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Biomedical subjects

M Ling

Publications and source records attributed to M Ling.

At least 19 recordsLinked to original sources
PubMed2001

Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.

BACKGROUND: A sustained virological response (SVR) rate of 41% has been achieved with interferon alfa-2b plus ribavirin therapy of chronic hepatitis C. In this randomised trial, peginterferon alfa-2b plus ribavirin was compared with interferon alfa-2b plus ribavirin. METHODS: 1530 patients with chronic hepatitis C were assigned interferon alfa-2b (3 MU subcutaneously three times per week) plus ribavirin 1000-1200 mg/day orally, peginterferon alfa-2b 1.5 microg/kg each week plus 800 mg/day ribavirin, or peginterferon alfa-2b 1.5 microg/kg per week for 4 weeks then 0.5 microg/kg per week plus ribavirin 1000-1200 mg/day for 48 weeks. The primary endpoint was the SVR rate (undetectable hepatitis C virus [HCV] RNA in serum at 24-week follow-up). Analyses were based on patients who received at least one dose of study medication. FINDINGS: The SVR rate was significantly higher (p=0.01 for both comparisons) in the higher-dose peginterferon group (274/511 [54%]) than in the lower-dose peginterferon (244/514 [47%]) or interferon (235/505 [47%]) groups. Among patients with HCV genotype 1 infection, the corresponding SVR rates were 42% (145/348), 34% (118/349), and 33% (114/343). The rate for patients with genotype 2 and 3 infections was about 80% for all treatment groups. Secondary analyses identified bodyweight as an important predictor of SVR, prompting comparison of the interferon regimens after adjusting ribavirin for bodyweight (mg/kg). Side-effect profiles were similar between the treatment groups. INTERPRETATION: In patients with chronic hepatitis C, the most effective therapy is the combination of peginterferon alfa-2b 1.5 microg/kg per week plus ribavirin. The benefit is mostly achieved in patients with HCV genotype 1 infections.

Adult↗
PubMed2001

Enhancement of Sindbis virus self-replicating RNA vaccine potency by linkage of Mycobacterium tuberculosis heat shock protein 70 gene to an antigen gene.

Recently, self-replicating RNA vaccines (RNA replicons) have emerged as an effective strategy for nucleic acid vaccine development. Unlike naked DNA vaccines, RNA replicons eventually cause lysis of transfected cells and therefore do not raise the concern of integration into the host genome. We evaluated the effect of linking human papillomavirus type 16 E7 as a model Ag to Mycobacterium tuberculosis heat shock protein 70 (HSP70) on the potency of Ag-specific immunity generated by a Sindbis virus self-replicating RNA vector, SINrep5. Our results indicated that this RNA replicon vaccine containing an E7/HSP70 fusion gene generated significantly higher E7-specific T cell-mediated immune responses in vaccinated mice than did vaccines containing the wild-type E7 gene. Furthermore, our in vitro studies demonstrated that E7 Ag from E7/HSP70 RNA replicon-transfected cells can be processed by bone marrow-derived dendritic cells and presented more efficiently through the MHC class I pathway than can wild-type E7 RNA replicon-transfected cells. More importantly, the fusion of HSP70 to E7 converted a less effective vaccine into one with significant potency against E7-expressing tumors. This antitumor effect was dependent on NK cells and CD8(+) T cells. These results indicated that fusion of HSP70 to an Ag gene may greatly enhance the potency of self-replicating RNA vaccines.

Adjuvants, Immunologic↗
PubMed2001

Improving vaccine potency through intercellular spreading and enhanced MHC class I presentation of antigen.

The potency of naked DNA vaccines is limited by their inability to amplify and spread in vivo. VP22, a HSV-1 protein, has demonstrated the remarkable property of intercellular transport and may thus provide a unique approach for enhancing vaccine potency. Therefore, we created a novel fusion of VP22 with a model Ag, human papillomavirus type 16 E7, in a DNA vaccine that generated enhanced spreading and MHC class I presentation of AG: These properties led to a dramatic increase in the number of E7-specific CD8(+) T cell precursors in vaccinated mice (around 50-fold) and converted a less effective DNA vaccine into one with significant potency against E7-expressing tumors. In comparison, nonspreading VP22(1-267) mutants failed to enhance vaccine potency. Our data indicated that the potency of DNA vaccines may be dramatically improved through intercellular spreading and enhanced MHC class I presentation of Ag.

