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Results for “SCID mouse”

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At least 685 records · Page 38Linked to original sources

PubMed2005

Vascular dendritic cells in giant cell arteritis.

Giant cell arteritis (GCA) is a granulomatous vasculitis that selectively targets medium-sized and large arteries, especially the cranial branches of the aorta. The inflammatory activity of vascular lesions is driven by adaptive immune responses, with CD4 T cells undergoing clonal expansion in the vessel wall and releasing interferon gamma. Recent studies have described a distinctive population of dendritic cells (DCs) localized at the adventitia-media border of normal medium-sized arteries that appear to play a critical role in the initiation of vasculitis. Immune effector functions of this DC population are being examined in human artery-severe combined immunodeficient (SCID) mouse chimeras. In their constitutive form, CD11c+ fascin+ adventitial DCs are not recognized by alloreactive T cells. Triggering with Toll-like receptor (TLR) ligands is sufficient to break this state of tolerance and initiate DC activation, T-cell recruitment, T-cell activation, and T-cell retention in the arterial wall. Systemic administration of ligands for TLR2 or -4 in human artery-SCID chimeras drives differentiation of adventitial DCs into chemokine-producing effector cells with high-level expression of both CD83 and CD86 and mediates T-cell regulatory function through release of interleukin 18. In established vasculitis, fully matured DCs retain antigen-presenting function; antibody-mediated DC depletion disrupts T-cell and macrophage activation and has marked anti-inflammatory effects. We conclude that adventitial DCs, an indigenous cell population of the arterial wall, are responsive to pathogen-derived macromolecules and have gatekeeper function in regulating T-cell recruitment and retention to the arterial adventitia. A switch of adventitial DCs from being nonstimulatory to T-cell activating emerges as a critical event in the initiation of vasculitis.

Dendritic Cells↗

PubMed1994

The functional state of follicular dendritic cells in severe combined immunodeficient (SCID) mice: role of the lymphocytes.

In the present study, we have investigated the capacity of follicular dendritic cells (FDC) to trap immune complexes (IC) in the splenic white pulp of severe combined immunodeficient (SCID) mice and the influence of lymphocyte transfer on FDC function. FDC are absent in the splenic white pulp of naive SCID mice as revealed by in vitro IC trapping assay. One week after transfer of syngeneic lymphocytes, functional FDC with complement receptors appeared in the primary follicles coincident with B cell segregation, and IC were trapped on those FDC in a complement-dependent manner. Next, we immunized the reconstituted SCID mouse to see whether another type of FDC could be induced in the secondary follicle. Antigenic stimulation induced FDC with an additional capacity to capture IC via FcR gamma II. As seen in immunocompetent mice, this type of FDC was located only in the light zone of the secondary follicle. The newly generated FDC did not carry H-2 antigen of transferred lymphocytes from F1 mice. In SCID mice, in which normally no functional FDC are detectable, the microenvironments of the splenic white pulp have a capacity to develop and differentiate normally after transfer of lymphocytes. Apparently, the generation of functional IC-trapping FDC causes the induction of complement receptor(s) and Fc receptor on meshwork cells, which requires the presence of the lymphocytes.

Animals↗

PubMed2000

Overexpression of Fas-ligand by neuroblastoma: a novel mechanism of tumor-cell killing.

