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At least 307 records · Page 17Linked to original sources
PubMed2006

Transduced monocyte/macrophages targeted to murine skin by UV light.

We have selectively targeted monocyte/macrophages overexpressing an immunomodulatory molecule, latency-associated peptide (LAP), a naturally occurring antagonist for transforming growth factor-beta1, to murine skin utilizing UV light to produce a cutaneous influx of transduced monocyte/macrophages. Bone marrow (BM) cells from BALB/c mice were transduced in vitro with a retroviral construct containing green fluorescent protein (GFP) for detection and human LAP (hLAP) as a test molecule. The transduced BM cells were then cultured in vitro with granulocyte-macrophage colony-stimulating factor (GM-CSF) to produce differentiation to monocyte/macrophages. More than 80% of transduced BM cells were CD11b-positive and MOMA-positive by fluorescence-activated cell-sorter analysis and secreted LAP by ELISA after 10 days of culture in granulocyte-macrophage colony-stimulating factor (GM-CSF). Transduced monocyte/macrophages containing either GFP or hLAP-GFP were then injected intravenously into BALB/c mice. One-half of recipients in each group were exposed to UVB (72 mJ) to induce monocyte/macrophage infiltration into skin. Recipients were sacrificed 60 h after UV irradiation. We found transduced cutaneous macrophages expressing GFP by examining with fluorescence microscopy frozen skin sections of recipient mice immunostained with antibodies to GFP and to macrophage marker F4/80. We identified hLAP sequences by polymerase chain reaction (PCR) of total DNA in recipient blood and UV-irradiated skin but not in unirradiated skin. LAP sequences were also detected at much lower levels in other organs (lung, spleen, and liver) by PCR. Therefore, we have shown that genetically altered monocytic cells can be injected intravenously and targeted to mouse skin by UV exposure. This macrophage-based gene-transfer method may be a potentially useful immunotherapeutic approach for delivering monocyte/macrophage-derived products to skin.

Animals↗
PubMed2006

Patient-derived dendritic cells transduced with an a-fetoprotein-encoding adenovirus and co-cultured with autologous cytokine-induced lymphocytes induce a specific and strong immune response against hepatocellular carcinoma cells.

BACKGROUND/AIMS: Breaking immunologic tolerance towards the hepatocellular carcinoma (HCC)-associated alpha-fetoprotein (AFP) antigen is possible. The use of this potential for the treatment of immunocompromised HCC patients is limited. In this study, we analyzed whether dendritic cells (DCs) from HCC patients transduced with a human AFP (hAFP)-expressing adenovirus and co-cultured with cytokine-induced killer (CIK) cells can induce a strong specific immune response against HCC-cells. METHODS: An hAFP-encoding adenovirus (Ad-hAFP) was generated. DCs from healthy donors or patients were transduced at a very high efficacy. Afterwards, DCs were co-cultured with autologous CIK-cells, and their ability to lyse HCC-cells was analyzed. RESULTS: AFP-transduced DCs stimulated CIK cells strongly to lyse about 70% of AFP-expressing HCC cells. Cytotoxicity was significantly higher when lymphocytes were co-cultured with Ad-hAFP-transduced DCs than with Ad-mock-transduced DCs, indicating an AFP-specific immune response. More interestingly, CIK cells from patients with AFP-positive HCC could be stimulated to lyse AFP-expressing HCC cells as effectively as CIK cells from healthy individuals and stronger than CIK cells from patients without AFP-expressing HCC. CONCLUSIONS: The data demonstrate that patient-derived DCs that were transduced with an AFP-expressing adenovirus and co-cultured with autologous CIK cells induce an AFP-specific, strong immune response against HCC cells. Therefore, this approach may have a potential for an adoptive and/or DC-based immunotherapy for HCC patients.

Adenoviridae↗
PubMed2002

Optimizing the shape of ultrasound transducers for interstitial thermal ablation.

