Efficient and persistent gene transfer of AAV-CFTR in maxillary sinus.
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Clinical Trials, Phase I as Topic↗
Biomedical subjects
R B Moss
Publications and source records attributed to R B Moss.
A phase I/II study of tgAAV-CF for the treatment of chronic sinusitis in patients with cystic fibrosis.
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Adolescent↗
Bone acquisition and loss in children and adults with cystic fibrosis: a longitudinal study.
OBJECTIVES: To determine patterns of bone mineral acquisition in children and young adults with cystic fibrosis (CF) and to identify clinical and laboratory correlates of change in bone mineral density (BMD). STUDY DESIGN: Bone mineral and clinical status were assessed in 41 patients with CF (26 female, aged 9 to 50 years) at baseline and 1.5 years later. Bone mineral content of the lumber spine, femoral neck, and whole body was determined by dual-energy x-ray absorptiometry and expressed as BMD and bone mineral apparent density (BMAD). Changes in weight, height, pubertal status, glucocorticoid use, physical activity, disease severity, and biochemical markers of bone turnover were examined for associations with changes BMD and BMAD. RESULTS: Mean BMD Z-scores (adjusted for age and sex) were reduced at the spine, hip, and whole body at baseline in both adults and youths, and decreased further at all sites among youths at follow-up (-0.4 at spine, p < 0.05; -0.3 at hip, p < 0.10; -0.5 for whole body, p < 0.0005). These data indicate failure to gain bone mineral at the expected rate. BMAD was also reduced at follow-up, suggesting that the observed osteopenia could not be explained by small bone size. Bone loss at multiple sites was observed in four youths and two adults. In general glucocorticoid use, change in body mass, physical activity, and disease severity were the most significant correlates for change in BMD and in BMD Z-score. CONCLUSIONS: Osteopenia in CF generally reflects inadequate gains in bone mineral, although bone loss may occur, particularly in patients requiring glucoc therapy. Late gains in bone mineral may accompany weight gain and pubertal development, but the catch-up appears to be incomplete.
Adolescent↗
Whole-killed gp120-depleted HIV-1 antigen in a murine model for prophylactic vaccination.
In this study, the effects were examined of dose and adjuvant of whole-killed gp120-depleted HIV-1 antigen on antibody and cytokine responses in a murine model. Immunization with increasing doses of inactivated HIV-1 antigen in Incomplete Freund's Adjuvant (IFA) resulted in increased production of IL-4 and IgG1 antibody with decreased production of interferon gamma. Immunization with inactivated HIV-1 antigen in Detox PC adjuvant produced TH1 type predominant cytokine patterns along with IgG2a subclass antibody. Higher levels of interferon gamma were associated with immunization with inactivated HIV-1 antigen in Detox PC compared with inactivated HIV-1 in IFA or inactivated HIV-1 in saline. Inactivated HIV-1 antigen in Detox PC adjuvant produced a trend of lower levels of the beta-chemokine MIP-1 alpha compared with inactivated HIV-1 in IFA or saline. Dose and adjuvant play an important role in the type of immune response elicited to a whole-killed HIV vaccine. Low doses of inactivated HIV-1 antigen in Detox PC adjuvant are currently being studied in animal models in order to optimize cell-mediated immunity against HIV infection.
AIDS Vaccines↗
In vitro p24 antigen-stimulated lymphocyte proliferation and beta-chemokine production in human immunodeficiency virus type 1 (HIV-1)-seropositive subjects after immunization with an inactivated gp120-depleted HIV-1 immunogen (Remune).
We examined the effect of immune stimulation by a human immunodeficiency virus type 1 (HIV-1) immunogen (Remune) compared to a non-HIV vaccine (influenza) on HIV-1-specific immune responses in HIV-1-seropositive subjects. HIV-1 p24 antigen-stimulated lymphocyte proliferation was not augmented after immunization with the influenza vaccine. In contrast, subjects increased their lymphocyte proliferative responses to p24 antigen after one immunization with HIV-1 immunogen (Remune) (gp120-depleted inactivated HIV-1 in incomplete Freund's adjuvant). Furthermore, p24 antigen-stimulated beta-chemokine production (RANTES, MIP-1alpha, MIP-1beta) was also augmented after immunization with the HIV-1 immunogen but not influenza vaccine. Taken together, these results suggest that in this cohort, HIV-specific immune responses to p24 antigen can be augmented after immunization with an HIV-1 immunogen. The ability to upregulate immune responses to the more conserved core proteins may have important implications in the development of immunotherapeutic interventions for HIV-1 infection.
