scholarly journals Humoral Immunity to Adeno-Associated Virus Type 2 Vectors following Administration to Murine and Nonhuman Primate Muscle

2000 ◽  
Vol 74 (5) ◽  
pp. 2420-2425 ◽  
Author(s):  
Narendra Chirmule ◽  
Weidong Xiao ◽  
Alemseged Truneh ◽  
Michael A. Schnell ◽  
Joseph V. Hughes ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Neutralizing Antibodies ◽  
Cell Function ◽  
Capsid Proteins ◽  
Adeno Associated Virus ◽  
Blocking Antibody ◽  
Humoral Immune

ABSTRACT Adeno-associated virus (AAV) is being developed as a vector capable of conferring long-term gene expression, which is useful in the treatment of chronic diseases. In most therapeutic applications, it is necessary to readminister the vector. This study characterizes the humoral immune response to AAV capsid proteins following intramuscular injection and its impact on vector readministration. Studies of mice and rhesus monkeys demonstrated the formation of neutralizing antibodies to AAV capsid proteins that persisted for over 1 year and then diminished, but this did not prevent the efficacy of vector readministration. More-detailed studies strongly suggested that the B-cell response was T cell dependent. This was further evaluated with a blocking antibody to human CD4, primatized for clinical trials, in a biologically compatible mouse in which the endogenous murine CD4 gene was functionally replaced with the human counterpart. Transient pharmacologic inhibition of CD4 T cells with CD4 antibody prevented an antivector response long after the effects of the CD4 antibody diminished; readministration of vector without diminution of gene expression was possible. Our studies suggest that truly durable transgene expression (i.e., prolonged genetic engraftment together with vector readministration) is possible with AAV in skeletal muscle, although it will be necessary to transiently inhibit CD4 T-cell function to avoid the activation of memory B cells.

scholarly journals Repeat Transduction in the Mouse Lung by Using Adeno-Associated Virus Vectors with Different Serotypes

2000 ◽  
Vol 74 (3) ◽  
pp. 1524-1532 ◽  
Author(s):  
Christine L. Halbert ◽  
Elizabeth A. Rutledge ◽  
James M. Allen ◽  
David W. Russell ◽  
A. Dusty Miller
Keyword(s):  
Gene Expression ◽  
Neutralizing Antibodies ◽  
Mouse Lung ◽  
Airway Epithelial ◽  
Alveolar Cells ◽  
Adeno Associated Virus ◽  
Primary Vector ◽  
Prior Administration ◽  
Vector Transduction

ABSTRACT Vectors derived from adeno-associated virus type 2 (AAV2) promote gene transfer and expression in the lung; however, we have found that while gene expression can persist for at least 8 months in mice, it was reduced dramatically in rabbits over a period of 2 months. The efficiency and persistence of AAV2-mediated gene expression in the human lung have yet to be determined, but it seems likely that readministration will be necessary over the lifetime of an individual. Unfortunately, we have found that transduction by a second administration of an AAV2 vector is blocked, presumably due to neutralizing antibodies generated in response to the primary vector exposure. Here, we have explored the use of AAV2 vectors pseudotyped with capsid proteins from AAV serotypes 2, 3, and 6 for readministration in the mouse lung. We found that an AAV6 vector transduced airway epithelial and alveolar cells in the lung at rates that were at least as high as those of AAV2 pseudotype vectors, while transduction rates mediated by AAV3 were much lower. AAV6 pseudotype vector transduction was unaffected by prior administration of an AAV2 or AAV3 vector, and transduction by an AAV2 pseudotype vector was unaffected by prior AAV6 vector administration, showing that cross-reactive neutralizing antibodies against AAV2 and AAV6 are not generated in mice. Interestingly, while prior administration of an AAV2 vector completely blocked transduction by a second AAV2 pseudotype vector, prior administration of an AAV6 vector only partially inhibited transduction by a second administration of an AAV6 pseudotype vector. Analysis of sera obtained from mice and humans showed that AAV6 is less immunogenic than AAV2, which helps explain this finding. These results support the development of AAV6 vectors for lung gene therapy both alone and in combination with AAV2 vectors.