Adjuvants, Immunologic↗
PubMed2001

Cancer immunotherapy using a DNA vaccine encoding the translocation domain of a bacterial toxin linked to a tumor antigen.

Certain domains of bacterial toxins have been shown to facilitate translocation from extracellular and vesicular compartments into the cytoplasm. This feature represents an opportunity to enhance class I presentation of exogenous antigen to CD8(+) T cells. We investigated this notion by creating a novel fusion of the translocation domain (domain II) of Pseudomonas aeruginosa exotoxin A (ETA(dII)) with a model tumor antigen, human papillomavirus type 16 E7, in the context of a DNA vaccine. Our in vitro studies indicated that cells transfected with ETA(dII)/E7 DNA or dendritic cells pulsed with lysates containing ETA(dII)/E7 protein exhibited enhanced MHC class I presentation of E7 antigen. Vaccination of mice with ETA(dII)/E7 DNA generated a dramatic increase in the number of E7-specific CD8(+) T cell precursors ( approximately 30-fold compared with wild-type E7 DNA) and converted a less effective DNA vaccine into one with significant potency against human papillomavirus type 16 E7-expressing murine tumors via a CD8-dependent pathway. These results indicate that fusion of the translocation domain of a bacterial toxin to an antigen may greatly enhance vaccine potency.

ADP Ribose Transferases↗
PubMed2001

Enhancement of sindbis virus self-replicating RNA vaccine potency by targeting antigen to endosomal/lysosomal compartments.

Self-replicating RNA vaccines (RNA replicons) have emerged as an attractive approach for tumor immunotherapy. RNA replicons do not integrate into host chromosomes, eliminating the concern for oncogenicity associated with a DNA vaccine. In this study, we used human papillomavirus type 16 (HPV-16) E7 as a model antigen and evaluated E7-specific immunity generated by a Sindbis virus self-replicating RNA vector, SIN-rep5. Three different constructs were created to target E7 antigen to different cellular localizations: (1) E7, a cytosolic/nuclear protein; (2) Sig/E7, a secretory protein; (3) Sig/E7/LAMP-1, in which we linked the transmembrane and cytoplasmic regions of the lysosome-associated membrane protein 1 (LAMP-1) to E7 protein to target E7 to the endosomal/lysosomal compartment. We found that the RNA replicon vaccine containing the Sig/E7/LAMP-1 fusion gene generated the highest E7-specific T cell-mediated immune responses and antitumor effects relative to RNA vaccines containing either wild-type E7 or Sig/E7. Our in vitro studies demonstrated that E7 antigen from Sig/E7/LAMP-1 RNA replicon-transfected apoptotic cells can be taken up by bone marrow-derived dendritic cells (DCs) and presented more efficiently through the MHC class I pathway than wild-type E7 RNA replicon-transfected apoptotic cells. Furthermore, our data revealed that CD8(+) T cells, CD4(+) T cells, and NK cells were important for the antitumor effects generated by Sig/E7/LAMP-1 RNA vaccination. These results indicate that targeting antigen to the endosomal/lysosomal compartment via fusion to LAMP-1 may greatly enhance the potency of self-replicating RNA vaccines.

Animals↗
PubMed2001

Enhancement of DNA vaccine potency by linkage of antigen gene to a gene encoding the extracellular domain of Fms-like tyrosine kinase 3-ligand.

Recently, Flt3 (Fms-like tyrosine kinase 3)-ligand has been identified as an important cytokine for the generation of professional antigen-presenting cells (APCs), particularly dendritic cells (DCs). A recombinant chimera of the extracellular domain of Flt3-ligand (FL) linked to a model antigen may potentially target the antigen to DCs and their precursor cells. Using human papillomavirus-16 E7 as a model antigen, we evaluated the effect of linkage to FL on the potency of antigen-specific immunity generated by naked DNA vaccines administered intradermally via gene gun. We found that vaccines containing chimeric FL-E7 fusion genes significantly increased the frequency of E7-specific CD8+ T cells relative to vaccines containing the wild-type E7 gene. In vitro studies indicated that cells transfected with FL-E7 DNA presented E7 antigen through the MHC class I pathway more efficiently than wild-type E7 DNA. Furthermore, bone marrow-derived DCs pulsed with cell lysates containing FL-E7 fusion protein presented E7 antigen through the MHC class I pathway more efficiently than DCs pulsed with cell lysates containing wild-type E7 protein. More importantly, this fusion converted a less effective vaccine into one with significant potency against established E7-expressing metastatic tumors. The FL-E7 fusion vaccine mainly targeted CD8+ T cells, and antitumor effects were completely CD4 independent. These results indicate that fusion of a gene encoding the extracellular domain of FL to an antigen gene may greatly enhance the potency of DNA vaccines via CD8-dependent pathways.