AIDS Vaccines↗
Introduction: getting to the HAART of the matter: immune responses against the virus.
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Anti-HIV Agents↗
A primer on HIV type 1-specific immune function and REMUNE.
The ability to recognize HIV antigens is lost early in HIV-1 infection. Individuals with nonprogressive HIV disease have been observed to mount strong immune responses against the virus and have become a paradigm to emulate with immune-based therapies. Highly active antiviral drug therapy (HAART) has now become the standard of care for HIV-1-infected individuals. Because HIV-specific anergy occurs early in HIV infection, HAART initiated after primary infection may not reconstitute HIV-specific immune function. We have been investigating the effects of an immune-based therapy, called REMUNE, in HIV-1-seropositive individuals. REMUNE has been observed to stimulate HIV-1-specific immune function measured by delayed-type hypersensitivity, lymphocyte proliferation, Th1 cytokine, and beta-chemokine production. Multiple Phase II studies and a Phase III clinical end-point study are ongoing in thousands of seropositive individuals in order to test the clinical utility of REMUNE. The clinical testing of REMUNE and other promising immune-based therapies may provide additional treatment modalities useful in the chronic management of HIV-1.
AIDS Vaccines↗
Activation of eosinophils in the airways of lung transplantation patients.
UNLABELLED: Eosinophils are important inflammatory cells involved in liver and renal allograft rejection. The role of these cells is less well defined in lung allograft rejection. Eosinophils may be activated in lung rejection and release cytotoxic eosinophil cationic protein (ECP). Other states of disease in lung transplant recipients, such as cytomegalovirus (CMV) and bacterial infection, may also be associated with activated eosinophils. We postulated that ECP may be detectable and elevated in the airway lavage samples obtained from lung transplant patients and may contribute to disease pathogenesis. METHODS: Fifty BAL samples were collected from 38 lung transplant patients. Their most recent pulmonary function test results within 1 week of collection were noted. The samples were analyzed for the concentration of ECP, WBC count and differential cell count, and total protein level. The results were analyzed to identify the presence of disease or abnormal lung function associated with a positive ECP test. Student's t test was used and a p value of <0.05 was considered significant. RESULTS: We found that ECP levels were elevated in 36% (n=14) of the patients. Those patients with a positive test result were more likely to have acute rejection, CMV disease, or the presence of a cultured pathogen in BAL compared to patients with a negative test result (p<0.01). CONCLUSIONS: The presence of BAL ECP is associated with disease in lung transplant patients. Since ECP is directly cytotoxic, it may contribute to disease pathogenesis.
Adult↗
Effect of immunization with an inactivated gp120-depleted HIV-1 immunogen on beta-chemokine and cytokine production in subjects with HIV-1 infection.
OBJECTIVE: To measure beta-chemokine and cytokine production in HIV-1-infected subjects undergoing treatment with HIV-1 immunogen (REMUNE). DESIGN: Open label treatment study. METHODS: beta-Chemokine and cytokine production in peripheral blood mononuclear cell (PBMC) culture. RESULTS: Interferon-gamma production (p = 0.04) and lymphocyte proliferation (p = 0.001) to HIV-1 antigen-stimulated PBMCs increased after immunization with the HIV-1 immunogen. A correlation was demonstrated after immunization between HIV-1 antigen-stimulated lymphocyte proliferation and interferon-gamma levels (r = 0.53, p = 0.04). No significant change after immunization was seen for interleukin-4 production. A significant increase in mean levels of HIV-1 antigen-stimulated RANTES (i.e., regulated upon, activation normal T-cell expressed and secreted), was evident 1 month after immunization (p = 0.002) and remained elevated 3 months after immunization. RANTES production was decreased in CD8-depleted PBMC cultures. Mean serum HIV-1 RNA copy numbers and CD4 cell counts remained stable after immunization (p > 0.5). A correlation was demonstrated between HIV-1 antigen-stimulated interferon-gamma and RANTES production (r = 0.54, p = 0.002). CONCLUSIONS: This report describes an augmentation of beta-chemokines and TH1-type cytokines from PBMCs after immunization with the HIV-1 immunogen.
