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J C Atkinson

Publications and source records attributed to J C Atkinson.

At least 19 recordsLinked to original sources
PubMed2002

Salivary gland delivery of pDNA-cationic lipoplexes elicits systemic immune responses.

OBJECTIVE: To test the ability of two cationic lipoplexes, Vaxfectin and GAP-DLRIE/DOPE, to facilitate transfection and elicit immune responses from plasmid DNAs (pDNAs) after retrograde instillation into salivary glands. METHODS: Two pDNA expression vectors encoding either the influenza NP protein or human growth hormone (hGH) were complexed with the cationic lipid transfection reagents, GAP-DLRIE/DOPE or Vaxfectin, and delivered to the submandibular glands of rats. Samples from rats receiving the influenza NP protein pDNA and cationic lipoplexes were analyzed for anti-influenza NP-specific IgG1, IgG2a, and IgG2b in serum, and IgA in saliva, by an enzyme- linked immunosorbent assay (ELISA). Cytotoxic T-cell lymphocyte (CTL) assays were also performed. Transgene protein expression (hGH) was determined from extracts of submandibular glands of rats receiving hGH lipoplexes. RESULTS: Serum antibodies (IgG) against the NP protein developed and were highest in all rats vaccinated with GAP-DLRIE/DOPE or Vaxfectin. The major serum IgG subclass stimulated by this route of immunization was IgG2b, followed by IgG2a. CTL assay results showed statistically significantly higher percentage killing in the Vaxfectin group than controls (P < 0.05). No rats developed IgA antibodies to NP protein in saliva. Animals receiving plasmid encoding hGH and either lipoplex expressed significantly higher amounts of hGH compared with those receiving the hGH plasmid and water. Although hGH expression was higher in the animals receiving pDNA/Vaxfectin (approximately 30-fold > pDNA/water), the difference with those receiving pDNA/GAP-DLRIE/DOPE (approximately 10-fold > pDNA/water) was not significant. CONCLUSIONS: Retrograde instillation of pDNA complexed with Vaxfectin into the salivary glands can stimulate cytotoxic and humoral responses to the influenza NP protein antigen. Optimization of the conditions required to stimulate humoral and secretory antibody formation may facilitate use of this tissue for specific clinical applications of pDNA immunization.

Analysis of Variance↗
PubMed2001

Dental health and viridans streptococcal bacteremia in allogeneic hematopoietic stem cell transplant recipients.

Viridans streptococci were the most common cause of bacteremia in 61 consecutive myeloablative allogeneic hematopoietic stem cell transplant (HSCT) recipients, occurring in 19 of 31 bacteremic patients (61%) during the period of post-transplant neutropenia. Seven of the 19 had more than one viridans streptococcus in the same blood culture. Twenty isolates from 15 patients were Streptococcus mitis. Most viridans streptococci were resistant to norfloxacin, used routinely for prophylaxis. Comparison of the 19 patients with viridans streptococcal bacteremia with a contemporaneous group of 23 allogeneic HSCT recipients with fever and neutropenia but no identified focus of infection found that patients with viridans streptococcal bacteremia were more likely to have severe intraoral pathology while neutropenic (26% vs 0%) and slightly shorter interval between the last dental procedure and the onset of neutropenia (11 vs 14 days). Poor underlying dental health and the use of norfloxacin thus appear to predispose to viridans streptococcal bacteremia.

Adult↗
PubMed2001

Oral manifestations in patients with aplastic anemia.

OBJECTIVE: The aim of the present study was to characterize the prevalence and risks of oral complications in aplastic anemia (AA). STUDY DESIGN: Approximately 79 patients with AA (age, 37 +/- 17 years) and 66 control patients with schizophrenia (age, 33 +/- 12 years) were examined. Records were reviewed for demographic, clinical, and radiographic information. Prior medical therapy, laboratory values, disease duration, and medical treatment response were noted for patients with AA. Odds ratios (OR) and 95% CI were calculated for oral manifestations in cases and in control subjects. Univariate analysis identified important variables for logistic regression. RESULTS: Patients with AA presented more frequently with oral petechiae (OR = 49; 95% CI, 2.9-825), gingival hyperplasia (OR = 27; 95% CI, 1.6-463.5), spontaneous gingival bleeding (OR = 27; 95% CI, 1.6-463.5), and herpetic lesions (OR = 27; 95% CI, 1.6-463.5). Prior cyclosporine use was associated with gingival hyperplasia (P =.0001). No other predictors for oral manifestations or treatment outcomes were found. CONCLUSIONS: Oral soft tissue changes and infections were more common in patients with AA. Prior cyclosporine use was predictive of the presence of gingival hyperplasia.