Heat deposition by interstitial routes, especially with ultrasound-based instruments, is becoming a valuable therapeutic option for the treatments of sites, which are difficult to access from outside of the body. The active part of most interstitial ultrasound applicators described in the literature is logically tubular to induce cylindrical volumes of coagulation necrosis. Because the pressure generated by such tubular transducers falls off rapidly with radial distance, we previously proposed using a rotating plane transducer. For a plane wave, the pressure fall-off is only due to attenuation, which makes deeper lesions and shorter treatment times possible. This work represents an advance in the development of ultrasound applicators designed for interstitial applications. This new applicator used a rotating slightly focused transducer. A brief theoretical analysis resulted in the choice of a long focal distance of 22 mm to obtain a nearly constant pressure all along the therapeutic depth. To experimentally validate this focal distance, pressure measurements were made in a tissue mimicking liquid phantom and the results were compared with those obtained with a plane transducer. In vitro experiments showed that necrosis could be induced at a depth of 15 mm. In the same conditions, the greatest depth attained with a plane transducer was only 10 mm. Because each individual lesion is narrower, more lesions and more time are required to necrose a cylindrical volume. The main advantage of this new type of applicator is that it can be used to induce necrosis at a greater depth without varying either the frequency, the intensity or the transducer cooling efficiency.

Acoustics↗
PubMed2002

Design of optimal configuration for generating A0 Lamb mode in a composite plate using piezoceramic transducers.

This work concerned a technique for a health monitoring system based on the generation and sensing of Lamb waves in composite structures by thin surface-bonded piezoceramic transducers. The objective was to develop transducers that are adapted for the damage detection in orthotropic composites. The key problem with the investigated Lamb waves was to select a mode to be sensitive to the damage. A hybrid modeling technique was therefore used to conceive transducers that were adapted to achieve such a feature. This modeling technique enabled studying the influence of the transducer characteristics on the Lamb waves propagating in orthotropic plates. It was demonstrated that a Lamb mode could be generated dominantly to other modes by using a multi-element transducer. The effectiveness of this technique was successfully verified experimentally on composite plates. It was shown that the dominant Lamb mode, obtained by use of dual-element transducers, was an appropriate mode for successfully detecting a damage in composites.

Journal Article↗
PubMed2002

Study on the prestressed sandwich piezoelectric ceramic ultrasonic transducer of torsional-flexural composite vibrational mode.

Based on the classical torsional and flexural vibrational theory of a slender rod, the prestressed sandwich torsional-flexural composite mode piezoelectric ceramic ultrasonic transducer is studied. This type of transducer consists of the slender metal rods and the longitudinally and tangentially polarized piezoelectric ceramic rings. The resonance frequency equations for the torsional and flexural vibrations in the transducers are derived. The simultaneous resonance of the torsional and flexural vibrations in the transducer is acquired by correcting the length of the metal slender rods resulting from the piezoelectric ceramic elements. The experimental results show that the measured resonance frequencies of the transducers are in good agreement with the computed ones, and the measured resonance frequencies of the torsional and the flexural vibrations in the composite transducers are also in good agreement with each other.

Journal Article↗
PubMed2003

Optimization of structural variables of a flextensional transducer by the statistical multiple regression analysis method.

The performance of an acoustic transducer is determined by the effects of many structural variables, and in most cases the influences of these variables are not linearly independent of each other. To achieve optimal performance of an acoustic transducer, we must consider the cross-coupled effects of its structural variables. In this study, with the finite-element method, the variation of the operation frequency and sound pressure of a flextensional transducer in relation to its structural variables is analyzed. Through statistical multiple regression analysis of the results, functional forms of the operation frequency and sound pressure of the transducer in terms of the structural variables were derived, with which the optimal structure of the transducer was determined by means of a constrained optimization technique, the sequential quadratic programming method of Phenichny and Danilin. The proposed method can reflect all the cross-coupled effects of multiple structural variables, and can be extended to the design of general acoustic transducers.