BACKGROUND/PURPOSE: Binding of Fas ligand (Fas-L) to the membrane-bound Fas receptor incites a series of intracellular events that results in programmed cell death or apoptosis. Although this apoptotic phenomenon plays a key role in down-regulating cytotoxic T cells, the authors have shown previously that pancreatic beta cells (bTC) overexpressing Fas-L paradoxically undergo accelerated rejection that is dependent on a Fas/Fas-L interaction. This study evaluates whether a neuroblastoma (NB) cell line manipulated to overexpress Fas-L undergoes similar destruction and whether tumor-specific protective immunity can be produced. METHODS: The authors transfected NB cells (SK-N-MC) with either mFas-L cloned into a pcDNA3.1/Zeo plasmid vector (NB/Fas-L) or with the vector alone (NB/control). Successful transfection of Fas-L was characterized by reverse transcription polymerase chain reaction (RT-PCR) and the ability of transfectants to induce apoptosis of Fas-sensitive T cells (Jurkat). Expression of Fas and Fas-L in untransfected NB clones was characterized by immunohistochemistry and RNase protection assay (RPA). Apoptosis was measured by FACScan analysis using an Annexin V assay. A total of 3x10(6) NB/control and NB/Fas-L cells were implanted subcutaneously into the hind leg of Balb/C SCID mice. Tumor-specific protective immunity was also tested in this model by inoculating mice with NB/Fas-L before implanting NB/control cells. RESULTS: Zeocin resistance and RT-PCR confirmed successful transfection of Fas-L into NB cells. Fas Ligand transfectants induced apoptosis in 17.6%+/-2.9% of Fas-sensitive T cells, whereas controls induced apoptosis in only 2.8%+/-1.2% (P = .01, n = 3). Although Fas appears to be constitutively expressed by NB in low amounts, introduction of Fas-L into NB cells did not induce suicide or affect tumor cell growth in vitro. In vivo, NB cells expressing Fas-L failed to grow in SCID mice (n = 3), whereas controls grew rapidly in all animals until death (n = 3). NB/control cells implanted into the opposite leg of mice that rejected initial NB/Fas-L transfectants also grew rapidly (n = 3) implying no protective immunity. CONCLUSIONS: Overexpression of Fas-L in NB clones targets such cells for rapid destruction even in immune compromised hosts, suggesting potential utility of Fas-L in combating NB. In this SCID mouse model, the observed effect is probably neutrophil mediated and does not provide tumor-specific protective immunity.

Animals↗

PubMed2002

Murine models for human immunodeficiency virus type 1-associated dementia: the development of new treatment testing paradigms.

The neuroimmune events leading to human immunodeficiency virus (HIV)-1-associated dementia (HAD) are linked to macrophage secretory neurotoxins (cellular and viral toxins). To study such events, we developed a murine model of HIV-1 encephalitis (HIVE), the pathological equivalent of HAD. Severe combined immunodeficient (SCID) mice injected with HIV-1-infected monocyte-derived macrophages (MDMs) into basal ganglia exhibited many of the pathological features of human HIVE. Moreover, behavioral and cognitive abnormalities in the HIVE mice were associated with neuronal dysfunction and decreased synaptic density. Thus, the rationale for testing novel therapeutic approaches (anti-inflammatory, antiretroviral, or neuroprotective) in the HIVE SCID mice is clear. Animals treated with anti-inflammatory compounds (platelet-activating factor [PAF] antagonist and tumor necrosis factor [TNF]-alpha release inhibitor) showed a marked reduction in brain inflammation and a reduction in neuronal injury. Comparative analyses of highly active antiretroviral therapy (HAART) regimens provided direction for which one might be most efficient for reduction of viral load in infected brain tissue. Moreover, modifications of the HIVE model might serve as a vehicle for testing vaccine approaches. Reconstitution of immunodeficient animals with syngeneic T lymphocytes followed by injection of HIV-1-infected MDMs in the brain resulted in cytotoxic antivirus T lymphocyte (CTL) response. CD8-positive T cells migrated to the sites of human MDMs, leading to the cell-mediated destruction of HIV-1 infected MDMs. These results, taken together, strongly support the use of HIVE SCID mouse model as a novel system for studies of the neuropathogenesis of HIV-1 infection, as well as for testing novel therapeutic and vaccine interventions for human disease.

AIDS Dementia Complex↗

PubMed2000

Evaluation of antiretroviral drug efficacy for HIV-1 encephalitis in SCID mice.

