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Jim Xiang

Publications and source records attributed to Jim Xiang.

At least 55 records · Page 3Linked to original sources
PubMed2004

Engineered fusion hybrid vaccine of IL-18 gene-modified tumor cells and dendritic cells induces enhanced antitumor immunity.

Dendritic cell (DC)-tumor fusion hybrid vaccines that facilitate antigen presentation represent a novel powerful strategy in cancer immunotherapy. In our study, we investigated the antitumor immunity derived from the vaccination of fusion hybrids between engineered J558/IL-18 myeloma cells secreting Th1 cytokine IL-18 and DCs. DC/J558/IL-18 could secret a higher level of IL-18 than DCs, efficiently expressed J558 tumor antigen P1A, and enhanced ability of allogeneic T cell stimulation when compared to J558/IL-18. Our data showed that the immunization of BALB/c mice with DC/J558/IL-18 hybrids induced the most potent protective immunity against 1 x 10(6) cells with a J558 tumor challenge, compared to those immunized with the mixture of DCs and J558/IL-18, J558/IL-18, or J558. Furthermore, the immunization of mice with engineered DC/J558/IL-18 hybrids elicited stronger NK activity and J558 tumor-specific cytotoxic T lymphocyte (CTL) responses in vitro. In addition, DC/J558/IL-18 tumor cells into syngeneic mice induced a Th1 dominant immune response to J558 and resulted in tumor regression, which indicated that the antitumor effect mediated by DC/J558/IL-18 appeared to be dependent on TH1 cytokine production. These results demonstrate that the engineered fusion hybrid vaccines that combine Th1 gene-modified tumor with DCs may be an attractive strategy for cancer immunotherapy.

Animals↗
PubMed2004

Enhanced antitumor immunity derived from a novel vaccine of fusion hybrid between dendritic and engineered myeloma cells.

AIM: Dendritic cell-tumor cell fusion hybrid vaccines which facilitate antigen presentation represent a new powerful strategy in cancer immunotherapy. The clinical frequency of objective responses to the conventional fusion hybrid vaccines is still quite low, indicating that the current conventional protocol of simply fusing dendritic cells (DCs) and tumor cells needs further improvement to enhance its antitumor efficiency. METHODS: In the present study, we generated a novel fusion hybrid DC/J558(CD40L) by fusing DCs and an engineered J558(CD40L) myeloma cells expressing CD40 ligand (CD40L) molecule using polyethylene glycol (PEG). The fusion efficiency was approximately 20%. We investigated the antitumor immunity derived from vaccination of the fusion hybrid DC/J558(CD40L). RESULTS: Our results showed that vaccination of mice with DC/J558(CD40L) hybrids induced more efficient cytotoxic T lymphocyte (CTL) responses and protective immunity against J558 tumor cells, than that of the conventional fusion hybrid DC/J558 from the fusion of DCs and J558 tumor cells. The antitumor immunity derived from vaccination of DC/J558(CD40L) was mainly mediated by CD4(+) and CD(8+)cT cells, but not natural killer (NK) cells. CONCLUSION: Therefore, this novel fusion hybrid vaccine which combines gene-modified tumor and DC vaccines may be an attractive strategy for cancer immunotherapy.

Animals↗
PubMed2003

CpG-containing oligodeoxynucleotide 1826 converts the weak uveitogenic rat interphotoreceptor retinoid-binding protein peptide 1181-1191 into a strong uveitogen.

Aberrant activation of autoreactive T cells is one of the major causes of autoimmune disease. Autoantigens are sequestered and in many cases weak immunogens. For example, in experimental autoimmune uveitis, immunization of naive rats with autologous interphotoreceptor retinoid-binding protein (IRBP) fails to induce intraocular inflammation or a strong T cell response, whereas bovine IRBP is a strong inducer of experimental autoimmune uveitis. Such observations challenge the view that the autoantigen alone is responsible for the development of autoimmunity. Here, we demonstrate that autologous rat IRBP is converted to a strong immunogen in the presence of a small dose of CpG-containing oligodeoxynucleotides. Our results indicate that specific CpG-containing oligodeoxynucleotides may play an important role in the activation and expansion of autoreactive T cells in vivo, leading to autoimmune disease.