Adult↗
PubMed2001

Salivary enhancement: current status and future therapies.

Saliva provides the principal protective milieu for teeth by modulating oral microbial ecosystems and reversing the initial phases of caries development. Patients with inadequate salivary function are at increased risk for dental decay. Therefore, it is likely that therapies that increase overall fluid output of these individuals will reverse early carious lesions. The most common causes of salivary dysfunction are medication usage, Sjögren's syndrome, and damage of salivary parenchyma during therapeutic irradiation. For patients with remaining functional acinar tissue, treatment with the parasypathomimetic secretogogues pilocarpine and Cevimeline may provide relief. However, these medications do not benefit all patients. The possibilities of using gene therapy and tissue engineering to develop treatments for those with severe salivary dysfunction are discussed.

Animals↗
PubMed2000

Adenoviral-mediated gene transfer to mouse salivary glands.

Adenoviral vectors effectively transfer genes to rat salivary glands. However, potent immune responses limit their use in vivo. Mice offer more opportunities than rats for the study of these immune processes. We first established conditions for infection of mouse salivary glands, with an adenoviral vector. The effects of time, viral dose, viral diluent buffer volume, and dexamethasone on expression of a transgene, luciferase, were determined by means of the recombinant vector AdCMVluc. Optimal luciferase expression was observed when the vector was suspended in 50 microL of buffer. This volume completely filled the gland parenchyma and slightly distended the capsule. Dexamethasone increased immediate transgene expression and reduced the acute inflammation one day following viral administration, but did not alter subsequent mononuclear inflammation or transgene expression 14 or 28 days later. An adenoviral vector encoding either anti-inflammatory cytokine IL-4 or IL-10 was co-administered with AdCMVluc to increase transgene expression at 14 and 28 days. While this strategy did not extend the duration of luciferase expression, co-administration of AdCMVIL-10 with AdCMVluc almost completely eliminated the chronic inflammatory infiltrate in the glands after 28 days. This study demonstrates that adenoviral-mediated gene transfer to mouse submandibular glands is possible by intraductal cannulation and that reduction of either the acute or chronic inflammatory infiltrates was insufficient to increase long-term transgene expression in this tissue.

Adenoviridae↗
PubMed2000

Oral manifestations of primary immunological diseases.

BACKGROUND: Primary immunodeficiencies have many oral manifestations. The clinical presentation of these diseases demonstrates the roles of different immune cells for the maintenance of oral health. METHODS: The authors reviewed selected literature describing systemic and oral manifestations of the primary immunodeficiencies published between 1966 and 1999. RESULTS: The authors found that oral candidiasis and herpetic infections are seen frequently in patients with T-cell deficiencies, while patients with B-cell deficiencies are most susceptible to bacterial infections. Periodontitis and oral candidiasis are found in some, but not all, phagocyte deficiencies. CONCLUSIONS: These findings demonstrate that T cells, B cells and phagocytes all have roles in oral immunity. CLINICAL IMPLICATIONS: Acquired conditions that affect the immune system such as diabetes, alcoholism and acquired immunodeficiency syndrome, as well as certain medications, will affect oral defense mechanisms. The effects that acquired immunodeficiencies will have on oral health can be predicted from the oral manifestations of primary immunodeficiencies.

B-Lymphocytes↗
PubMed1999

Polarized secretion of transgene products from salivary glands in vivo.