Journal Article↗
PubMed2000

Maximum a posteriori deconvolution of ultrasonic signals using multiple transducers

A new method for deconvolution of ultrasonic pulse-echo measurements employing multiple-transducer setup is proposed in the paper. An optimal way of estimating the material reflection sequence for a linear signal generation model using maximum a posteriori estimation is proposed. The method combines the measurements from a number of transducers covering different frequency bands yielding an optimal estimate of the reflection sequence. The main idea of this approach is to complement the information unavailable from one transducer in some frequency bands with the information from the other transducers. The method is based on the assumption that the measurements are performed using transducers with identical apertures and apodization, which are located exactly at the same position relative to the test object during the measurement. An error analysis presented in the paper proves that when the above assumptions are fulfilled, the proposed method, by utilizing more data for estimation, consistently yields more accurate reflection sequence estimates than the classical Wiener filter. Experimental evidence is presented using both simulated and real ultrasonic data as a verification of the correctness of the multiple-transducer model and the estimation scheme. An illustration of the advantages of the method is also given using real ultrasonic data.

Journal Article↗
PubMed1987

Rec dependence of mu transposition from P22-transduced fragments.

Derivatives of bacteriophage Mu carrying a lac operon and a selectable drug resistance element (Mu d phages) are frequently used tools of bacterial genetics. Mu d prophages used in this way can be treated as transposons, in that the inserted material can be transduced from one strain to another by general transducing phages, such as P1 and P22. When a Mu d prophage is transduced into a new recipient by P1 or P22, the Mu d element can transpose from the transduced fragment into the bacterial chromosome. Transposition of the Mu d element from a P22-transduced fragment shows several striking differences from transposition of a Mu d genome injected by a Mu virion. First, the frequency of transposition from a transduced fragment is greatly enhanced by a P22 helper genome. Second, transposition requires the host recA, B, and C functions. Transposition of Mu following injection by a Mu virion is rec independent. While the basis of these observations is not understood, we suggest that the Mu X protein, a 65-kilodalton protein injected by a Mu virion and required for Mu transposition, may not be packaged by P22. We suggest that the effects seen reflect the behavior of a Mu genome in the absence of the X protein.

Bacteriophage mu↗
PubMed1989

Evolution of chemotactic-signal transducers in enteric bacteria.

The methyl-accepting chemotactic-signal transducers of the enteric bacteria are transmembrane proteins that consist of a periplasmic receptor domain and a cytoplasmic signaling domain. To study their evolution, transducer genes from Enterobacter aerogenes and Klebsiella pneumoniae were compared with transducer genes from Escherichia coli and Salmonella typhimurium. There are at least two functional transducer genes in the nonmotile species K. pneumoniae, one of which complements the defect in serine taxis of an E. coli tsr mutant. The tse (taxis to serine) gene of E. aerogenes also complements an E. coli tsr mutant; the tas (taxis to aspartate) gene of E. aerogenes complements the defect in aspartate taxis, but not the defect in maltose taxis, of an E. coli tar mutant. The sequence was determined for 5 kilobases of E. aerogenes DNA containing a 3' fragment of the cheA gene, cheW, tse, tas, and a 5' fragment of the cheR gene. The tse and tas genes are in one operon, unlike tsr and tar. The cytoplasmic domains of Tse and Tas are very similar to those of E. coli and S. typhimurium transducers. The periplasmic domain of Tse is homologous to that of Tsr, but Tas and Tar are much less similar in this region. However, several short sequences are conserved in the periplasmic domains of Tsr, Tar, Tse, and Tas but not of Tap and Trg, transducers that do not bind amino acids. These conserved regions include residues implicated in amino-acid binding.

Amino Acid Sequence↗
PubMed1999

Identification of methylation sites and effects of phototaxis stimuli on transducer methylation in Halobacterium salinarum.