Adjuvants, Immunologic↗
PubMed2003

Dendritic cells engineered to express the Flt3 ligand stimulate type I immune response, and induce enhanced cytoxic T and natural killer cell cytotoxicities and antitumor immunity.

BACKGROUND: Tumor antigen presentation by dendritic cells (DCs) to T cells in lymphoid organs is crucial for induction of antitumor immune responses. Fms-like tyrosine kinase 3 ligand (Flt3L) is a regulator of hematopoietic cell development. METHODS: To investigate the potential effect of Flt3L transgene expression on DC-based cancer vaccines, we constructed a recombinant adenovirus AdVFlt3L expressing Flt3L, transfected DCs with AdVFlt3L, and investigated the efficacy of antitumor immunity by vaccination of DC(Flt3L) engineered to express Flt3L transgene. RESULTS: Our data demonstrated that AdVFlt3L transfection up-regulated the expression of cytokine IL-1beta and chemokines MIP-1alpha, MIP-1beta, IP-10, MCP-1 and MIP-2, and stimulated DC(Flt3L) cell proliferation in vitro and migration toward regional lymph nodes in vivo. Our data also demonstrated that vaccination of Mut1-pulsed DC(Flt3L) cells was able to stimulate (i). a type 1 immune response comprising CD4(+) Th1 and CD8(+) Tc1 activation and (ii). around 2- and 3-fold enhanced tumor-specific cytotoxic T lymphocyte (CTL) and non-specific NK responses (p < 0.05) than vaccination with similarly pulsed control virus-transfected and untransfected DCs, respectively. More importantly, vaccination of Mut1-pulsed DC(Flt3L) cells induced enhanced antitumor immunity in vivo, even against poorly immunogenic 3LL tumor cells. Vaccinations of Mut1-pulsed DCs, DC(pLpA) and DC(Flt3L) all protected mice from challenge of low dose (0.5 x 10(5)) tumor cells. However, only vaccination of the last one was able to protect 63% (6/8) mice from challenge of high dose (3 x 10(5)) 3LL tumor cells (p < 0.01). CONCLUSIONS: DCs engineered to secrete Flt3L may offer a new strategy in DC-based cancer vaccines.

Adenoviridae↗
PubMed2003

Tumour necrosis factor-alpha (TNF-alpha) transgene-expressing dendritic cells (DCs) undergo augmented cellular maturation and induce more robust T-cell activation and anti-tumour immunity than DCs generated in recombinant TNF-alpha.

Tumour antigen presentation by dendritic cells (DCs) to T cells in lymphoid organs is crucial for induction of anti-tumour immune responses. It has been previously reported that tumour necrosis factor-alpha (TNF-alpha) is required for DC activation and subsequent induction of optimal immune responses, and thus DCs for anti-tumour vaccination are often generated by culture in exogenous TNF-alpha. In the present study, we investigated the effect on anti-tumour immunity of vaccination with Mut1 tumour peptide-pulsed DCs engineered to express a TNF-alpha transgene. Our data shows that transfection of DCs with recombinant adenovirus AdV-TNF-alpha resulted in greater maturation of the DCs than occurred with control DCs cultured in exogenous TNF-alpha, as determined by up-regulated expression of pro-inflammatory cytokines (e.g. interleukins 1beta and 18), chemokines [e.g. interferon-gamma-inducible protein-10 and macrophage inflammatory protein-1beta (MIP-1beta)], the CC chemokine receptor CCR7, and immunologically important cell surface molecules (CD40, CD86 and intercellular adhesion molecule-1). These transgenic DCs stimulated stronger allogeneic T-cell responses in vitro and T-cell activation in vivo; displayed 2.4-fold enhanced chemotactic responses to the MIP-3betain vitro (P<0.05); and, perhaps most importantly, trafficked into the draining lymph nodes dramatically (seven-fold, P<0.01) more efficiently than the control DCs. Our data also demonstrate that vaccination of mice with Mut1 peptide-pulsed, AdV-TNF-alpha-transfected DCs stimulated more efficient in vitro Mut1-specific CD8+ cytotoxic T-cell responses and solid tumour immunity in vivo, when compared to the in vitro TNF-alpha-cultivated DCs. Thus, DCs engineered to secrete TNF-alpha may offer a new strategy in DC cancer vaccines.