Previously (Kagami et al. Hum. Gene Ther. 1996;7:2177-2184) we have shown that salivary glands are able to secrete a transgene-encoded protein into serum as well as saliva. This result and other published data suggest that salivary glands may be a useful target site for vectors encoding therapeutic proteins for systemic delivery. The aim of the present study was to assess in vivo if transgene-encoded secretory proteins follow distinct, polarized sorting pathways as has been shown to occur "classically" in cell biological studies in vitro. Four first-generation, E1-, type 5 recombinant adenoviruses were used to deliver different transgenes to a rat submandibular cell line in vitro or to rat submandibular glands in vivo. Subsequently, the secretory distribution of the encoded proteins was determined. Luciferase, which has no signal peptide, served as a cell-associated, negative control and was used to correct for any nonspecific secretory protein release from cells. The three remaining transgene products tested, human tissue kallikrein (hK1), human growth hormone (hGH), and human alpha1-antitrypsin (halpha1AT), were predominantly secreted (>96%) in vitro. Most importantly, in vivo, after a parasympathomimetic secretory stimulus, both hK1 and hGH were secreted primarily in an exocrine manner into saliva. Conversely, halpha1AT was predominantly secreted into the bloodstream, i.e., in an endocrine manner. The aggregate results are consistent with the recognition of signals encoded within the transgenes that result in specific patterns of polarized protein secretion from rat submandibular gland cells in vivo.

Adenoviridae↗
PubMed1999

Salivary gland cytokine expression in NOD and normal BALB/c mice.

The autoimmune diabetes-prone nonobese diabetic (NOD) mouse develops a chronic lymphocytic infiltration of endocrine and exocrine glands. The objectives of this study were to characterize the salivary immune infiltration and cytokine expression of NOD mice and compare these findings to those of normal BALB/c mice. A decline in salivary flow rates in NOD mice began between 8 and 12 weeks of age. At this same time lymphocytic foci are detectable in the salivary glands. Lymphocytic infiltration in the salivary glands of NOD mice increased with age and simultaneously salivary function declined. No lymphocytic infiltration was seen in BALB/c salivary tissues. Messenger RNA expression of several inflammatory cytokines, including interleukin-1beta (IL-1beta), IL-2, IL-10, interferon-gamma, and tumor necrosis factor-alpha was detected in the submandibular glands of both NOD and BALB/c mice by the reverse transcription polymerase chain reaction. IL-4 synthesis was also present in some tissues. Immunohistochemical analysis demonstrated the intense expression of inflammatory cytokines within lymphocytic infiltrates and epithelial cells of all NOD mice. Minimal expression of the same cytokines was detected only occasionally in BALB/c tissues stained in parallel. These results demonstrate cytokine expression in the salivary glands of normal mice and suggest that the overexpression of these inflammatory cytokines is likely involved in the development and progression of the organ-localized autoimmunity in the salivary glands of NOD mice.

Animals↗
PubMed1999

Effect of clodronate on macrophage depletion and adenoviral-mediated transgene expression in salivary glands.

Expression of transgenes from adenoviral vectors is short-lived in salivary glands, in part because of immune responses to the virus and/or transgene product. Previous studies demonstrated that depletion of macrophages with multilamellar liposomes containing clodronate (Cl2MBP) increases adenoviral-mediated transgene expression in the liver. This technique was tested in salivary glands. Rats were treated with Cl2MBP-liposomes or control liposomes by femoral vein, intraperitoneal, or carotid artery injections. Thereafter, a recombinant adenovirus, AdCMVluciferase, was instilled intraductally in submandibular glands (SMGs), or delivered to the liver via femoral vein injection. Marked depletion (>94%) of liver macrophages and increased levels of luciferase activity in the liver (45-fold higher than controls) were present in animals receiving Cl2MBP-liposomes. In contrast, the same treatment never depleted more than 41% of SMG macrophages nor increased luciferase activity in SMGs, regardless of the route of administration. In conclusion, while macrophage depletion with Cl2MBP-liposomes is associated with markedly increased adenoviral-mediated transgene expression, this strategy was ineffective for salivary glands.

Adenoviridae↗
PubMed1998

Repetitive adenovirus administration to the parotid gland: role of immunological barriers and induction of oral tolerance.

