Alp Oran | University of Ottawa | Université d'Ottawa (original) (raw)

Papers by Alp Oran

Journal of immunology (Baltimore, Md. : 1950), 2004

DNA vaccines represent a novel and powerful alternative to conventional vaccine approaches. They ... more DNA vaccines represent a novel and powerful alternative to conventional vaccine approaches. They are extremely stable and can be produced en masse at low cost; more importantly, DNA vaccines against emerging pathogens or bioterrorism threats can be quickly constructed based solely upon the pathogen's genetic code. The main drawback of DNA vaccines is that they often induce lower immune responses than traditional vaccines, particularly in nonrodent species. Thus, improving the efficacy of DNA vaccines is a critical issue in vaccine development. In this study we have enhanced the efficacy of DNA vaccines by adopting strategies that increase gene expression. We generated influenza-hemagglutinin (HA)-encoding DNA vaccines that contain the hybrid CMV enhancer/chicken ␤-actin (CAG) promoter and/or the mRNA-stabilizing post-transcriptional regulatory element from the woodchuck hepatitis virus (WPRE). Mice were immunized with these DNA vaccines, and the influenza-HA-specific cellular and humoral immune responses were compared with a conventional, HA-encoding DNA vaccine whose gene expression was driven by the CMV immediate-early promoter (pCMV-HA). CAG promoter-driven DNA vaccines elicited significantly higher humoral and cellular immune responses compared with the pCMV-HA vaccine. DNA vaccines consisting of both CAG and WPRE elements (pCAG-HA-WPRE) induced the highest level of protective immunity, such that immunization with 10-fold lower DNA doses prevented death in 100% of the mice upon lethal viral challenge, whereas all mice immunized with the conventional pCMV-HA vaccine succumbed to influenza infection.

Irreversible marking of dendritic cells in vivo: for contributed volumes

Advances in experimental medicine and biology, 2002

1. Adv Exp Med Biol. 2002;512:177-81. Irreversible marking of dendritic cells in vivo: for contri... more 1. Adv Exp Med Biol. 2002;512:177-81. Irreversible marking of dendritic cells in vivo: for contributed volumes. Garg S, Oran A, Maris C, Jaco J. Vaccine Research Center, Emory University, Atlanta, GA 30329, USA. PMID: 12405202 [PubMed - indexed for MEDLINE]. ...

Journal of immunology (Baltimore, Md. : 1950), 2002

Journal of immunology (Baltimore, Md. : 1950), 2005

Apoptosis-mediated enhancement of DNA-raised immune responses by mutant caspases

Nature Biotechnology, 2001

Apoptotic bodies can be used to target delivery of DNA-expressed immunogens into professional ant... more Apoptotic bodies can be used to target delivery of DNA-expressed immunogens into professional antigen-presenting cells (APCs). Here we show that antigen-laden apoptotic bodies created by vectors co-expressing influenza virus hemagglutinin (HA) or nucleoprotein (NP) genes and mutant caspase genes markedly increased T-cell responses. Both CD8 and CD4 T-cell responses were affected. The adjuvant activity was restricted to partially inactivated caspases that allowed immunogen expression before the generation of apoptotic bodies. Active-site mutants of murine caspase 2 and an autocatalytic chimera of murine caspase 2 prodomain and human caspase 3 induced apoptosis that did not interfere with immunogen expression. The adjuvant activity also enhanced B-cell responses, but to a lesser extent than T-cell responses. The large increases in T-cell responses represent one of the strongest effects to date of a DNA adjuvant on cellular immunity.

Journal of Virology, 2000

Maternal antibody is the major form of protection from disease in early life when the neonatal im... more Maternal antibody is the major form of protection from disease in early life when the neonatal immune system is still immature; however, the presence of maternal antibody also interferes with active immunization, placing infants at risk for severe bacterial and viral infection. We tested the ability of intramuscular and gene gun immunization with DNA expressing influenza virus hemagglutinin (HA) and nucleoprotein (NP) to raise protective humoral and cellular responses in the presence or absence of maternal antibody. Neonatal mice born to influenza virus-immune mothers raised full antibody responses to NP but failed to generate antibody responses to HA. In contrast, the presence of maternal antibody did not affect the generation of long-lived CD8 ؉ T-cell responses to both HA and NP. Thus, maternal antibody did not affect cell-mediated responses but did affect humoral responses, with the ability to limit the antibody response correlating with whether the DNA-expressed immunogen was localized in the plasma membrane or within the cell.

Vaccine, 2001

In these studies, we address the ability of DNA encoding Th1 cytokines to bias the isotype of ant... more In these studies, we address the ability of DNA encoding Th1 cytokines to bias the isotype of antibody raised by neonatal or adult immunization with an influenza hemagglutinin expressing DNA (HA-DNA). Neonatal mice coimmunized with HA-DNA and either IL-12 or IFN-k-expressing DNA developed IgG2a-biased immune responses, regardless of inoculation method. In contrast, the Th1 genetic adjuvants had no effect on IgG subtype patterns in adults. In neonatal mice, the Th1 genetic adjuvants also shifted the pattern of lymphokine production by recall splenocytes from a mixed response of IFN-k and IL-5 to exclusively IFN-k. In adults, despite the failure to change the isotype pattern of the antibody response, a shift towards IFN-k production also occurred for recall splenocytes following coimmunzation with IL-12. Thus, coinoculation of Th1 genetic adjuvants had greater effects on the nature of the immune response in the neonate than in adults.

