Byram Bridle - Academia.edu (original) (raw)

Papers by Byram Bridle

Society of Nuclear Medicine Annual Meeting Abstracts, May 1, 2009

Canadian journal of veterinary research = Revue canadienne de recherche vétérinaire, 2006

To evaluate immunocompetence in commercially raised chickens, we immunophenotyped Dekalb Delta an... more To evaluate immunocompetence in commercially raised chickens, we immunophenotyped Dekalb Delta and H&N White Leghorn (WLH) hybrids, 20 chickens in each of 3 age groups (9 wk [juvenile], 25 wk [young adult], and 79 or 80 wk [adult]), for circulating CD3+, CD4+, CD8+, TCR1+, TCR2+, and TCR3+ lymphocytes. The proportion of CD3+ T cells, including CD4+ and CD8+ subsets, was increased in the hybrids as compared with published values for laboratory-raised outbred WLH chickens. The proportion of the TCR2+ (Vbeta1) T cell subpopulation was also increased. An age-related decrease in the proportion of TCR1+ (gammasigma) T cells was noted in both hybrids. Further, a remarkably low CD4:CD8 ratio was evident in all age groups of both hybrids, indicating decreased immunocompetence. Overall, these experiments provide age-related proportions of various peripheral-blood T lymphocyte subpopulations in commercially raised Dekalb Delta and H&N chickens that diverge from the proportions in laboratory-ra...

Oncoimmunology, 2013

The ability of heterologous prime-boost vaccination to elicit robust CD8(+) T cell responses has ... more The ability of heterologous prime-boost vaccination to elicit robust CD8(+) T cell responses has been well documented. In contrast, relatively little is known about how this immunotherapeutic strategy impacts the functional qualities of expanded T cells in the course of effector and memory responses. Using vesicular stomatitis virus (VSV) as a boosting vector in mice, we demonstrate that a massive secondary expansion of CD8(+) T cells can be achieved shortly after priming with recombinant adenoviral vectors. Importantly, VSV-boosted CD8(+) T cells were more potent than those primed by adenoviruses only, as measured by cytokine production, granzyme B expression, and functional avidity. Upon adoptive transfer, equivalent numbers of VSV-expanded CD8(+) T cells were more effective (on a per-cell basis) in mediating antitumor and antiviral immunity than T cells only primed with adenoviruses. Furthermore, VSV boosting accelerated the progression of expanded CD8(+) T lymphocytes to a centr...

Xenotransplantation, 2006

Xenotransplantation seeks to have cells with discordant genotypes co-exist. The hypothesis that h... more Xenotransplantation seeks to have cells with discordant genotypes co-exist. The hypothesis that host genotype modulates xenogeneic immune response (IR) was tested. Two inbred rat strains [Dark Agouti (DA) and Lewis (LEW)] representing diverse IR phenotypes were immunized with porcine blood mononuclear cells (BMC). Delayed-type hypersensitivity (DTH), immunoglobulin (Ig), antibody (Ab) and isotype bias of Ab response were evaluated. DTH to pig BMC was greater in DA than in LEW rats. Natural Ab was qualitatively different between strains (IgM and IgA predominated in DA, IgM and IgG(2a) predominated in LEW). Twice as much IgG was elicited from DA than LEW rats and DA utilized all isotypes whereas LEW did not use IgG(2a) or IgG(2c). IR bias was diametrically opposed; type 1 in DA but type 2 in LEW. Strains even differed in Ig profiles and dermal responses to saline injections and mitogen. The DA rats were the higher responders to pig BMC. Recipient genotype had significant and broad effects on IR to porcine BMC and may influence xenograft rejection and xenotolerance induction. Moreover, this study suggests that caution should prevail when interpreting data derived from a single inbred strain, particularly given that humans, the target species, are genetically diverse.