CD4 Lymphocyte Count↗
Cross-clade immune responses after immunization with a whole-killed gp120-depleted human immunodeficiency virus type-1 immunogen in incomplete Freund's adjuvant (HIV-1 immunogen, REMUNE) in human immunodeficiency virus type-1 seropositive subjects.
Lymphocyte proliferation responses to gp120-depleted HZ321 virus (clade A) antigen were compared to BAL human immunodeficiency virus (HIV) virus antigen (clade B) responses, clade E HIV virus antigen responses, and purified native p24 antigen responses in 15 human immunodeficiency virus type-1 (HIV-1) seropositive subjects immunized with a whole-killed inactivated gp120-depleted HIV-1 antigen in Incomplete Freund's adjuvant (HIV-1 immunogen, REMUNE). A significant increase in lymphocyte proliferation to HZ321 antigen was observed after immunization with the HIV-1 immunogen (p = 0.02). A strong association was demonstrated between the HIV-1 immunizing antigen, HZ321, and native p24 antigen responses (r = 0.80, p < 0.0001). Furthermore, a strong association in terms of proliferative responses was demonstrated between HZ321 virus (clade A) responses and BAL virus (clade B) (r = 0.95, p < 0.0001) and clade E virus antigen (r = 0.92, p < 0.0001). Proliferative responses to HIV antigens also correlated with baseline CD4 counts. Taken together, these results support the specificity of immune responses induced by REMUNE (HIV-1 immunogen). The development of cross-reactive immune responses between clades and to the more conserved epitopes of the virus have implications in the development of therapeutic and prophylactic HIV vaccines.
AIDS Vaccines↗
Microsporidium-associated sinusitis.
Two cases of biopsy-proven Microsporidium-associated chronic sinusitis in HIV-seropositive patients are presented. Spores of Septata intestinalis were identified by light microscopy and confirmed by electron microscopy in each case. Both patients displayed severe deficiencies of nasal mucosa CD4-positive cells, demonstrated by immunohistochemical methods. Only two other cases of Septata intestinalis-associated sinusitis have been reported previously. Our observations agree with the theory that functional defects in local mucosal immunity may partially explain the acquisition of opportunistic mucosal infections in many HIV-seropositive patients.
AIDS-Related Opportunistic Infections↗
Constitutive mRNA and immunoreactivity for IL-2 in human nasal mucosa.
BACKGROUND: The nasal mucosa is the initial site in the upper airway of host defence against antigenic challenge in the form of airborne allergens, irritants, toxins and infectious agents, and yet little is known about nasal mucosal cytokine expression and function. We hypothesized that IL-2 might play a role in immunocompetence of the upper airway. METHODS: IL-2 immunoreactivity was measured by ELISA in nasal secretions and by Western blot. Immunohistochemistry and electron microscopy were performed on turbinated tissue. mRNA for IL-2 was evaluated by RTPCR and Southern hybridization. RESULTS: IL-2 immunoreactivity was demonstrated by Western blot and quantitated by an enzyme immunoassay. Immunohistochemical and electron microscopy analysis of turbinate tissue revealed interstitial staining for IL-2. By RTPCR, IL-2 message was evident in 5/5 atopics and 5/5 non-atopics. IL-2 message was expressed in all subjects by Southern hybridization to an internal probe after PCR. CONCLUSION: This study has demonstrated constitutive expression of IL-2 protein and mRNA in the upper airway of healthy individuals. The further characterization of cytokines in the upper airway could provide useful insights into immune regulation at the mucosal level.
Base Sequence↗
Early clinical markers and CD4 percentage in subjects with human immunodeficiency virus infection.