Neutralizing antibodies are positively associated with CD4+ T-cell counts and T-cell function in long-term AIDS-free infection

AIDS ◽  
1998 ◽  
Vol 12 (13) ◽  
pp. 1591-1600 ◽  
Author(s):  
Patrizia Carotenuto ◽  
Dennis Looij ◽  
Lian Keldermans ◽  
Frank de Wolf ◽  
Jaap Goudsmit
Keyword(s):  
T Cell ◽  
Neutralizing Antibodies ◽  
Cell Function ◽  
Cd4 T Cell ◽  
Cell Counts ◽  
T Cell Function

scholarly journals Long-Term SARS-CoV-2 Specific Immunity Is Affected by the Severity of Initial COVID-19 and Patient Age

2021 ◽  
Vol 10 (19) ◽  
pp. 4606
Author(s):  
Margarethe Konik ◽  
Monika Lindemann ◽  
Markus Zettler ◽  
Lara Meller ◽  
Sebastian Dolff ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Neutralizing Antibodies ◽  
Patient Age ◽  
Factors Affecting ◽  
Humoral Immune ◽  
Specific Immunity ◽  
Cell Immunity ◽  
Patient Âgé

The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently the greatest medical challenge. Although crucial to the future management of the pandemic, the factors affecting the persistence of long-term SARS-CoV-2 immunity are not well understood. Therefore, we determined the extent of important correlates of SARS-CoV-2 specific protection in 200 unvaccinated convalescents after COVID-19. To investigate the effective memory response against the virus, SARS-CoV-2 specific T cell and humoral immunity (including virus-neutralizing antibodies) was determined over a period of one to eleven months. SARS-CoV-2 specific immune responses were present in 90% of individual patients. Notably, immunosuppressed patients did not have long-term SARS-CoV-2 specific T cell immunity. In our cohort, the severity of the initial illness influenced SARS-CoV-2 specific T cell immune responses and patients’ humoral immune responses to Spike (S) protein over the long-term, whereas the patients’ age influenced Membrane (M) protein-specific T cell responses. Thus, our study not only demonstrated the long-term persistence of SARS-CoV-2 specific immunity, it also determined COVID-19 severity and patient age as significant factors affecting long-term immunity.

scholarly journals Tumor-Released Survivin Induces a Type-2 T Cell Response and Decreases Cytotoxic T Cell Function, in Vitro

2012 ◽  
Vol 6 (1) ◽  
pp. 57-68 ◽  
Author(s):  
Jessica M. S. Jutzy ◽  
Salma Khan ◽  
Malyn May Asuncion-Valenzuela ◽  
Terry-Ann M. Milford ◽  
Kimberly J. Payne ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Response ◽  
Cell Function ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
T Cell Function

scholarly journals Deteriorating beta‐cell function in type 2 diabetes: a long‐term model

QJM ◽  
2003 ◽  
Vol 96 (4) ◽  
pp. 281-288 ◽  
Author(s):  
A. Bagust ◽  
S. Beale
Keyword(s):  
Type 2 Diabetes ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Term Model

Tu-P10:422 Disregulated T-cell function and acute phase response in type 1 and type 2 diabetes mellitus

2006 ◽  
Vol 7 (3) ◽  
pp. 277
Author(s):  
S. Giubilato ◽  
S. Brugaletta ◽  
D. Pitocco ◽  
V. Colafrancesco ◽  
M. Narducci ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
T Cell ◽  
Acute Phase ◽  
Acute Phase Response ◽  
Cell Function ◽  
Phase Response

Efficient and sustained gene expression in primary T lymphocytes and primary and cultured tumor cells mediated by adeno-associated virus plasmid DNA complexed to cationic liposomes

1994 ◽  
Vol 14 (4) ◽  
pp. 2411-2418
Author(s):  
R Philip ◽  
E Brunette ◽  
L Kilinski ◽  
D Murugesh ◽  
M A McNally ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Cells ◽  
Plasmid Dna ◽  
Interleukin 2 ◽  
Cationic Liposomes ◽  
Lymphoid Cells ◽  
Chromosomal Dna ◽  
Adeno Associated Virus ◽  
Cultured Tumor Cells