OBJECTIVES: To compare the efficacy of the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir, zidovudine (AZT), lamivudine (3TC), didanosine (ddI), and stavudine (d4T) to inhibit viral replication in brain macrophages. A severe combined immunodeficiency (SCID) mouse model of HIV-1 encephalitis (HIVE) was used to monitor spreading viral infection in the CNS. BACKGROUND: The development of antiretroviral therapies with CNS efficacy against neuroinvasive virus is important if eradication of HIV-1 can be achieved within critical "hidden reservoirs." METHODS: HIV-1-infected human monocyte-derived macrophages (MDMs) (after a single round of viral replication) were inoculated into the caudate and putamen of SCID mice. This resulted in the spreading of viral infection with a concomitant multinucleated giant cell encephalitis (astrogliosis, microglial activation, and neuronal injury). NRTIs were administered to animals at the time of intracerebral MDM inoculations and continued until the time of sacrifice. Antiretroviral effects were assessed by viral load and percentages of infected MDMs. RESULTS: In brains of SCID mice with HIVE, abacavir and lamivudine reduced HIV-1 p24 antigen-positive cells by 80% and 95%, respectively, whereas both decreased viral load by approximately 1 log. Zidovudine, didanosine, and stavudine showed variable effects. CONCLUSION: Abacavir and lamivudine showed significant antiretroviral activity in SCID mice with HIVE when compared with other NRTIs. The extrapolation of these results to humans with HIV-1 dementia awaits future investigations.

AIDS Dementia Complex↗

PubMed1998

Nucleotide sequence of an attenuated mutant of coxsackievirus B3 compared with the cardiovirulent wildtype: assessment of candidate mutations by analysis of a revertant to cardiovirulence.

BACKGROUND: Coxsackievirus B3 (CVB3) causes myocarditis in the SWR (H2q) mouse model and persistence of CVB3 in myocardium disposes to the development of dilated cardiomyopathy. An attenuated strain of CVB3 has been isolated, sequenced and several candidate mutations for attenuation identified. Derivation of a revertant to cardiovirulence allows the significance of these mutations to be assessed. OBJECTIVES: To ascertain which candidate mutation(s) determine(s) the attenuated phenotype. STUDY DESIGN: A revertant to cardiovirulence was isolated following passage through severe combined immunodeficient disease (SCID) mouse heart. The 5'-non-translated region (NTR) and region coding for capsid proteins were sequenced and compared to the wildtype and attenuant. RESULTS: There are five candidates for attenuation: (1) A-G at base 580 in the 5'-NTR; (2) A-T at base 690 in the 5'-NTR; (3) CG-GC at bases 1401/2 (Thr to Ser at amino acid 151 in VP2); (4) AA-GT at bases 2691/2 (Lys to Ser at amino acid 80 in VP1); (5) A-G at base 2916 (Asp to Gly at amino acid 155 in VP1). It was shown previously that mutations at 580, 690 and 2691/2 are not important in attenuation. Additionally, there are three novel mutations in the coding region of the revertant and one in the 5'-NTR which are unlikely to be relevant for attenuation as they are not present in the attenuant. Of nucleotide changes seen at 1401/2 and 2916 in the attenuant, only 2916 reverts to the wildtype sequence and so is a strong candidate for a determinant of attenuation.

Amino Acid Substitution↗

PubMed1994

High efficiency of muscle regeneration after human myoblast clone transplantation in SCID mice.

SCID mouse tibialis anterior muscles were first irradiated to prevent regeneration by host myoblasts and injected with notexin to damage the muscle fibers and trigger regeneration. The muscles were then injected with roughly 5 million human myoblasts. 1 mo later, 16-33% of the normal number of muscle fibers were present in the injected muscle, because of incomplete regeneration. However, > 90% of these muscle fibers contained human dystrophin. Some newly formed muscle fibers had an accumulation of human dystrophin and desmin on a part of their membrane. Such accumulations have been demonstrated at neuromuscular junctions before suggesting that the new muscle fibers are innervated and functional. The same pool of clones of human myoblasts produced only < or = 4% of muscle fibers containing human dystrophin when injected in nude mice muscles. Several of the human myoblasts did not fuse and remained in interstitial space or tightly associated with muscle fibers suggesting that some of them have formed satellite cells. Moreover, cultures of 98% pure human myoblasts were obtained from transplanted SCID muscles. In some mice where the muscle regeneration was not complete, the muscle fibers containing human dystrophin also expressed uniformly HLA class 1, confirming that the fibers are of human origin. The presence of hybrid muscle fibers containing human dystrophin and mouse MHC was also demonstrated following transplantation. These results establish that in absence of an immune reaction, transplanted human myoblasts participate to the muscle regeneration with a high degree of efficacy even if the animals were killed only 1 mo after the transplantation.