Animals↗
PubMed2001

Recombinant DNA vaccines protect against tumors that are resistant to recombinant vaccinia vaccines containing the same gene.

Antigen-specific cancer immunotherapy involves the delivery of tumor-associated antigen to the host for the generation of tumor-specific immune responses and antitumor effects. We hypothesized that different delivery systems may influence the pattern of antigen-specific immune response and the outcome of antitumor effect. We therefore evaluated recombinant vaccinia virus and naked DNA for the generation of antigen-specific immune responses and antitumor effects. We previously found that recombinant vaccinia and naked DNA vaccines containing the chimeric Sig/E7/LAMP-1 gene were capable of controlling the growth of HPV-16 E7-expressing tumor cells (TC-1). In this study, we performed a head-to-head comparison of optimized delivery of Sig/E7/LAMP-1 vaccinia and DNA vaccines using dose-escalating tumor challenge. At a dose of 1 x 10(6) TC-1 cells per mouse, Sig/E7/LAMP-1 DNA provided 100% protection against subcutaneous growth of tumors, while Vac-Sig/E7/LAMP-1 protected only 40% of the mice. Furthermore, Sig/E7/LAMP-1 DNA vaccines are capable of protecting against challenge with a more stringent subclone of TC-1 (TC-1 P2) established from TC-1 tumors that survived initial Sig/E7/LAMP-1 vaccinia vaccination. Immunological assays revealed that both vaccines induced comparable levels of CD8(+) T cell precursors and anti-E7 antibody titers. Interestingly, Sig/E7/LAMP-1 vaccinia induced both E7-specific IFN-gamma- and IL4-secreting CD4(+) T cell precursors while Sig/E7/LAMP-1 DNA induced only E7-specific IFN-gamma-secreting CD4(+) T cell precursors. We also found that IL-4 knockout C57BL/6 mice vaccinated with Sig/E7/LAMP-1 vaccinia exhibited a more potent antitumor effect than vaccinated wild-type C57BL/6 mice in our tumor protection experiments. These results suggest that IL-4 may play a detrimental role in the antitumor effect mediated by vaccinia vaccines. Our findings suggested that DNA vaccines may provide better tumor protection than vaccinia vaccines employing the same gene, which may have implications in the future design of antigen-specific cancer immunotherapy.

Animals↗
PubMed2001

Enhancement of suicidal DNA vaccine potency by linking Mycobacterium tuberculosis heat shock protein 70 to an antigen.

Naked DNA vaccines represent an attractive approach for generating antigen-specific immunity because of their stability and simplicity of delivery. There are particular concerns with DNA vaccines however, such as potential integration into the host genome, cell transformation, and limited potency. The usage of DNA-based alphaviral RNA replicons (suicidal DNA vectors) may alleviate the concerns of integration or transformation since suicidal DNA vectors eventually cause lysis of transfected cells. To improve further the potency of suicidal DNA vaccines, we evaluated the effect of linking Mycobacterium tuberculosis heat shock protein 70 (Hsp70) to human papillomavirus type 16 (HPV-16) E7 as a model antigen on antigen-specific immunity generated by a DNA-based Semliki Forest virus (SFV) RNA vector, pSCA1. Our results indicated that this suicidal DNA vaccine containing E7/Hsp70 fusion genes generated significantly higher E7-specific T cell-mediated immune responses than vaccines containing the wild-type E7 gene in vaccinated mice. More importantly, this fusion converted a less effective vaccine into one with significant potency against established E7-expressing metastatic tumors. The antitumor effect was predominantly CD8-dependent. These results indicate that linkage of Hsp70 to the antigen may greatly enhance the potency of suicidal DNA vaccines.

Animals↗
PubMed2001

Classification of the kinetics of factor VIII inhibitors in haemophilia A: plasma dilution studies are more discriminatory than time-course studies.

