediate zone, and caput epididymidis, with weaker labeling in other regions. Clear cells of the proximal caput epididymidis revealed intensely labeled lysosomes for anti-cathepsin D antibodies. In the distal caput, clear cells showed a variable reaction pattern from intensely labeled to unreactive. Basal cells of teh intermediate zone and proximal caput region were intensely reactive for anti-cathepsin D antibodies. There was no staining over clear or basal cells with anti-cathepsin B antibodies. Taken together, these results demonstrate cell-specific and regional differences in the distribution of cathepsins B and D in cells of the male reproductive system. Such results suggest substrate specificity with regard to protein turnover within lysosomes of cells of testis and epididymis.

Animals↗
PubMed1990

The clinical significance of variant-morphology small-cell carcinoma of the lung.

Past attempts to subclassify small-cell lung cancer (SCCL) histology (oat cell, fusiform, polygonal, intermediate, etc) have not been useful because of interrater variability and a lack of clinical significance. A review of outcome in a previous series suggested that a different histologic subtype, small-cell/large-cell (SC/LC) conferred an inferior response and survival analogous to the relative chemotherapy and radiation resistance seen in the variant-morphology (SC/LC) cultured cell lines. To evaluate the clinical impact of SC/LC we applied the proposed International Association for the study of Lung Cancer (IASLC) histology subclassification that incorporates the SC/LC category for patients with extensive-disease SCCL entering Eastern Cooperative Oncology Group (ECOG) protocol 1582. All cases were reviewed for eligibility by one pathologist, and all possible SC/LC (variant) plus 10% of all cases were reviewed together with a second pathologist; 577 of the 628 patients who entered were eligible, of whom 550 had histologic material submitted for review and are considered for this analysis. Initial review disclosed 24 cases with SC/LC (4.4%) and 526 with "classic" histology. The second review showed 100% agreement for classic form, but only 11 SC/LC cases with concordance between the reviewing pathologists. Eight of 24 (33%) cases from first review and three of 11 (27%) with concordance on second review achieved complete response (CR) compared with 101 of 526 (19%) for "classic" SCCL (P = .11 and .45, respectively, for the first and second review groups).(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Risk of seizures in survivors of newborn heart surgery using deep hypothermic circulatory arrest.

OBJECTIVE: To identify pre- and intraoperative variables associated with postoperative acute neurologic events (ANEs), including seizures and coma, in newborn survivors of congenital heart surgery undergoing deep hypothermic circulatory arrest (DHCA), and to risk-stratify this population on the basis of preoperative risk variables for the purpose of designing future neuroprotection trials. METHODS: Survivors of newborn heart surgery who were enrolled in a neuroprotection trial provided a comprehensive database for the evaluation of pre- and intraoperative variables that influence the postoperative occurrence of ANEs (seizures or coma). Patients with hypoplastic heart syndrome were excluded. After characterization of the study population, stepwise logistic regression, combined with clinical judgment, was used to identify variables that were most likely to be associated with an increased risk of seizures in the study sample and that were most likely to be generalized to other populations. RESULTS: Data were available on 164 nonhypoplastic left heart syndrome survivors who underwent newborn heart surgery using DHCA. ANEs occurred in 31 (18.9%) including "seizures alone" (n = 28), "coma alone" (n = 2) or "seizures and coma" (n = 1). A preoperative risk model was constructed demonstrating that infants with a genetic condition and aortic arch obstruction had a 47.8% risk of ANEs compared with all other remaining infants, who had a 9.9% risk. It was also found that prolonged DHCA time (>or=60 minutes) can be a significant risk for infants who have a preexisting genetic condition; however, infants who have genetic conditions and do not undergo prolonged DHCA time or have an aortic arch obstruction are not at increased risk of ANEs. CONCLUSIONS: This study provides new information about the occurrence of ANEs after newborn heart surgery. Seizures or coma, which appeared in approximately 19% of all non-hypoplastic left heart syndrome survivors, were not random events but were significantly associated with specific types of congenital heart disease, the presence of genetic conditions, and prolonged DHCA time. The 3 identified variables permitted individual cases to be assigned to low-, intermediate-, or high-risk categories. Because neonatal seizures are a good surrogate marker of long-term neurologic outcome, these models provide useful information to stratify individual patients for risk of seizures in future neuroprotection trials.

Aortic Arch Syndromes↗
PubMed2001

Photodamage induced by Zinc(II)-phthalocyanine to microtubules, actin, alpha-actinin and keratin of HeLa cells.