Current Biology, 1999

Background: The human immunodeficiency virus type 1 (HIV-1) Nef protein is required for efficient... more Background: The human immunodeficiency virus type 1 (HIV-1) Nef protein is required for efficient virus replication in vivo and displays a number of distinct and apparently unrelated biological activities in vitro. Of these, one of the most readily demonstrated is the efficient internalization and degradation of cell-surface CD4, the receptor for the HIV-1 envelope protein. The biological purpose of this internalization has, however, remained unclear.Results: Using human 293T cells expressing high levels of cell-surface CD4 or CD8, we demonstrate that CD4, but not CD8, can dramatically reduce the release of infectious virions bearing the HIV-1 envelope protein and induce a concomitant increase in the accumulation of cell-associated HIV-1 structural proteins. In contrast, CD4 had no effect on the release of HIV-1 bearing a heterologous envelope protein unable to bind CD4. Nef expression totally reversed CD4-mediated inhibition but only if the CD4 used remained susceptible to Nef-induced internalization.Conclusions: These results support the hypothesis that cell-surface CD4 can interact with the envelope protein present on budding HIV-1 virions to inhibit their release. The internalization and degradation of cell-surface CD4 induced by the viral Nef protein can fully reverse this inhibition and is, therefore, likely to facilitate the spread of virus in vivo.

Molecular Immunology, 1998

Journal of Virology, 2004

For this study, we used DNA-based immunizations to elicit gamma interferon-producing (Tc1) or int... more For this study, we used DNA-based immunizations to elicit gamma interferon-producing (Tc1) or interleukin 4 (IL-4)-producing (Tc2) CD8 T cells to the influenza virus nucleoprotein. We examined the response of these cells to an intranasal viral challenge. Both the Tc2-and Tc1-biased responses were present in mice with predominantly IL-4-producing (Th2) CD4 T cells. After viral challenge, Tc1 cells underwent more efficient expansion than did Tc2 cells, and only Tc1 cells were detected at the site of infection. In contrast, the CD4 response remained IL-4 biased. However, only a limited number of CD4 cells appeared in the postchallenge lung, and these were strongly enriched for the Th1 phenotype. Thus, the type of memory T-cell response induced by DNA vaccination does not determine the type of response that will predominate at the site of an infection.

Expression of Leukemia Inhibitory Factor and Interleukin11 by Human Melanoma Cell Lines: LIF, IL6, and IL11 Are Not Coregulated

Journal of Interferon and Cytokine Research, 1995

Dysregulation in cytokines has been associated with melanomas. For example, loss of growth inhibi... more Dysregulation in cytokines has been associated with melanomas. For example, loss of growth inhibition in advanced melanomas has been associated with interleukin-6 (IL-6) expression. Because IL-6 belongs to the hematopoietic cytokine family, which includes leukemia inhibitory factor (LIF) and interleukin-11 (IL-11), we examined the possibility of coordinate expression of LIF, IL-6, and IL-11 in three human melanoma cell lines derived from primary lesions (early) and in four lines derived from metastatic tumors (advanced). All lines examined produced at least low levels of LIF and IL-11 mRNA as measured by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR). By enzyme-linked immunosorbent assay (ELISA), two of three early and three of four advanced lines were found to secrete LIF protein. IL-11 was assayed using growth of the responsive B9/11 cell line, but only one of seven lines made a low but measurable amount of IL-11. Cytokine protein production was not strictly correlated with mRNA abundance, nor was it strongly correlated with tumor staging. Recombinant LIF and IL-11 protein had no effect on the proliferation of any of the seven lines, suggesting that they do not act as autocrine growth factors for these melanomas. Assay of IL-6, IL-11, and LIF protein in conditioned medium from early and advanced melanoma lines gave no evidence of coordinate expression of these cytokines. We conclude that LIF and IL-11 production by melanomas may have some paracrine or endocrine function in the course of melanoma progression.

Nature Immunology, 2003

are key regulators of immune responses that activate naive antigen-specific T lymphocytes. In dra... more are key regulators of immune responses that activate naive antigen-specific T lymphocytes. In draining lymph nodes, antigen-bearing DCs are reported to be rare and short-lived. How such small numbers of short-lived DCs can activate rare antigen-specific T cells is unclear. Here we show that after immunization of mouse skins by gene gun, the number of antigen-bearing DCs that migrate to draining lymph node is 100-fold higher than previously estimated and that they persist for approximately 2 weeks. The substantial frequency and longevity of DCs in situ ensures ample antigen presentation and stimulation for the rare antigen-specific T cells in draining lymph nodes.