Animals↗

PubMed1996

Identification of human antigenic epitopes in an alanine-rich repeating region using sera from hu-PBL-SCID mice immunized with a surface protein antigen of Streptococcus mutans.

A 190-kDa surface protein antigen (PAc) of Streptococcus mutans is considered to play an important role in dental caries. To identify antigenic epitopes of the PAc in humans, we immunized severe combined immunodeficient (SCID) mice with recombinant PAc that was transplanted with human peripheral blood mononuclear cells (PBMC). The reactivities of the sera from the immunized hu-PBL-SCID mice to the recombinant PAc and 24 19-mer synthetic peptides covering the alanine-rich repeating region (A-region) presented in the PAc molecule were then examined. The results showed that the immunized mice produced a significant recombinant PAc-specific human antibody, and among 24 19-mer peptides, 6 19-mer peptides showed a strong reaction with the antibodies. In addition, 4 19-mer peptides containing human antigenic epitope in a donor were identified with enzyme-linked immunosorbent assay (ELISA) inhibition assays using the recombinant PAc protein. In this study, the SCID mouse was useful in identifying human antigenic epitopes.

Adult↗

PubMed2000

[Modulation of experimental myasthenia gravis by IVIg].

Myasthenia Gravis (MG) is an autoimmune disease mediated by antibodies directed against the acetylcholine receptor (AChR). Treatment by IVIg is effective in acute forms of myasthenia gravis. In order to determine the in vivo effects of the various fractions of human immunoglobulins, we used an experimental model of myasthenia gravis in SCID mice. To this end, thymic cells from MG patients are transferred to these mice according to a well defined protocol. When establishing of the model, we noticed the appearance of anti-AChR antibodies and the loss of AChR expression at the muscle level. After treatment with IVIgG or IVIgM, the mice displayed a lower anti-AChR antibody titer compared to control mice (albumin treated) and the loss of the AChR number at the muscle was significantly reduced. These results obtained from one MG patient indicate that the human immunoglobulin preparations induce significant effects on pathogenic parameters in the SCID mouse model. Therefore this model is interesting to approach the mechanisms of action of human immunoglobulins and deserves further investigation.

Acetylcholine↗

PubMed2006

Characterization of the murine cytomegalovirus m136 gene.

The 230-kbp murine cytomegalovirus (MCMV) genome is predicted to encode 182 open reading frames (orfs). One gene whose functional role is not known is encoded by the 762-bp m136 orf. Sequence analysis of rat cytomegalovirus (RCMV) strains Maastricht and English revealed homologous orfs, pr136, and ORF HJ4, respectively. Conservation of these orfs suggested that m136 and the RCMV homologs might play a role during virus replication. Expression of an epitope tagged form of m136 (m136-V5) yielded a polypeptide of 34 kDa that localized to the perinuclear region of transfected mouse 3T3 fibroblasts. Three independently generated MCMV m136 mutants were isolated and characterized. Mutations were introduced into the m136 orf by inserting either a beta-glucuronidase (m136-beta-gluc) or a guanosine phosphoribosyl transferase (m136-gpt) expression cassette into a unique BglII site, or by inserting a gpt cassette into a deleted region (Deltam136) of m136. No differences were observed in viral yield, plaque size, and plaque morphology between the parental strain and any of the m136 mutant viruses. In vivo analysis using a SCID mouse virulence model showed a consistently measurable attenuated phenotype for all three m136 mutants. The results showed that although the m136 gene was not essential for replication in vitro or in vivo, an intact m136 gene was necessary to yield wild type virulence during infection of the host.