Adenoviridae↗
PubMed2003

Mapping protein: carbohydrate interactions.

Many biologically important interactions occur between proteins and carbohydrates. The examination of these interactions at the atomic level is critical not only in understanding the nature of these interactions and their biological role, but also in the design of effective modulators of these interactions. While experimentally obtained structural information is preferred, quite often this information is unavailable. In order to address this, several methods have been developed to probe the interactions between protein and carbohydrate in the absence of structural data. These methods map the interactions between protein and carbohydrate, and identify the groups involved, both at the carbohydrate and protein level. Here, we review these developments, and examine the strengths, weaknesses, and pitfalls of these methods.

Animals↗
PubMed2002

DNA microarray analysis of the gene expression profiles of naïve versus activated tumor-specific T cells.

T cells are a key element in effective cancer immunity, recognizing MHC-antigen peptide complexes on the surface of antigen presenting cells and translating these signals into cytotoxic effector T cell responses. In this study, we systematically investigated by DNA array analysis the expression profiles of 514 immunologically relevant genes in naïve and SP2/0 tumor-specific activated mouse T cell populations. Our data shows that naïve T cells expressed 37 (i.e., 7.6% of the 514) transcripts with expression level (EL) values of > or =2.0, while the activated T cells expressed 101 such transcripts. The expression levels of 9 (1.75% of 514) of the shared transcripts were equivalent in the two populations of T cells. Ninety-six genes were differently expressed upon T cell activation, with 71 (13.81%) being up-regulated and 25 (4.86%) down-regulated. The list of significantly affected genes includes numerous cytokines and their receptors (e.g., IL-2Ralpha, IL-6Ralpha, IL-7Ralpha, IL-16, IL-17R, TGF-beta), chemokines and chemokine receptors (e.g., RANTES, CCR7, CXCR4), alternate surface proteins (e.g., 4-1BB, GITR, integrins-alphaL and -beta7, L-selectin, CD6, CD45 and EMMPRIN), cytoplasmic signaling intermediates (e,g., GATA-3, 14-3-3-eta, CIS1, SMAD4 and JAK1) and an array of other molecules (e.g., NFkappa-B inducing kinase, LTBP3 and persephin), several of which are associated with Th1 responses, and T cell self-regulation or migration. Taken together, our data contribute to our understanding of the generalized processes that accompany T cell activation and, more specifically, to our understanding of the processes associated with T cell activation during antitumor responses.

Animals↗
PubMed2002

Synergistic enhancement of antitumor immunity with adoptively transferred tumor-specific CD4+ and CD8+ T cells and intratumoral lymphotactin transgene expression.