In a clinical trial involving asymptomatic, HIV-seropositive subjects treated with either the HIV-1 immunogen (an inactivated, gp120-depleted HIV-1 virus in incomplete Freund's adjuvant) or an adjuvant control, we examined the relationship between changes in the percentage of CD4 cells over time and early clinical markers of HIV disease progression. Subjects who had an early clinical event were more likely to have a greater decline in the percentage of CD4 cells than those subjects who did not have a clinical event (p = 0.054). The greatest decline in CD4 percentage occurred within 10 weeks prior to a clinical event (mean 11% decrease from baseline). Subjects from the quartile with the greatest decline in CD4 percentage had a fivefold greater risk of having a clinical event than subjects from the quartile with the second largest decline (p = 0.045). These results demonstrate a relationship between changes in the percentage of CD4 cells and early clinical events. Further validation of this association may be useful in clinical monitoring and in evaluating therapies to treat HIV infection.
AIDS Dementia Complex↗
Nasal mucosal cells in human immunodeficiency virus type 1-seropositive patients with sinusitis.
Recently, sinusitis has been recognized as a frequent clinical problem in human immunodeficiency virus (HIV-1)-infected individuals. We hypothesized that quantitative defects in immune cells in the nasal mucosa of HIV-positive subjects might mirror those in the peripheral blood and explain a predisposition to sinus disease in this population. Nasal mucosa biopsies were obtained from three different groups of patients-HIV-1 seropositive with sinusitis, HIV-1 seronegative with sinusitis, and HIV-1 seronegative without sinusitis (normal volunteer)-and phenotyped for cluster of differentiation antigen (CD) markers. In this study, we found patients with HIV-1 and sinus disease to have significantly lower numbers of both CD3 and CD4 nasal mucosa lymphocytes than seronegative controls in the nasal mucosa (P < 0.05, P < 0.01, respectively). A correlation between nasal mucosal CD4 cells and peripheral-blood CD4 cells was noted (R = 0.67, P < or = 0.01). No deficiency in the number of nasal mucosa T or TC type mast cells was noted for the HIV-1-positive sinusitis group. Further study is warranted to define more completely the pathophysiology and microbiology of, and therapy for, this important clinical problem.
Acquired Immunodeficiency Syndrome↗
Viral load, CD4 percentage, and delayed-type hypersensitivity in subjects receiving the HIV-1 immunogen and antiviral drug therapy.
Two trials of subjects inoculated with the inactivated, gp120-depleted HIV-1 Immunogen are reported. In one study, in which 19 subjects received ZDV and 8 subjects received ddI, treatment with the HIV-1 Immunogen did not affect the pharmacokinetic parameters of the antiviral drugs. In another study, 65 subjects who were previously immunized with the HIV-1 Immunogen over a mean period of 4.0 years (range, 1.2-5.4 years) received inoculations at 0 and 6 months. At some point during this 48-week study, 72% of the subjects (47/65) were receiving antiviral drug therapy. The HIV-1 DNA load in CD4 cells and CD4 percentage were found to be stable over the 48-week period. Delayed-type hypersensitivity to HIV-1 antigens increased after two inoculations with the HIV-1 Immunogen. In these two trials, no serious treatment-related adverse events were documented in the subjects. The two studies presented herein are the first to suggest that an immune-based therapy such as the HIV-1 Immunogen can be combined safely with antiviral drugs, supporting further study to evaluate the clinical utility of this approach.
AIDS Vaccines↗
Reduced IL-10 secretion by CD4+ T lymphocytes expressing mutant cystic fibrosis transmembrane conductance regulator (CFTR).