Animals↗

PubMed2001

In vivo antitumor activity of bis(4,7-dimethyl-1,10-phenanthroline) sulfatooxovanadium(IV) (METVAN [VO(SO4)(Me2-Phen)2]).

The compound bis(4,7-dimethyl-1,10-phenanthroline) sulfatooxovanadium(IV) (METVAN [VO(SO4)(Me2-Phen)2]), exhibits potent cytotoxicity against human cancer cells at low micromolar concentrations. At concentrations > or = 1 microM, METVAN treatment was associated with a nearly complete loss of the adhesive, migratory, and invasive properties of the treated tumor cell populations. METVAN did not cause acute or subacute toxicity in mice at dose levels ranging from 12.5 mg/kg to 100 mg/kg. Therapeutic plasma concentrations > or = 5 microM were rapidly achieved and maintained in mice for at least 24 h after i.p. bolus injection of a single 10 mg/kg nontoxic dose of METVAN. At this dose level, the maximum plasma METVAN concentration was 37.0 microM, which was achieved with a t(max) of 21.4 min. Plasma samples (diluted 1:16) from METVAN-treated mice killed 85% of human breast cancer cells in vitro. METVAN was slowly eliminated with an apparent plasma t(1/2) of 17.5 h and systemic clearance of 42.1 ml/h/kg. In accordance with its potent in vitro activity and favorable in vivo pharmacokinetics, METVAN exhibited significant antitumor activity and delayed tumor progression in CB.17 severe combined immunodeficient (SCID) mouse xenograft models of human glioblastoma and breast cancer. In these experiments, METVAN was administered in daily injections of a single nontoxic 10 mg/kg i.p. dose on 5 consecutive days per week for 4 consecutive weeks beginning the day after the s.c. inoculation of U87 glioblastoma or MDA-MB-231 breast cancer cells. At 40 days after the inoculation of tumor cells, the U87 tumor xenografts in the vehicle-treated control SCID mice were much larger than those of the mice treated with METVAN (4560 +/- 654 mm(3) versus 1688 +/- 571 mm(3); P = 0.003). Similarly, the MDA-MB-231 tumors in SCID mice treated with METVAN were much smaller 40 days after tumor cell inoculation than those of the vehicle-treated control SCID mice (174 +/- 29 mm(3) versus 487 +/- 82 mm(3); P = 0.002). The favorable in vivo pharmacodynamic features and antitumor activity of METVAN warrants further development of this novel oxovanadium compound as a potential new anticancer agent.

Animals↗

PubMed1997

In vivo toxicity, pharmacokinetics, and antileukemic activity of TXU (anti-CD7)-pokeweed antiviral protein immunotoxin.

We evaluated the TXU (anti-CD7)-pokeweed antiviral protein (PAP) immunotoxin in both murine and nonhuman primate models. TXU-PAP caused dose-limiting cardiac toxicity in BALB/c mice. In a SCID mouse model of invariably fatal human T-lineage acute lymphoblastic leukemia (ALL), TXU-PAP therapy resulted in a marked improvement of leukemia-free survival without any side effects. Whereas 100% of control mice treated with PBS, unconjugated TXU antibody, or B43-PAP (an immunotoxin that does not react with T-lineage ALL cells) died of disseminated human leukemia within 80 days (median survival, 37 days), 80 +/- 13% of SCID mice treated with 15 microgram of TXU-PAP (median survival, >120 days) and 100% of mice treated with 30 microgram of TXU-PAP (median survival, > 120 days) remained alive and free of leukemia for >120 days. In cynomolgus monkeys, TXU-PAP showed favorable pharmacokinetics with an elimination half-life of 8.1-8.7 h. The monkeys treated with TXU-PAP at dose levels of 0.05 mg/kg/day x 5 days and 0.10 mg/kg/day x 5 days tolerated the therapy very well, without any significant clinical compromise or side effects, and at necropsy, no gross or microscopic lesions were found. This study provides a basis for further evaluation of TXU-PAP as an investigational biotherapeutic agent in the treatment of T-lineage ALL.