This study assessed the mucosal and systemic immune responses following repetitive adenoviral vector instillation to the parotid glands. Also, we investigated the feasibility of oral tolerance induction as a rational strategy to overcome the immunological reactions. The replication-deficient recombinant adenovirus vector AdCMVCAT was instilled into rat parotid glands. Chloramphenicol acetyltransferase (CAT) activity in the parotid was observed after a first or second AdCMVCAT infection, but not after a third vector administration. ELISA assays showed increased anti-adenovirus immunoglobulin G (IgG) and IgM in serum, and also anti-adenovirus IgA in gland extracts and saliva after virus administration. The results of in vivo neutralization experiments demonstrated that salivary IgA and IgM prevented reinfection of the parotids with adenoviral vectors. Subsequently, studies were conducted to induce tolerance to adenovirus by peroral feedings of ultraviolet (UV)-inactivated virus before gene administration to the parotid glands. Between 3 and 13 doses of virus were fed to rats. Final parotid gene expression was dependent on the number of viral feedings and the amount fed. Tolerized animals showed prolonged and heightened gene expression in the salivary glands compared to control animals and displayed gene expression even after three administrations of vector. Mononuclear cells from the spleens of these animals showed reduced proliferation following adenovirus stimulation. This same cell population was depleted of CD8+ T cells and found to produce less interferon-gamma (IFN-gamma) after virus challenge. This profile indicates the down regulation of Th1 cell-mediated responses. These results indicate that oral tolerance induction is a potentially useful adjunct to virus-based gene therapy.

Adenoviridae↗
PubMed1998

Safety of salivary gland-administered replication-deficient recombinant adenovirus in rats.

We have examined the safety of a replication-deficient recombinant adenovirus administered at a single, high dose intraductally to rat submandibular glands or systemically via the femoral vein. The virus used directed the synthesis of human aquaporin-1, a water channel protein, and is termed AdhAQP1. Comparisons were made 1 and 9 days post-infection with animals administered either a similar virus encoding no transgene or the viral suspension buffer. Animals were specifically not given anti-inflammatory drugs to impede the well-known immunopathologic response to recombinant adenoviral administration. Serum chemistries and hematological parameters were monitored. Rats were subjected to complete gross necropsy and selected tissues were evaluated by histopathology. Most clinical chemistry and hematology values were within normal ranges; however, evidence of inflammation (e.g., elevated lactic dehydrogenase, total leukocyte count) was seen. Gross pathology was normal, as was histopathology, excepting rare focal areas of necrosis. The results show that intrasalivary gland or intravenous AdhAQP1 administration leads to low levels of toxicity in rats.

Adenoviridae↗
PubMed1998

The mouth is a gateway to the body: gene therapy in 21st-century dental practice.

Gene therapy may become an integral tool in dental practice early in the 21st century. It and other biological therapies are expected to be applied to oral diseases and disorders during the midpractice lifetime of today's dental students. If the applications of oral gene transfer are expanded to systemic diseases, oral health care providers in the future could routinely be "gene therapists" with therapeutic targets well outside the oral cavity.

Animals↗
PubMed1996

Collagen VI regulates normal and transformed mesenchymal cell proliferation in vitro.

Suggestions exist that, in addition to traditional growth factors, the extracellular matrix (ECM) of a cell can regulate its proliferation. This hypothesis was investigated with normal and transformed fibroblasts because they exhibit specific intracellular responses after adherence to ECM and produce large quantities of ECM proteins. Although cells cultured on different ECM proteins grew more rapidly than those on plastic, adherence and cell growth on an individual ECM protein were not correlated. To test if ECM can stimulate cell growth, soluble ECM proteins were given to cells after plating. In this culture system only collagen VI (CVI), at a concentration of 20 microg/ml in medium, increased 3T3 cell number to 402% of control by 72 h. Similar increases of human fibroblasts and HT 1080 cell numbers were noted. DNA synthesis of all three cell types increased 24 h after addition of soluble CVI. A mixture of CVI single chains, yielded by reduction and alkylation, was not stimulatory. However, this mixture efficiently inhibited the DNA synthesis induced by native CVI. Antibody inhibition studies showed that the region of CVI stimulating proliferation differs from the site bound by the integrin receptor alpha2beta1, which mediates cell adhesion to immobilized CVI. Heparin inhibited a portion of CVI-induced proliferation. These data demonstrate that CVI can stimulate mesenchymal cell growth via a pathway that is independent of the integrin alpha2beta1 and that the stimulatory region appears to be within the native helical portion of the collagen.

3T3 Cells↗
PubMed1995

Taste performance in Sjogren's syndrome.