The lack of efficient T-cell infiltration of tumors is a major obstacle to successful adoptive T-cell therapy. We have shown that transplanted SP2/0 myeloma tumors that have been engineered to express lymphotactin (Lptn) invariably regress under the influence of infiltrating XCR1+T cells and neutrophils. Herein, we characterize these T cells and investigate their therapeutic efficacy, either alone or with Lptn gene therapy. After stimulation with SP2/0 cells, these T cells were CD25+FasL+L-selectin-, expressed XCR-1, and were chemoattracted by Lptn in vitro. They comprised 66% CD4+ Th1 and 33% CD8+ Tc1 cells, both of which expressed significant amounts of IFN-gamma, perforin, and tumor necrosis factor-alpha, but not interleukin-4. The CD4+ Th1 and CD8+ Tc1 cells, which were inhibited and stimulated, respectively, for proliferation with Lptn signaling, displayed 38 and 84% specific killing, respectively, for Ia(d)/H-2K(d)-expressing SP2/0 tumor cells (E:T ratio, 100). In vivo, combined intratumoral Lptn gene transfer and adoptive immunotherapy with these CD4+ and CD8+ T cells eradicated well-established SP2/0 tumors in six of eight mice, and dramatically slowed tumor growth in the other two mice. Cell tracking using labeled T cells confirmed that these cells infiltrated better into the Lptn-expressing tumors than non-Lptn-expressing ones. Control or Lptn adenoviral treatments by themselves did not alter the lethal outcome for tumor-bearing mice, nor did T-cell therapy by itself, although the latter two treatments did slow its time frame. Combined Lptn gene transfer and adoptive CD4+ or CD8+ cell transfers were not nearly as efficacious as the combined Lptn gene and unfractionated T-cell transfers. Taken together, our data provide solid evidence of a potent synergy between adoptive CD4+ and CD8+ T-cell therapy and Lptn gene transfer into tumor tissues, which culminated in the eradication of well-established tumor masses.

Adenoviridae↗
PubMed2002

Analysis of the gene expression profiles of immature versus mature bone marrow-derived dendritic cells using DNA arrays.

Dendritic cells (DCs) are professional antigen-presenting cells of the immune system and can be generated in vitro from bone-marrow cells. In this study, we systematically investigated by DNA array analysis the expression profiles of 514 immunologically relevant genes in two populations of mouse bone marrow-derived DC, immature (DC(IMAT)), and lipopolysaccharide (LPS)-stimulated mature (DC(MAT)) DCs. Our data showed that DC(IMAT) expressed transcripts for 69 (13.42% of the 514) of these genes and that, upon maturation, 32 (6.23%) of these were up-regulated and 40 (7.78%) down-regulated. Maturation-dependent up-regulation, defined by a differential expression (DE) ratio of >2, was observed among five cytokine (Flt-3L, TNF-alpha, IL-1alpha and -1beta, and IL-6), three chemokine (RANTES, MIP-2 and GROa) and three other (iNOS, MMP-13, and STRAP) genes. Reciprocally, maturation-dependent down-regulation occurred with one cytokine (IGF-1), two chemokine receptor (CCR2 and CCR5), and three other (RP105, Ax1, and UCP2) genes. Lower level, but nevertheless significantly enhanced expression of the chemokine receptor CCR7 and of NF-kappaB was also observed upon DC maturation. This DC maturation profile confirms previous findings from other lab, but it also substantially broadens our view of these cells by documenting expression changes among genes (e.g., IGF-1, MMP-13, STRAP) not reported previously in these cells.

Animals↗
PubMed2002

Engineered fusion hybrid vaccine of IL-4 gene-modified myeloma and relative mature dendritic cells enhances antitumor immunity.