Animals↗

PubMed1995

Immunolocalization of hepatic metastases of human colonic cancer by chimeric anti-TAG72 antibody in SCID mice.

TAG72 is a well-characterized, human tumor-associated antigen present in > 85% of human colonic cancers. In this study, we established an animal model of hepatic metastases of human colonic carcinoma. The high-mucin variant cell line, designated HM7, was derived from the human colonic carcinoma cell line LS174T. Following intrasplenic injection, HM7 was able to induce much greater hepatic metastases in SCID mice compared to its parental cell line LS174T. Numerous hepatic metastases were evident 18 days subsequent to the intrasplenic injection of tumor cells. Using the chimeric anti-TAG72 antibody ccM4, immunohistochemistry demonstrated strong expressions of the TAG72 antigen in these metastases. Our biodistribution and imaging data also showed that the radiolabelled ccM4 antibody was able to localize hepatic metastases in the SCID mice. Based upon these findings, w anticipate that the herein described SCID mouse model will prove most useful in studying hepatic metastases of human colonic carcinoma by using anti-TAG72 therapeutic immunoreagents.

Adenocarcinoma↗

PubMed1999

Microglial and astrocyte chemokines regulate monocyte migration through the blood-brain barrier in human immunodeficiency virus-1 encephalitis.

The numbers of immune-activated brain mononuclear phagocytes (MPs) affect the progression of human immunodeficiency virus (HIV)-1-associated dementia (HAD). Such MPs originate, in measure, from a pool of circulating monocytes. To address the mechanism(s) for monocyte penetration across the blood-brain barrier (BBB), we performed cross-validating laboratory, animal model, and human brain tissue investigations into HAD pathogenesis. First, an artificial BBB was constructed in which human brain microvascular endothelial and glial cells-astrocytes, microglia, and/or monocyte-derived macrophages (MDM)-were placed on opposite sides of a matrix-coated porous membrane. Second, a SCID mouse model of HIV-1 encephalitis (HIVE) was used to determine in vivo monocyte blood-to-brain migration. Third, immunohistochemical analyses of human HIVE tissue defined the relationships between astrogliosis, activation of microglia, virus infection, monocyte brain infiltration, and beta-chemokine expression. The results, taken together, showed that HIV-1-infected microglia increased monocyte migration through an artificial BBB 2 to 3.5 times more than replicate numbers of MDM. In the HIVE SCID mice, a marked accumulation of murine MDM was found in areas surrounding virus-infected human microglia but not MDM. For human HIVE, microglial activation and virus infection correlated with astrogliosis, monocyte transendothelial migration, and beta-chemokine expression. Pure cultures of virus-infected and activated microglia or astrocytes exposed to microglial conditioned media produced significant quantities of beta-chemokines. We conclude that microglial activation alone and/or through its interactions with astrocytes induces beta-chemokine-mediated monocyte migration in HAD.

AIDS Dementia Complex↗

PubMed2003

Ex vivo expansion of human hematopoietic stem cells by direct delivery of the HOXB4 homeoprotein.

Expansion of human hematopoietic stem cells (HSCs) is a major challenge in cellular therapy, and currently relies on the use of recombinant cytokines or on gene transfer of transcription factors. Of these, the HOXB4 homeoprotein protein is of particular interests as it promotes the expansion of mouse HSCs without inducing the development of leukemia. To eliminate any deleterious effects that might be associated with stable HOXB4 gene transfer into human cells, we took advantage of the ability of HOX proteins to passively translocate through cell membranes. Here we show that when cultured on stromal cells genetically engineered to secrete HOXB4, human long-term culture-initiating cells (LTC-ICs) and nonobese diabetic-severe combined immunodeficiency (NOD-SCID) mouse repopulating cells (SRCs) were expanded by more than 20- and 2.5-fold, respectively, over their input numbers. This expansion was associated with enhanced stem cell repopulating capacity in vivo and maintenance of pluripotentiality. This method provides a basis for developing cell therapy strategies using expanded HSCs that are not genetically modified.