Veterinary Immunology and Immunopathology, 2004

A variety of commercial DNA arrays specific for humans and rodents are widely available; however,... more A variety of commercial DNA arrays specific for humans and rodents are widely available; however, microarrays containing well-characterized genes to study pathway-specific gene expression are not as accessible for domestic animals, such as cattle, sheep and pigs. Therefore, a small-scale application-targeted bovine immune-endocrine cDNA array was developed to evaluate genetic pathways involved in the immune-endocrine axis of cattle during periods of altered homeostasis provoked by physiological or environmental stressors, such as infection, vaccination or disease. For this purpose, 167 cDNA sequences corresponding to immune, endocrine and inflammatory response genes were collected and categorized. Positive controls included 5 housekeeping genes (glyceraldehydes-3-phosphate dehydrogenase, hypoxanthine phosphoribosyltransferase, ribosomal protein L19, b-actin, b2-microglobulin) and bovine genomic DNA. Negative controls were a bacterial gene (Rhodococcus equi 17-kDa virulence-associated protein) and a partial sequence of the plasmid pACYC177. In addition, RNA extracted from un-stimulated, as well as superantigen (Staphylococcus aureus enterotoxin-A, S. aureus Cowan Pansorbin Cells) and mitogen-stimulated (LPS, ConA) bovine blood leukocytes was mixed, reverse transcribed and PCR amplified using gene-specific primers. The endocrine-associated genes were amplified from cDNA derived from un-stimulated bovine hypothalamus, pituitary, adrenal and thyroid gland tissues. The array was constructed in 4 repeating grids of 180 duplicated spots by coupling the PCR amplified 213-630 bp gene fragments onto poly-L-lysine coated glass slides. The bovine immune-endocrine arrays were standardized and preliminary gene expression profiles generated using Cy3 and Cy5 labelled cDNA from un-stimulated and ConA (5 mg/ml) stimulated PBMC of 4 healthy Holstein cows (2-4 replicate arrays/cow) in a time course study. Mononuclear cell-derived cytokine and chemokine (IL-2, IL-1a, TNFa, IFN-g, TGFb-1, MCP-1, MCP-2 and MIP-3a) mRNA exhibited a repeatable and consistently low expression in un-stimulated cells and at least a two-fold increased expression following 6 and 24 h ConA stimulation as compared to 0 h un-stimulated controls. In contrast, expression of antigen presenting molecules, MHC-DR, MHC-DQ and MHC-DY, were consistently at least two-fold lower following 6 and 24 h ConA stimulation. The only endocrine gene with differential expression following ConA stimulation was prolactin. Additionally, due to the high level of genetic homology between ovine, swine and bovine genes, RNA similarly acquired from sheep and pigs was evaluated and similar gene expression patterns were noted. These data demonstrate that this application-targeted array containing a set of well characterized genes can be used to determine the relative gene expression corresponding to immune-endocrine responses of cattle and related species, sheep and pigs. #

Transplant Immunology, 2007

Reducing or deviating xenogeneic immune response prior to xenotransplantation may enhance the eff... more Reducing or deviating xenogeneic immune response prior to xenotransplantation may enhance the efficacy of conventional immunosuppressive therapies in prolonging xenograft survival. The potential to suppress or steer immune responses by oral administration of xenoantigens was evaluated. Based on knowledge of oral tolerance, hypotheses tested were that feeding xenoantigens would inhibit cell-mediated immune response (CMIR) and production of antibodies associated with graft rejection and induce bystander suppression. DA and LEW rats, high and low responders to xenoantigens, respectively, were fed dead porcine blood mononuclear cells (PBMC) and subsequently received live PBMC and hen egg-white lysozyme (HEWL, a third-party antigen) by subcutaneous injection. Delayed-type hypersensitivity (DTH) to PBMC was an indicator of CMIR. Quantification of T(H)1 (IgG(2b)) and T(H)2 (IgG(1))-associated antibodies and their ratio measured magnitude and bias of the antibody-mediated response to PBMC and HEWL. Feeding PBMC reduced IgG(2b) antibody production by 90% (DA) and 71% (LEW) and increased IgG(1) antibodies by 116% in DA but not LEW rats (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;or=0.05). DTH was unaffected (DA) or increased (LEW) in antigen-fed rats. Bystander suppression was demonstrated by inhibition of antibodies to HEWL in DA rats. LEW rats did not respond to HEWL. Evaluation of tertiary immune response to PBMC revealed DTH and antibodies to xenoantigens was inhibited. These data demonstrated orally-induced immune deviation and bystander suppression in rats given PBMC that may favor discordant xenograft survival and suggests a method to suppress xenogeneic immunity in high responders by repeated immunization with xenoantigens.