The two transducers in the phototaxis system of the archaeon Halobacterium salinarum, HtrI and HtrII, are methyl-accepting proteins homologous to the chemotaxis transducers in eubacteria. Consensus sequences predict three glutamate pairs containing potential methylation sites in HtrI and one in HtrII. Mutagenic substitution of an alanine pair for one of these, Glu265-Glu266, in HtrI and for the homologous Glu513-Glu514 in HtrII eliminated methylation of these two transducers, as demonstrated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis autofluorography. Photostimulation of the repellent receptor sensory rhodopsin II (SRII) induced reversible demethylation of HtrII, while no detectable change in the extent of methylation of HtrI was observed in response to stimulation of its cognate sensory rhodopsin, the attractant receptor SRI. Cells containing HtrI or HtrII with all consensus sites replaced by alanine still exhibited phototaxis responses and behavioral adaptation, and methanol release assays showed that methyl group turnover was still induced in response to photostimulation of SRI or SRII. By pulse-chase experiments with in vivo L-[methyl-(3)H]methionine-labeled cells, we found that repetitive photostimulation of SRI complexed with wild-type (or nonmethylatable) HtrI induced methyl group turnover in transducers other than HtrI to the same extent as in wild-type HtrI. Both attractant and repellent stimuli cause a transient increase in the turnover rate of methyl groups in wild-type H. salinarum cells. This result is unlike that obtained with Escherichia coli, in which attractant stimuli decrease and repellent stimuli increase turnover rate, and is similar to that obtained with Bacillus subtilis, which also shows turnover rate increases regardless of the nature of the stimulus. We found that a CheY deletion mutant of H. salinarum exhibited the E. coli-like asymmetric pattern, as has recently also been observed in B. subtilis. Further, we demonstrate that the CheY-dependent feedback effect does not require the stimulated transducer to be methylatable and operates globally on other transducers present in the cell.

Amino Acid Sequence↗
PubMed1996

Prevention of adoptively transferred diabetes in nonobese diabetic mice with IL-10-transduced islet-specific Th1 lymphocytes. A gene therapy model for autoimmune diabetes.

Four pancreatic islet-specific CD4+ helper T (Th) 1 (Th1) clones and two Th1 clones transduced with an SRalpha promoter-linked murine IL-10 (mIL-10) cDNA of 2.0-6.0 x 10(6) cells were adoptively transferred to nonobese diabetic (NOD) mice at age 8 d. Cyclophosphamide (CY) was administered at age 37 d (plus CY), and the incidence of diabetes and the histological grade of insulitis were examined at age 47 d. After the adoptive transfer of IL-10-transduced Th1 cells, polymerase chain reaction (PCR) and reverse-transcription (RT)-PCR detected the neo gene and the retrovirus vector-mediated IL-10 mRNA in situ in recipient islets, respectively. RT-PCR detected the decrease of IFN-gamma mRNA relative to IL-10 mRNA in IL-10-transduced Th1 clones in vitro and also in recipient islets. All four wild type Th1 clones plus CY induced the insulitis grade of 2.75 and diabetes in 66% of recipient NOD mice. IL-10-transduced two Th1 clones plus CY induced periinsulitis with the grade of 1.43 and diabetes in 8.0%. The 1:1 mixture of wild type Th1 cells and IL-10-transduced Th1 cells plus CY induced periinsulitis with the grade of 1.85 and diabetes in 20%. The suppression of diabetes through decreasing IFN-gamma mRNA by the tissue-specific delivery of IL-10 to pancreatic islets with IL-10-transduced Th1 cells affords us the starting basis to develop the gene therapy for autoimmune diabetes.

Adoptive Transfer↗
PubMed2003

Bone formation by BMP-7-transduced human gingival keratinocytes.