We have studied the photosensitizing effects of zinc(II)-phthalocyanine (ZnPc) on the cytoskeleton of HeLa cells using sublethal (10(-7) M, followed by 1 or 3 min of red light to induce 20%, LD20, or 60%, LD60, cell death, respectively) or lethal (5 x 10(-6) M and 15 min of irradiation, LD100) experimental conditions. The immunofluorescent analysis of the cytoskeleton showed a variable photodamage to microtubules (MT), actin microfilaments (AF) and intermediate filaments of keratin (KF), as well as on alpha-actinin, which was dependent on treatment conditions. Both sublethal treatments induced deep alterations on interphase and mitotic MT. The mitotic index increased with time with the maximum at 18 h (12%) or 24 h (14%) after LD20 or LD60, respectively. The alterations on AF and alpha-actinin were much more severe than those observed on KF at any evaluated time. With the exception of the KF, which remained partially organized, the MT and AF network was severely damaged by the lethal treatment. Western blot analysis for alpha-tubulin, G-actin and alpha-actinin from soluble and insoluble fractions confirmed the results observed by immunofluorescence, thus indicating that these cytoskeletal components are involved in cell damage and death by ZnPc photosensitization.

Actinin↗
PubMed1986

Criteria for the diagnosis of primary endocrine carcinoma of the skin (Merkel cell carcinoma). A histological, immunohistochemical and ultrastructural study of 13 cases.

Thirteen cases of primary endocrine carcinoma of the skin (Merkel cell carcinoma) were reviewed with the aim of defining the morphological, immunohistochemical and ultrastructural criteria for diagnosis. The tumour cells were characterized by their scanty cytoplasm, generally small uniform nuclei with finely dispersed chromatin and multiple small nucleoli. Nuclear shapes varied from round to spindle, with larger and pleomorphic forms predominating in 2 tumours. A striking feature seen in 12 tumours was the occurrence of a "ball-in-mitt" pattern represented by 1 or 2 crescentic tumour cells closely wrapped around an oval cell. Staining for neuron-specific enolase was the most consistent marker of the tumour and the characteristic juxtanuclear globular staining for keratin and cytokeratin and the occasional coexpression of neurofilament set this tumour apart from other cutaneous neoplasms, in particular, metastatic carcinoid tumours and oat cell carcinoma from the lung. The fine structural features of note were striking paranuclear or juxtanuclear whorls of intermediate filaments, seen in 7 cases, the presence of variable numbers of membrane-bound dense core granules of 80-150 nm diameter in all cases and cytoplasmic spinous or microvillous projections containing microfilaments in 4 cases. Less consistent characteristics of primary endocrine carcinomas of the skin included cell moulding, argyrophilia and immunohistochemical staining for ACTH, VIP and calcitonin. The high frequency of vessel invasion in this series is in keeping with the high rate of local recurrence, lymph node metastases and visceral dissemination reported. The distinction from other similar appearing tumours in the skin is discussed.

Adult↗
PubMed2006

Increased level and longevity of protective immune responses induced by DNA vaccine expressing the HIV-1 Env glycoprotein when combined with IL-21 and IL-15 gene delivery.

We investigated the ability of a plasmid-derived IL-21 delivered alone or in combination with the IL-15 gene to regulate immune responses to the HIV-1 envelope (Env) glycoprotein induced by DNA vaccination. Mice were injected with the gp140DeltaCFI(HXB2/89.6) vector expressing a modified Env glycoprotein with C-terminal mutations intended to mimic a fusion intermediate, in which the most divergent region encoding the variable V1, V2, and V3 domains of CXCR4-tropic HxB2 virus was replaced with the dual-tropic 89.6 viral strain. Using a recombinant vaccinia virus expressing 89.6 Env glycoprotein (vBD3) in a mouse challenge model, we observed that IL-21 plasmid produced sustained resistance to viral transmission when injected 5 days after DNA vaccination. Moreover, IL-21 in a synergistic manner with IL-15 expression vector augmented the vaccine-induced recall responses to the vBD3 challenge compared with those elicited by immunization in the presence of either cytokine alone. The synergistic combination of IL-21 and IL-15 plasmids promoted expansion of CD8+CD127+ memory T cell pools specific for a subdominant HLA-A2-restricted Env(121-129) epitope (KLTPLCVTL). Our results also show that coimmunization with IL-21 and IL-15 plasmid combination resulted in enhanced CD8+ T cell function that was partially independent of CD4+ T cell help in mediating protection against vBD3 challenge. Furthermore, the use of IL-21 and IL-15 genes was able to increase Ab-dependent cellular cytotoxicity and complement-dependent lysis of Env-expressing target cells through augmentation of Env-specific IgG Ab levels. These data indicate that the plasmid-delivered IL-21 and IL-15 can increase the magnitude of the response to DNA vaccines.

AIDS Vaccines↗