Factor VIII inhibitors have previously been classified as type I or type II using complex experiments that study the time course of inactivation of factor VIII and the effect of varying the antibody concentration. Classification may be important to better understand inhibitor behaviour in vivo. To determine the most reliable method of classifying the kinetics of factor VIII inactivation, we studied 11 patients with haemophilia A, comprising five severe, three mild and three acquired cases, and compared the classification obtained from plasma dilution studies and time-course studies. The plasma dilution studies showed two distinctly different patterns: a steep slope with complete FVIII:C inactivation at high antibody concentrations for type I inhibitors and a FVIII:C plateau with incomplete inactivation for type II inhibitors. Six type I (four severe, one mild and one acquired) and two type II (one mild and one acquired) inhibitors were classified using either plasma samples or purified and concentrated IgG, while the remaining were undetermined owing to insufficient available plasma. In contrast, the time-course studies could not discriminate between these groups. We recommend that plasma dilution studies be used for the classification of in vitro kinetics of factor VIII inhibitors.

Adult↗
PubMed2001

[Experimental study on the influence of alginate induced immune complex on BALF cells].

Immune complex containing alginate and antialginate antibodies plays an important role in the disease-progress of chronic airway infection with mucoid-alginate producing strains. For the purpose of clarifying the immune-pathogenic influence of the alginate induced immune complex (alg-IC) on inflammatory cells in bronchoalveolar lavage fluid (BALF), an experimental study was performed. The alginate immunized mice were injected through the trachea with alg-IC extracted from the immunized mouse serum in advance, and the changes in BALF-cells, such as macrophage, neutrophil, lymphocyte, CD16/32 positive neutrophil, CD4+ lymphocyte, CD4+CD45+ lymphocyte, CD8+ lymphocyte, CD8+CD11b- lymphocyte were investigated along with the passage of time as compared with those of the non-immunized mice. 1) On the 2nd day after intratracheal injection, the time which was chosen as an acute phase, the total count of macrophages, neutrophils, lymphocytes were increased in both groups. However CD16/32 positive neutrophil (with the expression of Fc-gamma recepter on it) was significantly decreased in the immunized group. 2) On the 5th day being chosen as the resolving phase of acute inflammation, the number of the increased inflammatory cells tended to recover to the base line value in both groups. But the continuous decrease in CD16/32 positive cell and the significant increase in CD4+CD45+ lymphocytes were found in only the immunized group. 3) On the 16th day being chosen as the beginning of the chronic phase, all inflammatory cells investigated in the non-immunized group recovered to the base line level. In the immunized group, however, significantly higher values of neutrophil-count still remained, in spite of the decrease in CD 16/32 positive neutrophils. Also, CD4+CD45+, CD8+, CD8+CD11b- lymphocytes were significantly at a higher level. 4) Histological findings in the lung tissue was supported the above findings. 5) From the above, in the alginate immunized group, the scavenging function of neutrophils for the alg-IC deposited in lung tissue would be suppressed resulting from the decrease in CD16/32 positive neutrophils, in spite of the increase in total count of neutrophils. Consequently, long term deposition of alg-IC in the lung would induce an accumulation of cytotoxic CD8+ T lymphocyte or other lymphocytes as one of the cell-mediated immune responses. This indicates that such a harmful immune reaction induced by alg-IC leads the chronic infection with mucoid-alginate producing pathogens to be more intractable.

Alginates↗
PubMed2001

Enhancement of sindbis virus self-replicating RNA vaccine potency by linkage of herpes simplex virus type 1 VP22 protein to antigen.

Recently, self-replicating and self-limiting RNA vaccines (RNA replicons) have emerged as an important form of nucleic acid vaccines. Self-replicating RNA eventually causes lysis of transfected cells and does not raise the concern associated with naked DNA vaccines of integration into the host genome. This is particularly important for development of vaccines targeting proteins that are potentially oncogenic. However, the potency of RNA replicons is significantly limited by their lack of intrinsic ability to spread in vivo. The herpes simplex virus type 1 protein VP22 has demonstrated the remarkable property of intercellular transport and provides the opportunity to enhance RNA replicon vaccine potency. We therefore created a novel fusion of VP22 with a model tumor antigen, human papillomavirus type 16 E7, in a Sindbis virus RNA replicon vector. The linkage of VP22 with E7 resulted in a significant enhancement of E7-specific CD8+ T-cell activities in vaccinated mice and converted a less effective RNA replicon vaccine into one with significant potency against E7-expressing tumors. These results indicate that fusion of VP22 to an antigen gene may greatly enhance the potency of RNA replicon vaccines.

Animals↗
PubMed2001

Tumor-specific immunity and antiangiogenesis generated by a DNA vaccine encoding calreticulin linked to a tumor antigen.