BMPs are a family of pleiotropic signaling molecules involved at various stages in the formation of bones and teeth. In addition, recombinant BMP can induce bone and dentin regeneration when applied directly to adult tissues. We have shown that fibroblasts transduced ex vivo by BMP cDNA delivered by recombinant adenoviruses induce bone formation and convert to osteoblasts upon implantation in vivo. To determine if this osteogenic capacity was limited to fibroblasts, we found that BMP-7-transduced human oral keratinocyte cells (HOKC) also formed ectopic bone. The ossicles formed by the BMP-7-transduced HOKC were smaller and more dense than those formed by BMP-7-transduced human gingival fibroblasts (HGF). Implanted HOKC were localized adjacent to the developing bone by immunocytochemical detection of keratin expression. However, no bone-like tissue formed when HOKC were implanted into diffusion chambers in vivo. We conclude that BMP-transduced HOKC secrete BMP and form bone in vivo but, unlike BMP-transduced HGF, do not transdifferentiate to osteoblasts.

Adult↗
PubMed2006

WHIM syndrome myelokathexis reproduced in the NOD/SCID mouse xenotransplant model engrafted with healthy human stem cells transduced with C-terminus-truncated CXCR4.

WHIM(warts, hypogammaglobulinemia, recurrent bacterial infection, and myelokathexis) syndrome is a rare immunodeficiency caused in many cases by autosomal dominant C-terminal truncation mutations in the chemokine receptor CXCR4. A prominent and unexplained feature of WHIM is myelokathexis (hypercellularity with apoptosis of mature myeloid cells in bone marrow and neutropenia). We transduced healthy human CD34(+) peripheral blood-mobilized stem cells (PBSCs) with retrovirus vector encoding wild-type (wt) CXCR4 or WHIM-type mutated CXCR4 and studied these cells ex vivo in culture and after engraftment in a nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mouse xenograft model. Neither wt CXCR4 nor mutated CXCR4 transgene expression itself enhanced apoptosis of neutrophils arising in transduced PBSC cultures even with stimulation by a CXCR4 agonist, stromal cell-derived factor-1 (SDF-1 [CXCL12]). Excess wt CXCR4 expression by transduced human PBSCs enhanced marrow engraftment, but did not affect bone marrow (BM) apoptosis or the release of transduced leukocytes into PB. However, mutated CXCR4 transgene expression further enhanced BM engraftment, but was associated with a significant increase in apoptosis of transduced cells in BM and reduced release of transduced leukocytes into PB. We conclude that increased apoptosis of mature myeloid cells in WHIM is secondary to a failure of marrow release and progression to normal myeloid cell senescence, and not a direct effect of activation of mutated CXCR4.

Agammaglobulinemia↗
PubMed2001

Molecular mechanism for ganciclovir resistance in human T lymphocytes transduced with retroviral vectors carrying the herpes simplex virus thymidine kinase gene.

The herpes simplex virus thymidine kinase gene type 1 (HSV-Tk) ganciclovir (GCV) system is a novel therapeutic strategy for the modulation of graft-versus-host disease (GVHD), a major complication of allogeneic stem cell transplantation (allo-SCT). Retroviral-mediated gene transfer of the HSV-Tk gene into donor T lymphocytes before allo-SCT may allow their in vivo selective depletion after treatment with GCV. The expression of the HSV-Tk gene was analyzed in vitro in CEM cells, a human lymphoblastoid cell line, transduced with 2 different vectors, each containing the HSV-Tk gene and a selectable marker gene. GCV-resistant clones were identified within the clones expressing the marker gene. Characterization of the molecular events leading to this resistance revealed a 227-bp deletion in the HSV-Tk gene due to the presence of cryptic splice donor and acceptor sites within the HSV-Tk gene sequence. Furthermore, it was confirmed that this deletion was present in human primary T cells transduced with either vector and in 12 patients who received transduced donor T cells, together with a T-cell-depleted allo-SCT. In vivo circulating transduced T cells containing the truncated HSV-Tk gene were identified in all patients immediately after infusion and up to 800 days after transplantation. In patients who received GCV as treatment for GVHD, a progressive increase in the proportion of transduced donor T cells carrying the deleted HSV-Tk gene was observed. These results suggest that the limitations within the HSV-Tk/GCV system can be improved by developing optimized retroviral vectors to ensure maximal killing of HSV-Tk-transduced cells.