Dendritic cell (DC)-tumor fusion hybrid vaccine which facilitates antigen presentation represents a new powerful strategy in cancer therapy. In the present study, we investigated the antitumor immunity derived from vaccination of fusion hybrids between wild-type J558 or engineered J558-IL-4 myeloma cells secreting cytokine interleukin-4 (IL-4) and immature DCs (DC(IMAT)) or relative mature DCs (DC(RMAT)). DC(RMAT) displayed an up-regulated expression of immune molecules (Ia(d), CD40, CD54, CD80 and CD86) and certain cytokines/chemokines, and enhanced ability of allogeneic T cell stimulation when compared to DC(IMAT). These DCs were fused with myeloma cells by polyethylene glycol (PEG). The fusion efficiency was approximately 20%. Our data showed that immunization of C57BL/6 mice with DC(RMAT)/J558 hybrids induced protective immunity against a high dose of J558 tumor challenge (1x10(6) cells) in 3 out of 10 immunized mice, compared with no protection seen in mice immunized with DC(IMAT)/J558 hybrids. Furthermore, immunization of mice with engineered DC(RMAT)/J558-IL-4 hybrids elicited stronger J558 tumor-specific cytotoxic T lymphocyte (CTL) responses in vitro and induced more efficient protective immunity (10/10 mice; tumor free) against J558 tumor challenge in vivo than DC(RMAT)/J558 hybrid vaccines. The results demonstrate the importance of DC maturation in DC-tumor hybrid vaccines and indicate that the engineered fusion hybrid vaccines which combine gene-modified tumor and DC vaccines may be an attractive strategy for cancer immunotherapy.

Animals↗
PubMed2002

A randomized, double-blind, single-dose, crossover clinical trial of the onset and duration of protection from exercise-induced bronchoconstriction by formoterol and albuterol.

BACKGROUND: Inhaled short-acting beta(2)-adrenoceptor agonists are the most commonly used treatment for the prevention of exercise-induced bronchoconstriction (EIB). Formoterol, a long-acting beta(2)-adrenoceptor agonist, has been demonstrated to provide protection from EIB, although the onset and duration of this protection have not been defined. OBJECTIVE: The purpose of this study was to determine the onset and duration of the protective effect of a single dose of inhaled formoterol powder against EIB, comparing them with the effect of a single dose of placebo and albuterol administered via metered-dose inhaler (MDI). METHODS: In this double-dummy, 4-way crossover study, patients received single doses of formoterol (12 and 24 microg) via a powder inhaler, albuterol by MDI (180 microg), and placebo. Exercise challenge tests (ECTs) were conducted at 15 minutes and at 4, 8, and 12 hours postdose. Pulmonary function studies (forced expiratory volume in 1 second [FEV(1)] and peak expiratory flow rate) were performed before and after each exercise challenge. RESULTS: Twenty adolescent and adult patients (mean age, 23.8 years; range, 13-41 years; 9 male, 11 female) with asthma were enrolled in the study, and 17 completed all 4 treatment sequences. Compared with placebo, both doses of formoterol produced significantly greater inhibition of FEV(1) decreases at all time points (P < 0.01). There were no significant differences in efficacy measures between the 2 formoterol doses throughout the study. The exercise-induced decrease in FEV(1) after albuterol treatment was significantly reduced compared with placebo only at 15 minutes after dosing (P < 0.05). Formoterol and albuterol exhibited a similar rapid onset of action (<15 minutes), but formoterol continued to protect patients against EIB for at least 12 hours (P < 0.01), whereas albuterol was no longer clinically effective by the 4-hour ECT. CONCLUSIONS: Formoterol and albuterol, given as single-dose inhalations, both provided protection from EIB within 15 minutes in this group of patients. The bronchoprotection afforded by formoterol lasted up to 12 hours, whereas that of albuterol was no longer significant by 4 hours.

Administration, Inhalation↗
PubMed2002

Adenovirus-mediated CD40 ligand gene-engineered dendritic cells elicit enhanced CD8(+) cytotoxic T-cell activation and antitumor immunity.