Sjogren's Syndrome (SS) patients have impaired salivary gland function and an elevated frequency of oral complaints. The taste complaints are thought to be due to sensory deficits that arise in the absence of sufficient saliva to maintain taste receptors. We assessed the subjective complaints, salivary production and taste functioning of SS patients and unaffected individuals. We found the expected decreased salivary gland function and increased frequency of taste complaints. Our taste assessment with weak stimuli confirmed and expanded the previous report of decreased taste threshold sensitivity in SS. However, perception of stronger taste stimuli was not impaired. In contrast with previous reports, patient judgments of intensity were not significantly reduced for any of the four taste qualities. Although the salivary gland function of all patients was markedly impaired relative to that of controls, patients lacking measurable salivary flow were no more likely than patients with residual function to exhibit subjective complaints or taste impairments. Our observations are inconsistent with a simple causal chain running from salivary gland dysfunction to sensory loss to taste complaints.

Adult↗
PubMed1995

Anti-salivary antibodies in primary Sjögren's syndrome.

Earlier studies have described an antibody that recognized salivary ductal epithelium in sera from 15-50% of patients with primary Sjögren's syndrome; however, the specific salivary antigen in those studies was not identified. The present study further investigated this unknown salivary antigen. Twenty-nine of 31 patients (94%) with primary Sjögren's syndrome demonstrated IgG antinuclear antibodies that bound to an epithelial cell line with ductal characteristics derived from a human salivary gland. Seventy-seven percent of these patients had serum antibodies that bound to ductal cells of normal human parotid tissue after formalin fixation. Western blots of cell extracts, immunofluorescence, and adsorption studies indicated that SS-A/Ro and SS-B/La were the antigens recognized in the salivary cell line. The pattern of fluorescence seen when anti-SS-B/La bound to normal parotid tissue was identical to the fluorescence pattern of the anti-salivary ductal antibodies described in earlier literature.

Adult↗
PubMed1994

Effect of tumor necrosis factor-alpha and interferon-gamma on the growth of a human salivary gland cell line.

Interferon-gamma (IFN-gamma) is a product of activated T-lymphocytes, and tumor necrosis factor-alpha (TNF-alpha) is a product of both lymphocytes and macrophages. These cell types are often present at sites of tissue damage secondary to chronic infection or autoimmune disease. The purpose of this study was to characterize the effects of TNF-alpha and IFN-gamma on a human submandibular gland epithelial cell line (HSG). IFN-gamma caused a concentration-dependent decrease in HSG cell growth (approximately 70% in 6 days). Conversely, TNF-alpha alone had little effect on the growth of these cells. When these cytokines were added in combination (20 units/ml TNF-alpha and 1,000 units/ml of IFN-gamma), there was a synergistic antiproliferative effect; no apparent cell growth was observed. The cytokine-induced antiproliferative effect was reversible. After the apparent cessation of cell growth for 3-6 days, removal of the cytokines permitted complete growth recovery. Further, cells that recovered and exhibited growth patterns that were similar to control cells remained susceptible to the antiproliferative effects of the cytokines. Flow cytometry revealed that the percentage of cells in G0/G1 with the combination of cytokines was significantly increased by 24 h. The antiproliferative effect of IFN-gamma alone and that of IFN-gamma and TNF-alpha in combination were blocked completely using an antibody to the IFN-gamma receptor. A hypothesized mechanism of tissue damage in autoimmune inflammatory disorders is via up-regulation of cell surface markers such as intercellular adhesion molecule type I (ICAM-1) and histocompatibility antigen HLA-DR which can exacerbate the inflammatory process. Treatment of HSG cells with IFN-gamma, with or without TNF-alpha, resulted in increased levels of ICAM-1 and the acquisition of HLA-DR expression. These aggregate data suggest that IFN-gamma alone can regulate the expression of cell surface markers involved in the inflammatory process as well as cause a potent yet reversible inhibition of HSG cell growth that is modulated by the presence of TNF-alpha.

Antibodies↗
PubMed1994

Salivary gland dysfunction: causes, symptoms, treatment.

The three most common known causes of salivary gland dysfunction are medication usage, radiation therapy and Sjogren's syndrome. Current therapeutic options to treat salivary dysfunction are limited. Clinical considerations as well as the outlook for individuals experiencing salivary dysfunction are discussed.

Aged↗