Transplant Immunology, 2009

Immune response to xenoantigens is a barrier to xenotransplantation. The objective of this study ... more Immune response to xenoantigens is a barrier to xenotransplantation. The objective of this study was to determine if rat cell-mediated immunity (CMI) and antibody (Ab) to discordant porcine xenoantigens could be suppressed by oral administration of porcine protein with adjunct systemic cytokine therapy. Based on principles of oral tolerance, it was hypothesized that: a. Feeding proteins from porcine blood mononuclear cells (PBMC) would induce a type 2 response, inhibiting CMI and type 1 Ab (associated with xenograft rejection) but increasing the amount of type 2 Ab. b. IL-4, a type 2 cytokine would exaggerate type 2 bias, enhancing immune deviation. c. IFN-gamma, a type 1 cytokine was expected to down-regulate overall Ab production, but increase CMI and type 1 Ab. DA rats fed porcine proteins with or without subcutaneous and intraperitoneal injections of IFN-gamma or IL-4 received PBMC by subcutaneous injection. Dermal delayed-type hypersensitivity to PBMC was the indicator of CMI. The IgG Ab to porcine proteins was quantified and type 2 (IgG(1)+IgG(2a)) to type 1 (IgG(2b)) Ab ratios indicated IR bias. Unfed, PBMC-challenged controls had a type 1 response bias but feeding PBMC induced a type 2 bias that suppressed CMI and type 1 Ab and increased type 2 Ab but not total IgG Ab. Contrary to the T(H)1/T(H)2 paradigm, IL-4 decreased oral-induced type 2 IR deviation and did not provide significant benefits relative to feeding alone. Treatment with IFN-gamma prevented a switch to type 2 IR but feeding-induced suppression of CMI was not significantly compromised. The IFN-gamma potently suppressed Ab, including, surprisingly, type 1 IgG isotypes. Contrary to the hypothesis tested, feeding Ag in combination with systemic delivery of recombinant IFN-gamma apparently created an immunoregulatory environment most favorable to xenograft survival.

Molecular Therapy, 2009

Dendritic cell (DC)-based vaccines are a promising strategy for tumor immunotherapy due to their ... more Dendritic cell (DC)-based vaccines are a promising strategy for tumor immunotherapy due to their ability to activate both antigen-specific T-cell immunity and innate immune effector components, including natural killer (NK) cells. However, the optimal mode of antigen delivery and DC activation remains to be determined. Using M protein mutant vesicular stomatitis virus (DeltaM51-VSV) as a gene-delivery vector, we demonstrate that a high level of transgene expression could be achieved in approximately 70% of DCs without affecting cell viability. Furthermore, DeltaM51-VSV infection activated DCs to produce proinflammatory cytokines (interleukin-12, tumor necrosis factor-alpha, and interferon (IFN)alpha/beta), and to display a mature phenotype (CD40(high)CD86(high) major histocompatibility complex (MHC II)(high)). When delivered to mice bearing 10-day-old lung metastatic tumors, DCs infected with DeltaM51-VSV encoding a tumor-associated antigen mediated significant control of tumor growth by engaging both NK and CD8(+) T cells. Importantly, depletion of NK cells completely abrogated tumor destruction, indicating that NK cells play a critical role for this DC vaccine-induced therapeutic outcome. Our findings identify DeltaM51-VSV as both an efficient gene-delivery vector and a maturation agent allowing DC vaccines to overcome immunosuppression in the tumor-bearing host.

Molecular Therapy, 2013

MS-275 Divides Antitumor Immunity and Autoimmunity using Living Image v2.5 so ware (Xenogen, Alme... more MS-275 Divides Antitumor Immunity and Autoimmunity using Living Image v2.5 so ware (Xenogen, Almeda, CA). Images were captured under identical exposure, aperture and pixel binning settings. Statistical analyses. GraphPad Prism for Windows (GraphPad So ware, San Diego, CA) was used for graphing. For statistical analyses, GraphPad Prism and Minitab Statistical So ware (Minitab Inc., State College, PA) were used. If required, data were normalized by log transformation. Student's two-tailed t-test, one-or two-way analysis of variance or general linear modeling was used to query immune response data. Di erences between means were considered signi cant at P ≤ 0.05. Means plus standard error bars are shown. Survival data were analyzed using the Kaplan-Meier method and the logrank test.