CD40L, the ligand for CD40 on dendritic cells (DCs), plays an important role in their activation and is essential for induction of antigen-specific T-cell responses. In the present study, we investigated the efficacy of antitumor immunity induced by vaccination with DCs engineered to express CD40L and pulsed with Mut1 tumor peptide. Our data show that transfection of DCs with recombinant adenovirus AdV-CD40L resulted in activation of DCs with up-regulated expression of proinflammatory cytokines (IL-1beta and IL-12), chemokines (RANTES, IP-10, and MIP-1alpha), and immunologically important cell surface molecules (CD54, CD80, and CD86). Our data also demonstrate that DCs transfected with AdV-CD40L (DC(CD40L)) are able to stimulate enhanced allogeneic T-cell proliferation and Mut1-specific CD8(+) cytotoxic T-cell responses in vitro. Vaccination of mice with Mut1 peptide-pulsed control virus-transfected DC (DC(pLpA)) could only protect mice from challenge of a low dose (0.5 x 10(5) cells per mouse, 8/8 mice), but not a high dose (3 x 10(5) cells per mouse, 0/8 mice) of 3LL tumor cells. However, vaccination of Mut1 peptide-pulsed AdV-CD40L-transfected DC(CD40L) induced an augmented antitumor immunity in vivo by complete protection of mice (8/8) from challenge of both low and high doses of 3LL tumor cells. Thus, DCs engineered to express CD40L by adenovirus-mediated CD40 ligand gene transfer may offer a new strategy in production of DC cancer vaccines.

Adenoviridae↗
PubMed2002

Intratumoral coinjection of two adenoviral vectors expressing functional interleukin-18 and inducible protein-10, respectively, synergizes to facilitate regression of established tumors.

We have constructed two recombinant adenoviral vectors AdVIP-10 and AdVIL-18 expressing the functional chemokine IFN-gamma inducible protein (IP)-10 and cytokine interleukin (IL)-18, respectively. Injection of either AdVIP-10 or AdVIL-18 subcutaneously into tumor nodules derived from the J558 murine myeloma cell line delayed some tumor growth but it was not curative in all cases. Coinjection of these two vectors at the same tumor nodule not only significantly suppressed the tumor growth, but also cured established tumors in 8 of 10 (80% tumor free) mice. The latter treatment stimulated T-cell infiltration into tumors in association with tumor necrosis formation, induced a type 1 immune response and induced the activation of J558 tumor-specific cytotoxic T lymphocytes. Moreover, the antitumor activity of IP-10 and IL-18 combined gene therapy was significantly diminished in mice with depletion of either CD4(+) (50% tumor free) or CD8(+) (40% tumor free) T cells, and completely lost (0% tumor free) in T cell-deficient nude and IFN-gamma knockout mice, indicating the critical roles of T cells and IFN-gamma in this therapeutical model. Taken together, the findings of this study demonstrate that the combined use of two adenoviral vectors expressing IP-10 and IL-18, respectively, synergize to facilitate regression of established tumors. These observations also suggest the potential use of double-recombinant adenoviral vectors expressing chemokines and immunomodulatory cytokines in cancer gene therapy.

Adenoviridae↗
PubMed2002

Enhanced HER-2/neu-specific antitumor immunity by cotransduction of mouse dendritic cells with two genes encoding HER-2/neu and alpha tumor necrosis factor.

The present study uses an in vivo murine tumor model expressing the human HER-2/neu antigen to evaluate the potential vaccine using dendritic cells (DCs) infected with adenovirus AdVHER-2. We first investigated whether infected DCs (DC(HER-2)) engineered to express HER-2/neu could induce HER-2/neu-specific immune responses. Our data showed that (i) AdVHER2-infected DC(HER-2) expressed HER-2/neu by Western blot and flow cytometric analysis, and (ii) vaccination of mice with DC(HER-2) induced HER-2/neu-specific cytotoxic T-lymphocyte (CTL) responses, but protected only 25% of vaccinated mice from challenge of 3 x 10(5) MCA26/HER-2 tumor cells. Further, to enhance the efficacy of DC(HER-2) vaccine, we coinfected DCs with both AdVHER-2 and AdVTNF-alpha. The infected DCs (DC(HER-2/TNF-alpha)) displayed the expression of both HER-2/neu and TNF-alpha by flow cytometric and ELISA analysis. We next investigated whether DC(HER-2/TNF-alpha) could induce stronger HER-2/neu-specific immune responses. We found that DC(HER-2/TNF-alpha) displayed up-regulation of immunologically important CD40, CD86, and ICAM-I molecules compared with DC(HER-2), indicating that the former ones are more mature forms of DCs. Vaccination of DC(HER-2/TNF-alpha) induced stronger allogeneic T-cell proliferation and 36% enhanced HER-2/neu-specific T-cell responses in vitro than DC(HER-2) cells. More importantly, it stimulated the significant anti-HER-2/neu immunity in vivo, which protected 8/8 mice from challenge of 3 x 10(5) MCA26/HER-2 tumor cells. Therefore, DCs genetically engineered to express both the tumor antigen and cytokines such as TNF-alpha as an immunoadjuvant are likely to represent a new direction in DC vaccine of cancer.