Animals↗

PubMed1998

Parathyroid hormone-related protein-induced hypercalcemia in SCID mice engrafted with adult T-cell leukemia cells.

Parathyroid hormone-related protein (PTHrP) is considered to be one of the main causes of hypercalcemia associated with adult T-cell leukemia (ATL). To clarify the role of PTHrP and bone remodeling in the development of hypercalcemia in ATL, we examined the SCID mouse model of ATL that has previously been shown to mimic the disease in humans. Using this model, we found clear elevations in serum levels of calcium and C-terminal PTHrP (C-PTHrP). PTHrP mRNA was highly expressed in ATL cells proliferating in vivo. After the development of hypercalcemia, ATL mice were killed and bone histomorphometric analysis was performed. Bone volume was clearly decreased in the ATL mice. In comparison to control SCID mice, bone formation indices were very low in the ATL mice. Surprisingly, no significant difference was detected between the ATL mice and the control SCID mice in eroded surface/bone surface (ES/BS), a parameter of bone resorption. To our knowledge, the model presented here is the first animal model of ATL with humoral hypercalcemia. This is in contrast to previously reported, well-characterized animal models of human solid tumors associated with humoral hypercalcemia of malignancy (HHM). Furthermore, this model not only provides us with the opportunity to study the mechanisms underlying development of elevated calcium levels in ATL, but also allows us to test new therapeutic agents designed to treat hypercalcemia.

Animals↗

PubMed2006

Oncolytic viral therapy by bladder instillation using an E1A, E1B double-restricted adenovirus in an orthotopic bladder cancer model.

OBJECTIVES: To investigate the therapeutic effect of AxdAdB-3, a double-restricted oncolytic adenovirus harboring a mutant E1A and an E1B-55KD deletion, on human bladder cancer cell lines and the SCID mouse model of orthotopic bladder cancer. METHODS: The cytopathic effects of AxdAdB-3 were evaluated in several cell lines (YTS-1, YTS-3, T24, J82, 5637) derived from human bladder or ureteral cancer and in a normal bladder mucosa-derived cell line (HCV29) with AxCAlacZ (control) or AxE1AdB (E1B-55KD-defective adenovirus) or dl922-947 (E1A-mutated adenovirus). The efficacy of bladder instillation therapy with AxdAdB-3 for orthotopic bladder cancer of SCID mice was investigated. The oncolytic effects were monitored by ultrasound examination. RESULTS: AxdAdB-3 caused the oncolysis of bladder cancer cell lines in vitro, and it was more cytopathic than AxE1AdB or dl922-947 in the cancer cell lines. AxdAdB-3 was not cytotoxic against HCV29. Direct instillation of AxdAdB-3 into the bladder of the orthotopic model inhibited tumor growth, leading to significantly prolonged survival. CONCLUSIONS: Oncolytic viral therapy delivered by instillation of AxdAdB-3 is a promising tool for treating bladder cancer.

Adenoviridae↗

PubMed1994

Gene transfer to human fetal pulmonary tissue developed in immunodeficient SCID mice.

Human fetal lung rudiments (8-12 weeks of development) undergo considerable growth upon microsurgical ectopic implantation in the xenograft-tolerant SCID mouse, and differentiate into a lung-like tissue that includes: (i) bronchial structures lined with pseudostratified, secretory, ciliated epithelium surrounded by smooth muscle and cartilage rings, (ii) submucosal glands, and (iii) alveolar sacs. Normal expression of the cystic fibrosis transmembrane conductance regulator (CFTR) protein was detected by immunostaining in those grafts, and similar differentiation was observed from either normal or cystic fibrosis (CF) fetal lung rudiments. Upon microinjection into human CF or normal lung grafts in SCID mice, beta-galactosidase-adenovirus gene constructs were efficiently transduced into epithelial and glandular cells. Such an in vivo replica of the human respiratory tissue may be a useful experimental model to study normal and pathologic lung development, and to assay candidate therapeutic gene constructs preclinically.

Adenoviridae↗