Antiviral Agents↗
PubMed2002

Targeting transgene expression to antigen-presenting cells derived from lentivirus-transduced engrafting human hematopoietic stem/progenitor cells.

Hematopoietic stem cells (HSCs) represent an important target for the treatment of various blood disorders. As the source of critical cells within the immune system, genetic modification of HSCs can also be used to modulate immune responses. The effectiveness of HSC-mediated gene therapy largely depends on efficient gene delivery into long-term repopulating progenitors and targeted transgene expression in an appropriate progeny of the transduced pluripotent HSCs. Self-inactivating (SIN) lentiviral vectors have been demonstrated to be capable of transducing mitotically inactive cells, including HSCs, and accommodating a nonviral promoter to control the transgene expression in transduced cells. In this study, we constructed 2 SIN lentiviral vectors, EF.GFP and DR.GFP, to express the green fluorescent protein (GFP) gene controlled solely by the promoter of either a housekeeping gene EF-1alpha or the human HLA-DRalpha gene, which is selectively expressed in antigen-presenting cells (APCs). We demonstrated that both vectors efficiently transduced human pluripotent CD34+ cells capable of engrafting nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice. When the EF.GFP vector was used, constitutive high-level GFP expression was obtained in all the human HSC progeny detectable in NOD/SCID mice and in subsequent in vitro differentiation assays, indicating that engrafting human HSCs have been transduced. In contrast, the DR.GFP vector mediated transgene expression specifically in human HLA-DR+ cells and highly in differentiated dendritic cells (DCs), which are critical in regulating immunity. Furthermore, human DCs derived from transduced and engrafted human cells potently stimulated allogeneic T-cell proliferation. This study demonstrated successful targeting of transgene expression to APCs/DCs after stable gene transduction of pluripotent HSCs.

Animals↗
PubMed2002

Modulation of p210(BCR-ABL) activity in transduced primary human hematopoietic cells controls lineage programming.

Retroviral transduction of primary hematopoietic cells with human oncogenes provides a powerful approach to investigating the molecular mechanisms controlling the normal proliferation and differentiation of these cells. Here we show that primitive human CD34(+) cord blood cells, including multipotent as well as granulopoietic- and erythroid-restricted progenitors, can be efficiently transduced with a MSCV-BCR-ABL-IRES-GFP retrovirus, resulting in the sustained expression by their progeny of very high levels of tyrosine phosphorylated p210(BCR-ABL). Interestingly, even in the presence of growth factors that supported the exclusive production of granulopoietic cells from green fluorescent protein (GFP)-transduced control cells, BCR-ABL-transduced progenitor subpopulations generated large numbers of erythropoietin-independent terminally differentiating erythroid cells and reduced numbers of granulopoietic cells. Analyses of individual clones generated by single transduced cells in both semisolid and liquid cultures showed this BCR-ABL-induced erythroid differentiation response to be elicited at a high frequency from all types of transduced CD34(+) cells independent of their apparent prior lineage commitment status. Additional experiments showed that this erythroid differentiation response was largely prevented when the cells were transduced and maintained in the presence of the BCR-ABL-specific tyrosine kinase inhibitor, STI-571. These findings indicate that overexpression of BCR-ABL in primary human hematopoietic cells can activate an erythroid differentiation program in apparently granulopoietic-restricted cells through a BCR-ABL kinase-dependent mechanism, thus providing a new molecular tool for elucidating mechanisms underlying lineage fate determination in human hematopoietic cells and infidelity in human leukemia.