Molecular Therapy, 2014

The rhabdovirus Maraba has recently been characterized as a potent oncolytic virus. In the presen... more The rhabdovirus Maraba has recently been characterized as a potent oncolytic virus. In the present study, we engineered an attenuated Maraba strain, defined as MG1, to express a melanoma-associated tumor antigen. Its ability to mount an antitumor immunity was evaluated in tumor-free and melanoma tumor-bearing mice. Alone, the MG1 vaccine appeared insufficient to prime detectable adaptive immunity against the tumor antigen. However, when used as a boosting vector in a heterologous prime-boost regimen, MG1 vaccine rapidly generated strong antigen-specific T-cell immune responses. Once applied for treating syngeneic murine melanoma tumors, our oncolytic prime-boost vaccination protocol involving Maraba MG1 dramatically extended median survival and allowed complete remission in more than 20% of the animals treated. This work describes Maraba virus MG1 as a potent vaccine vector for cancer immunotherapy displaying both oncolytic activity and a remarkable ability to boost adaptive antitumor immunity.

The Journal of Immunology, 2013

Mucosal inflammation in conditions ranging from infective acute enteritis or colitis to inflammat... more Mucosal inflammation in conditions ranging from infective acute enteritis or colitis to inflammatory bowel disease is accompanied by alteration in serotonin (5-hydroxytryptamine [5-HT]) content in the gut. Recently, we have identified an important role of 5-HT in the pathogenesis of experimental colitis. 5-HT type 7 (5-HT 7 ) receptor is one of the most recently identified members of the 5-HT receptor family, and dendritic cells express this receptor. In this study, we investigated the effect of blocking 5-HT 7 receptor signaling in experimental colitis with a view to develop an improved therapeutic strategy in intestinal inflammatory disorders. Colitis was induced with dextran sulfate sodium (DSS) or dinitrobenzene sulfonic acid (DNBS) in mice treated with selective 5-HT 7 receptor antagonist SB-269970, as well as in mice lacking 5-HT 7 receptor (5-HT 7 2/2 ) and irradiated wild-type mice reconstituted with bone marrow cells harvested from 5-HT 7 2/2 mice. Inhibition of 5-HT 7 receptor signaling with SB-269970 ameliorated both acute and chronic colitis induced by DSS. Treatment with SB-269970 resulted in lower clinical disease, histological damage, and proinflammatory cytokine levels compared with vehicle-treated mice post-DSS. Colitis severity was significantly lower in 5-HT 7 2/2 mice and in mice reconstituted with bone marrow cells from 5-HT 7 2/2 mice compared with control mice after DSS colitis. 5-HT 7 2/2 mice also had significantly reduced DNBS-induced colitis. These observations provide us with novel information on the critical role of the 5-HT 7 receptor in immune response and inflammation in the gut, and highlight the potential benefit of targeting this receptor to alleviate the severity of intestinal inflammatory disorders such as inflammatory bowel disease. The Journal of Immunology, 2013, 190: 4795-4804. T he gastrointestinal (GI) tract is the largest producer of serotonin (5-hydroxytryptamine [5-HT]) in the body. About 95% of the body's 5-HT is located in the GI tract, and enterochromaffin (EC) cells are its main source (1, 2). 5-HT is also found in enteric neurons, but the 5-HT amount present in enteric neurons appears to be very small in comparison with that present in EC cells (∼90% of 5-HT is found in EC cells and 10% in enteric neurons) (3). Tryptophan hydroxylase (TPH) catalyzes the rate-limiting step in the synthesis of 5-HT from tryptophan and has been detected prominently in EC cells (4). Recent studies have shown that there are two isoforms of TPH enzymes regulating the 5-HT system. TPH1 is mainly present in EC cells and the spleen, whereas TPH2 predominates in the brainstem and enteric neurons (5, 6). Thus, 5-HT seems to be synthesized independently in EC cells and neurons by two different rate-limiting TPH isoenzymes. 5-HT is an important enteric mucosal signaling molecule involved in maintaining intestinal homeostasis, and alterations in 5-HT signaling are observed in various GI disorders including intestinal inflammatory conditions (7-9).