Adenoviridae↗
PubMed2002

Advances in dendritic cell-based vaccine of cancer.

Dendritic cells (DCs) are potent antigen presenting cells that exist in virtually every tissue, and from which they capture antigens and migrate to secondary lymphoid organs where they activate naïve T cells. Although DCs are normally present in extremely small numbers in the circulation, recent advances in DC biology have allowed the development of methods to generate large numbers of these cells in vitro. Because of their immunoregulatory capacity, vaccination with tumor antigen-presenting DCs has been proposed as a treatment modality for cancer. In animal models, vaccination with DCs pulsed with tumor peptides, lysates, or RNA or loaded with apoptotic/necrotic tumor cells could induce significant antitumor CTL responses and antitumor immunity. However, the results from early clinical trails pointed to a need for additional improvement of DC-based vaccines before they could be considered as practical alternatives to the existing cancer treatment strategies. In this regard, subsequent studies have shown that DCs that express transgenes encoding tumor antigens are more potent primers of antitumor immunity both in vitro and in vivo than DCs simply pulsed with tumor peptides. Furthermore, DCs that have been engineered to express certain cytokines or chemokines can display a substantially improved maturation status, capacity to migrate to secondary lymphoid organs in vivo, and abilities to stimulate tumor-specific T cell responses and induce tumor immunity in vivo. In this review we also discuss a number of factors that are important considerations in designing DC vaccine strategies, including (i) the type and concentrations of tumor peptides used for pulsing DCs; (ii) the timing and intervals for DC vaccination/boostable data on DC vaccination portends bright prospects for this approach to tumor immune therapy, either alone or in conjunction with other therapies.

Animals↗
PubMed2002

Antitumor immune responses derived from transgenic expression of CD40 ligand in myeloma cells.

Tumor cells engineered to express immunogenes have been used for cancer vaccines to induce the antitumor immunity and study the antitumor immune mechanisms derived from the immunogene expression. In the present study, we engineered a mouse myeloma cell line J558 with a cloned CD40 ligand (CD40L) gene. We demonstrated that (i) the engineered J558/CD40L tumor cells expressing the CD40 ligand molecule lost their tumorigenicity in syngeneic mice, and (ii) the inoculation of J558/CD40L tumor cells further lead to the protective immunity against wild-type J558 tumors. In animal studies using T-cell subset depleted mice, we further showed that the primary rejection of J558/CD40L tumors did not require T cells, but was mainly mediated by NK cells, whereas the effector phase of the protective immunity is mediated by CD8+ T cells. In addition, our data, for the first time, showed that the inoculation of engineered J558/CD40L tumor cells is able to stimulate stronger activation of dendritic cells with enhanced expression of B7-1 and ICAM-1 molecules than the wild-type J558 tumor cells Taken together, we demonstrated the antitumor effect of engineered J558/CD40L tumor cells that is mediated by the activation of the host dendritic cells in vivo. Our data indicate that the introduction of co-stimulatory CD40 ligand molecule will be useful as a new strategy of immunogene therapy against tumors.

Animals↗