Antigens, CD34↗
PubMed2003

Generation of cytotoxic T cell against HBcAg using retrovirally transduced dendritic cells.

AIM: Cytotoxic T lymphocytes (CTLs) play an important role in resolving HBV infection. In the present study, we attempted to evaluate the efficiency of bone marrow-derived dendritic cells (DCs) transduced with recombinant retroviral vector bearing hepatitis B virus (HBV) core gene and the capability of generating CTLs against HBcAg by genetically modified DCs in vivo. METHODS: A retroviral vector containing HBV core gene was constructed. Replicating DC progenitor of C57BL/6 mice was transduced by retroviral vector and continually cultured in the presence of recombinant mouse granulocyte-macrophage colony-stimulating factor (rmGM-CSF) and interleukin-4(IL-4) for 6 days. LPS was added and cultured for additional two days. The efficiency of gene transfer was determined by PCR, Western blot and FACS. Transduced DCs immunized C57BL/6 mice subcutaneously 2 times at an one-week interval. Intracellular IFN-gamma and IL-4 of immunized mice lymphocytes were analyzed. Generation of CTLs in lymphocytes stimulated with mitomycin C-treated EL4-C cell which stably expresses HBcAg was determined by LDH release assays. RESULTS: Recombinant retroviral expression vector (pLCSN) was positively detected by PCR as well as enzyme digestion with EcoRI and BamH I. Retroviruses were generated by pLCSN transfection packing cell and the virus titer was 3 x 10(5) CFU/ml. Indirect immunofluorescence and FACS showed that HBV core gene was expressed in murine fibroblasts. Transduced bone marrow cells had capability of differentiating into DCs in vitro in the presence of rmGM-CSF and rmIL-4. The result of PCR showed that HBV core gene was integrated into the genome of transduced DCs. Western blot analysis showed that HBV core gene was expressed in DCs. The transduction rate was 28 % determined by FACS. Retroviral transduction had no influence on DCs expressions of CD80 and MHC class II. HBcAg specific CTLs and Th1 type immune responses could be generated in the mice by using transduced DCs as antigen presenting cells (APCs). CONCLUSION: Retroviral transduction of myeloid DCs progenitors expresses efficiently HBcAg, and genetically modified DCs evoke a higher CTLs response than HBcAg in vivo.

Animals↗
PubMed1999

Induction of antitumor immunity with dendritic cells transduced with adenovirus vector-encoding endogenous tumor-associated antigens.

Dendritic cells (DCs) are professional Ag-presenting cells that are being considered as potential immunotherapeutic agents to promote host immune responses against tumor Ags. In this study, recombinant adenovirus (Ad) vectors encoding melanoma-associated Ags were used to transduce murine DCs, which were then tested for their ability to activate CTL and induce protective immunity against B16 melanoma tumor cells. Immunization of C57BL/6 mice with DCs transduced with Ad vector encoding the hugp100 melanoma Ag (Ad2/hugp100) elicited the development of gp100-specific CTLs capable of lysing syngeneic fibroblasts transduced with Ad2/hugp100, as well as B16 cells expressing endogenous murine gp100. The induction of gp100-specific CTLs was associated with long term protection against lethal s.c. challenge with B16 cells. It was also possible to induce effective immunity against a murine melanoma self Ag, tyrosinase-related protein-2, using DCs transduced with Ad vector encoding the Ag. The level of antitumor protection achieved was dependent on the dose of DCs and required CD4+ T cell activity. Importantly, immunization with Ad vector-transduced DCs was not impaired in mice that had been preimmunized against Ad to mimic the immune status of the general human population. Finally, DC-based immunization also afforded partial protection against established B16 tumor cells, and the inhibition of tumor growth was improved by simultaneous immunization against two melanoma-associated Ags as opposed to either one alone. Taken together, these results support the concept of cancer immunotherapy using DCs transduced with Ad vectors encoding tumor-associated Ags.

Adenoviridae↗