Antigen-specific cancer immunotherapy and antiangiogenesis have emerged as two attractive strategies for cancer treatment. An innovative approach that combines both mechanisms will likely generate the most potent antitumor effect. We tested this approach using calreticulin (CRT), which has demonstrated the ability to enhance MHC class I presentation and exhibit an antiangiogenic effect. We explored the linkage of CRT to a model tumor antigen, human papilloma virus type-16 (HPV-16) E7, for the development of a DNA vaccine. We found that C57BL/6 mice vaccinated intradermally with CRT/E7 DNA exhibited a dramatic increase in E7-specific CD8(+) T cell precursors and an impressive antitumor effect against E7-expressing tumors compared with mice vaccinated with wild-type E7 DNA or CRT DNA. Vaccination of CD4/CD8 double-depleted C57BL/6 mice and immunocompromised (BALB/c nu/nu) mice with CRT/E7 DNA or CRT DNA generated significant reduction of lung tumor nodules compared with wild-type E7 DNA, suggesting that antiangiogenesis may have contributed to the antitumor effect. Examination of microvessel density in lung tumor nodules and an in vivo angiogenesis assay further confirmed the antiangiogenic effect generated by CRT/E7 and CRT. Thus, cancer therapy using CRT linked to a tumor antigen holds promise for treating tumors by combining antigen-specific immunotherapy and antiangiogenesis.

Animals↗
PubMed2001

Recombinant single chain cardiac troponin I-C polypeptides: superior calibration and control materials for cardiac troponin I immunoassays.

There has been a need to create stable and reproducible calibration and control materials for cardiac troponin I assays. Free troponin I, native or recombinant, has been known to be unstable, while troponin CI complex can be easily dissociated in low concentrations or in the presence of chelating agents. In order to overcome these difficulties, two single chain troponin I-C polypeptides have been engineered and expressed separately in Escherichia coli. One consists of a full-length of human cardiac troponin I and C, termed as ScTnI-C and the other consists of a stable fragment (aa28-110) of human cardiac troponin I and a full-length troponin C, termed as ScTnI-C-2. Both ScTnI-C and ScTnI-C-2 were purified to homogeneity by affinity chromatography using anti-cTnI monoclonal antibodies. ScTnI-C and ScTnI-C-2 have apparent molecular weights of 45 kD and 30 kD by SDS-PAGE, respectively. Stability studies by Stratus showed that ScTn I-C and ScTnI-C-2 were stable for 4 months at 2-8 degrees C and at least one year at -20 degrees C. When incubated in human serum at 37 degrees C, ScTnI-C-2 was more resistant to proteolysis than ScTnI-C. ScTnI-C can be recognized by all commercial TnI immunoassays with excellent activity. ScTnI-C-2 can be recognized by all immunoassays that target the stable region of cardiac troponin I. Judging by their performances, ScTnI-C and ScTnI-C-2 are both superior materials to be used as calibrators and controls in clinical laboratories.

Antibodies, Monoclonal↗
PubMed2001

Efficacy and tolerability of once-daily tazarotene 0.1% gel versus once-daily tretinoin 0.025% gel in the treatment of facial acne vulgaris: a randomized trial.

Tazarotene 0.1% gel and tretinoin 0.025% gel are both effective in the treatment of acne vulgaris. Results of a multicenter, double-blind, randomized, parallel-group study that compared the efficacy and tolerability of these drugs are presented here. A total of 143 patients with mild-to-moderate facial acne vulgaris were randomized to receive tazarotene 0.1% gel or tretinoin 0.025% gel once daily for 12 weeks. Tazarotene 0.1% gel was more effective than tretinoin 0.025% gel in reducing the open comedo count (P < or = .05), the total noninflammatory lesion count (P < or = .05), and the total inflammatory lesion count (not statistically significant). At some time points, tazarotene was associated with increased irritation, but peeling, erythema, dryness, burning, and itching never exceeded trace levels. We conclude that tazarotene 0.1% gel is more effective than tretinoin 0.025% gel in reducing noninflammatory lesions and similarly effective in reducing inflammatory lesions.

Acne Vulgaris↗
PubMed2000

Requirement of the chemokine receptor CXCR3 for acute allograft rejection.