We have used cationic liposomes to facilitate adeno-associated virus (AAV) plasmid transfections of primary and cultured cell types. AAV plasmid DNA complexed with liposomes showed levels of expression several fold higher than those of complexes with standard plasmids. In addition, long-term expression (> 30 days) of the gene, unlike the transient expression demonstrated by typical liposome-mediated transfection with standard plasmids, was observed. Southern analysis of chromosomal DNA further substantiated the hypothesis that the long-term expression was due to the presence of the transgene in the AAV plasmid-transfected group and not in the standard plasmid-transfected group. AAV plasmid-liposome complexes induced levels of transgene expression comparable to those obtained by recombinant AAV transduction. Primary breast, ovarian, and lung tumor cells were transfectable with the AAV plasmid DNA-liposome complexes. Transfected primary and cultured tumor cells were able to express transgene product even after lethal irradiation. High-level gene expression was also observed in freshly isolated CD3+, CD4+, and CD8+ T cells from normal human peripheral blood. Transfection efficiency ranged from 10 to 50% as assessed by intracellular interleukin-2 levels in interleukin-2-transfected cells. The ability to express transgenes in primary tumor and lymphoid cells may be applied toward tumor vaccine studies and protocols which may eventually permit highly specific modulation of the cellular immune response in cancer and AIDS.

Abstract 16844: Effect of Canagliflozin on Gene Expression and CD34+ Function on Type 2 Diabetes Subjects

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Hassan Awal ◽  
Seshagiri Rao Nandula ◽  
Nabanita KUNDU ◽  
Mona Fakhri ◽  
Beda Brichacek ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 2 Diabetes ◽  
Mixed Model ◽  
Cell Function ◽  
Sglt2 Inhibitor ◽  
P Value ◽  
Vegf Receptor ◽  
Double Blind ◽  
Endothelial Cell Function

Introduction: CD34 +ve Endothelial progenitor cells (EPCs) has been shown to be dysfunctional in subjects with type 2 diabetes mellitus (T2DM) leading to poor endothelial cell function (ECF). Hypothesis: Canagliflozin, an SGLT2 inhibitor when added to other oral antidiabetic medication such Metformin, Insulin, GLP1-agonists, DPP-IV inhibitor, or sulfonylureas, may improve the cardiovascular risk by improving CD34+ EPCs function such as migration, colony formation and maturation towards endothelium. Methods: 29 subjects were enrolled in this 16 weeks, double-blind, two-arm, randomized placebo matched trial, with 100 mg Canagliflozin (Cana, low dose) compared to placebo. T2DM (30-70 years old), HbA1c of 6.5-10%, and all stages of CKD were included. Peripheral blood derived CD34+ cell number, migratory function, mRNA gene expression along with cardiometabolic parameters such as arterial stiffness, biochemistry, resting energy expenditure, and body composition were measured. Data were collected at weeks 0, 8, and 16. A mixed model regression analysis was done with a p-value <0.05 considered significant. Results: We found a statistically significant reduction in systolic (p=0.008) and diastolic (p=0.038) blood pressure. There was a reduction in blood glucose level (p=0.0047) and HbA1c (p=0.03). There was a statistically significant increase in adiponectin (p=0.0062) and trend level reduction in IL6 (p=0.16), indicating an anti-inflammatory effect of canagliflozin. There is also an increase in mRNA expression of genes associated with endothelial function in CD34+ cells such as VEGFA (p=0.049), VEGF receptor KDR (p=0.13), PECAM-1, a mature endothelial marker was also upregulated (p=0.002) and NOS3 (or eNOS) was also upregulated. There were no significant changes in CD34+ numbers by direct counting and parameters tested. We also tested for serum ketones bodies and found no difference at the dose tested. Data on urine podocyte specific exosome is pending Conclusions: Our study indicates that Canagliflozin improves several components of ECF by improving adiponectin, reducing inflammatory cytokines, and by increasing expression of endothelium specific genes.

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