The Journal of Immunology, 2010

Although vaccines targeting tissue differentiation Ags represent a promising strategy for cancer ... more Although vaccines targeting tissue differentiation Ags represent a promising strategy for cancer immunotherapy, the risk of triggering autoimmune damage to normal tissues remains to be determined. Immunizing against a melanoma-associated Ag, dopachrome tautomerase (DCT), which normal melanocytes and glial cells also express, allowed concurrent analysis of autoimmune consequences in multiple tissues. We show that vaccination with recombinant adenovirus expressing DCT elicited a strong CTL response in C57BL/6 mice, leading to protection against intracranial challenge with B16-F10 melanoma cells. Both histological analysis and behavioral testing indicated that there was no evidence of neuropathology in vaccinated animals and long-term survivors. Although vitiligo or demyelination could be induced by additional stimuli (i.e., surgery or inflammation) in DCT-vaccinated mice, it did not extend beyond the inflammatory area, suggesting that there is self-regulatory negative feedback in normal tissues. These results demonstrate that it is possible to vaccinate against a tumor embedded in a vital organ that shares the target Ag.

Cytokine & Growth Factor Reviews, 2010

The interactions between the immune system, a malignant tumour and an oncolytic virus are complex... more The interactions between the immune system, a malignant tumour and an oncolytic virus are complex and poorly understood. For oncolytic viruses to become successful therapeutics we need to better understand these interactions and identify strategies to take advantage of defects in the innate immune response within tumours and avoid cellular anti-viral responses while capitalizing on anti-tumoural immunity. In this review we will discuss the evidence for the induction of tumour-specific immune responses by oncolytic viruses as well as by cancer vaccines. We will then describe some of the barriers to successful cancer immunotherapy, and finally we will outline a strategy for enhancing anti-tumoural immunity while reducing anti-viral immunity by combining tumour vaccination with oncolytic viral therapy.

Cancer Research, 2009

Tumors that recur following surgical resection of melanoma are typically metastatic and associate... more Tumors that recur following surgical resection of melanoma are typically metastatic and associated with poor prognosis. Using the murine B16F10 melanoma and a robust antimelanoma vaccine, we evaluated immunization as a tool to improve tumor-free survival following surgery. We investigated the utility of vaccination in both neoadjuvant and adjuvant settings. Surprisingly, neoadjuvant vaccination was far superior and provided f100% protection against tumor relapse. Neoadjuvant vaccination was associated with enhanced frequencies of tumor-specific T cells within the tumor and the tumor-draining lymph nodes following resection. We also observed increased infiltration of antigen-specific T cells into the area of surgery. This method should be amenable to any vaccine platform and can be readily extended to the clinic.

Bulletin of Mathematical Biology, 2011

Recent advances in virology, gene therapy, and molecular and cell biology have provided insight i... more Recent advances in virology, gene therapy, and molecular and cell biology have provided insight into the mechanisms through which viruses can boost the anti-tumor immune response, or can infect and directly kill tumor cells. A recent experimental report (Bridle et al. in Molec. Ther. 18(8):1430-1439, 2010) showed that a sequential treatment approach that involves two viruses that carry the same tumor antigen leads to an improved anti-tumor response compared to the effect of each virus alone. In this article, we derive a mathematical model to investigate the anti-tumor effect of two viruses, and their interactions with the immune cells. We discuss the conditions necessary for permanent tumor elimination and, in this context, we stress the importance of investigating the long-term effect of non-linear interactions. In particular, we discuss multi-stability and multi-instability, two complex phenomena that can cause abrupt transitions between different states in biological and physical systems. In the context of cancer immunotherapies, the transitions between a tumor-free and a tumor-present state have so far been associated with the multi-stability phenomenon. Here, we show that multi-instability can also cause the system to switch from one state to the other. In addition, we show that the multi-stability is driven by the immune response, while the multi-instability is driven by the presence of the virus.

Blood, 2013

T cell recall responses + accelerate CD8