Chemokines provide signals for activation and recruitment of effector cells into sites of inflammation, acting via specific G protein-coupled receptors. However, in vitro data demonstrating the presence of multiple ligands for a given chemokine receptor, and often multiple receptors for a given chemokine, have led to concerns of biologic redundancy. Here we show that acute cardiac allograft rejection is accompanied by progressive intragraft production of the chemokines interferon (IFN)-gamma-inducible protein of 10 kD (IP-10), monokine induced by IFN-gamma (Mig), and IFN-inducible T cell alpha chemoattractant (I-TAC), and by infiltration of activated T cells bearing the corresponding chemokine receptor, CXCR3. We used three in vivo models to demonstrate a role for CXCR3 in the development of transplant rejection. First, CXCR3-deficient (CXCR3(-/)-) mice showed profound resistance to development of acute allograft rejection. Second, CXCR3(-/)- allograft recipients treated with a brief, subtherapeutic course of cyclosporin A maintained their allografts permanently and without evidence of chronic rejection. Third, CXCR(+/+) mice treated with an anti-CXCR3 monoclonal antibody showed prolongation of allograft survival, even if begun after the onset of rejection. Taken in conjunction with our findings of CXCR3 expression in rejecting human cardiac allografts, we conclude that CXCR3 plays a key role in T cell activation, recruitment, and allograft destruction.

Acute Disease↗
PubMed2000

Effects of administration of a single dose of a humanized monoclonal antibody to CD11a on the immunobiology and clinical activity of psoriasis.

BACKGROUND: CD11a/CD18 comprise subunits of leukocyte function associated antigen (LFA-1), a T-cell surface molecule important in T-cell activation, T-cell emigration into skin, and cytotoxic T-cell function. OBJECTIVE: We explored the immunobiologic and clinical effects of treating moderate to severe psoriasis vulgaris with a single dose of humanized monoclonal antibody against CD11a (hu1124). METHODS: This was an open label study with a single dose of hu1124 at doses of 0.03 to 10 mg/kg. Clinical (Psoriasis Area and Severity Index [PASI]) and immunohistologic parameters (epidermal thickness, epidermal and dermal T-cell numbers, and keratinocyte intercellular adhesion molecule 1 [ICAM-1] expression) were followed. RESULTS: Treatment with hu1124, at doses higher than 1.0 mg/kg (group III), completely blocks CD11a staining for at least 14 days in both blood and psoriatic plaques. At 0.3 to 1.0 mg/kg, T-cell CD11a staining was completely blocked; however, blockade lasted less than 2 weeks (group II). Only partial saturation of either blood or plaque cellular CD11a was observed at doses of hu1124 between 0.01 and 0.1 mg/kg (group I). This pharmacodynamic response was accompanied by decreased numbers of epidermal and dermal CD3(+) T cells, decreased keratinocyte and blood vessel expression of ICAM-1, and epidermal thinning. Statistically significant drops in PASI compared with baseline were observed in group II patients at weeks 3 and 4 and in group III patients at weeks 2 through 10. No significant drop in PASI score was observed in group 1. Adverse events were mild at doses of 0.3 mg/kg or less and included mild chills, abdominal discomfort, headache, and fever. At a single dose of 0.6 mg/kg or higher, headache was the most common dose-limiting toxicity observed. CONCLUSION: Targeting CD11a may improve psoriasis by inhibiting T-cell activation, T-cell emigration into the skin, and cytotoxic T-cell function.

Antibodies, Monoclonal↗
PubMed2000

Intramuscular administration of E7-transfected dendritic cells generates the most potent E7-specific anti-tumor immunity.

Dendritic cells (DCs) are highly efficient antigen-presenting cells capable of priming both cytotoxic and helper T cells in vivo. Recent studies have demonstrated the potential use of DCs that are modified to carry tumor-specific antigens in cancer vaccines. However, the optimal administration route of DC-based vaccines to generate the greatest anti-tumor effect remains to be determined. This study is aimed at comparing the levels of immune responses and anti-tumor effect generated through different administration routes of DC-based vaccination. We chose the E7 gene product of human papillomavirus (HPV) as the model antigen and generated a stable DC line (designated as DC-E7) that constitutively expresses the E7 gene. Among the three different routes of DC-E7 vaccine administration in a murine model, we found that intramuscular administration generated the greatest anti-tumor immunity compared with subcutaneous and intravenous routes of administration. Furthermore, intramuscular administration of DC-E7 elicited the highest levels of E7-specific antibody and greatest numbers of E7-specific CD4+ T helper and CD8+ T cell precursors. Our results indicate that the potency of DC-based vaccines depends on the specific route of administration and that intramuscular administration of E7-transfected DCs generates the most potent E7-specific anti-tumor immunity.

Animals↗