Expression of the CFTR protein is thought to be physiologically important only in exocrine epithelial cells. However, chronic respiratory inflammation and infection remain unexplained phenomena in disease pathogenesis. Non-transformed, antigen-responsive CD4+ T cells cloned from healthy controls and CF patients homozygous or heterozygous for the delta F508 mutation transcribed CFTR mRNA and expressed immunoreactive cytoplasmic CFTR protein. T cell clones (TCC) from controls and CF patients displayed equivalent Ca(2+)-mediated Cl- current; however, TCC from patients with CF but not controls displayed defective cAMP-mediated Cl-current. Although CF-derived TCC preserved mitogen and antigen proliferative responses and specificity to tetanus toxoid epitopes, they selectively secreted approximately 45% less IL-10 compared with control TCC after activation with concanavalin A (Con A) (624 +/- 101 versus 1564 +/- 401 pg/ml per 10(6) cells, respectively; P = 0.04) or anti-CD3/phorbol ester (5148 +/- 1634 versus 11788 +/- 2390 pg/ml; P = 0.05). This difference was independent of atopy. Secretion of interferon-gamma, IL-2, and IL-4 was comparable in CF and control TCC after both forms of activation, while IL-5 was reduced in CF TCC following anti-CD3/phorbol myristate acetate (PMA) but not after Con A. We conclude that expression of mutant CFTR in human TCC is accompanied by ion channel dysfunction characteristic of the CF phenotype, and is accompanied by a reduction in IL-10 secretion after polyclonal activation. It is possible that disruption of IL-10-mediated anti-inflammatory homeostasis may contribute to early onset sustained inflammation in CF airways.
Animals↗
Combination therapies against HIV-1 infection: exploring the concept of combining antiretroviral drug treatments with HIV-1 immune-based therapies in asymptomatic individuals.
The deleterious effect of HIV on the immune system begins at the time of infection. At seroconversion the virologic and immunologic factors that ultimately will dictate the rate of disease progression are believed to be already in place. The concept developed in this paper implies that, to impact significantly on the progression of disease, anti-HIV therapies should be initiated as early as possible in asymptomatic individuals. Published results have shown that combination drug therapies are potent in reducing HIV-1 RNA load in plasma in asymptomatic individuals, and that some HIV-1 immune-based therapies have a positive impact on immunological markers of disease progression, including HIV-1 cell-mediated immunity (CMI) and CD4 percent. The strategy discussed is to test a combination of antiretroviral therapy with HIV-1 immune-based therapy, such as the inactivated HIV-1 immunogen preparation, in asymptomatic individuals. The goal of this combination approach is to overcome the limitations of each therapy alone. Preliminary data suggest that antiretroviral therapy and the HIV-1 Immunogen can be combined with no noticeable interference and/or added toxicity in a broad range of HIV-1-infected individuals. Combining both therapies may enhance and expand the impact on key surrogate markers of disease progression, although they likely achieve this impact through different mechanisms. Thus, the primary question remains: Can these effects be synergistic?
Adjuvants, Immunologic↗
Correlates of osteopenia in patients with cystic fibrosis.
OBJECTIVE: As the expected survival improves for individuals with cystic fibrosis, these individuals face myriad medical complications. The goals of this study were to examine the prevalence of osteopenia in children and adults with cystic fibrosis and to elucidate the risk factors associated with deficits in bone mineral. METHODOLOGY: We compared bone mineral levels in 49 patients (30 female and 19 male) ages 8 through 48 years with those of age- and sex-matched control subjects. Lumbar spine, femoral neck, and whole-body bone mineral were measured by dual-energy radiographic absorptiometry and expressed in terms of bone mineral content, areal bone density (BMD), and bone mineral apparent density (BMAD), which corrects for differences in bone size. Clinical variables were evaluated as potential correlates of bone mineral. RESULTS: Patients with cystic fibrosis had significantly less bone mineral than did control subjects at all sites using all expressions of bone mass. Mean BMD z scores were -1.7 (lumbar spine), -1.9 (femoral neck), and -1.2 (whole body). BMAD z scores also were significantly low for age and gender. Twenty-six of the 49 patients (8 adolescents) had significant osteopenia according to their BMD z scores; 14 of the 45 patients (5 adolescents) with available BMAD z scores had significantly low values at one or more sites. Age, pubertal stage, body mass, caloric expenditure, illness severity, glucocorticoid therapy, and gonadal function predicted bone mineral status. Serum parathyroid hormone and calcium, carbohydrate intake, and weight-bearing activity had limited predictive value. Daily calcium intake and cystic fibrosis transmembrane regulator genotype did not predict bone mineral status. CONCLUSIONS: Osteopenia is common at all ages in cystic fibrosis, suggesting that inadequate bone mineral accretion as well as increased bone loss contribute to the deficits in bone mineral observed. Several clinical factors seem to contribute to these deficits.
Absorptiometry, Photon↗