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S Shu

Publications and source records attributed to S Shu.

At least 73 records · Page 4Linked to original sources
PubMed1996

Secretion of both IL-2 and IL-4 by tumor cells results in rejection and immunity.

The generation of a therapeutic immune response to malignancy is critically dependent on the inherent immunogenicity of the tumor. Our study demonstrates that secretion of both interleukin-2 (IL-2) and IL-4 by a seemingly nonimmunogenic tumor abrogates tumorigenicity, and mice that have rejected the genetically modified tumor are immune to challenges with the parental tumor. The induction of immunity by the IL-2/IL-4-secreting tumor was significantly better than that achieved with the admixture of tumor cells and the classic adjuvant, Corynebacterium parvum. To elicit a primary immune response, the majority of cells needed to secrete both cytokines. Ad-mixture of IL-2-secreting cells with IL-4-secreting cells did not result in tumor cell rejection. The IL-2/IL-4-secreting tumor cells were efficiently rejected in animals immunosuppressed by total body irradiation. Depletion of CD4+ or CD8+ T cells did not abrogate rejection of the tumor cells, but the animals depleted of CD4 cells failed to generate protective immunity. Our study demonstrates that secretion of the combination of IL-2 and IL-4 significantly enhances tumor immunogenicity. The requirement of cells secreting both cytokines suggests an intricate mechanism different from the mere presence of both cytokines at the tumor-inoculation site.

Animals↗
PubMed1996

IL-1, ICAM-1, LFA-3, and hydrocortisone differentially regulate cytokine secretion by human fetal thymic epithelial cells.

Human fetal thymic epithelial cells (TEC) were cultured under serum-free conditions. The TEC were analyzed for the secretion of 14C-labelled peptides and of IL-3, IL-6 IL-7, IL-8, GM-CSF, LIF, fibronectin and thymosin alpha 1 by ELISA tests. IL-3 and IL-7 were not detected from these TEC. Lack of IL-7 and presence of thymosin alpha 1 and of the surface molecule TE-4 depicts these cells as subcapsular/medullary TEC. TEC secreted constitutively IL-6, IL-8, fibronectin and thymosin alpha 1 but not GM-CSF of LIF. Stimulants included recombinant IL-1 and monoclonal antibodies to the surface adhesion molecules ICAM-1 and LAF-3. In addition, hydrocortisone (2.7 x 10(-7) M) was used to dissect secretion patterns. Recombinant IL-1, anti ICAM-1, and anti LFA-3 alone and collectively induced modest but significant increases in the secretions of 14C-labelled peptides and of IL-6 and IL-8 which were not inhibited by HC. Recombinant IL-1 but not anti ICAM-1 and anti LFA-3 induced GM-CSF and LIF. HC inhibited the secretion of GM-CSF and LIF induced by IL-1. None of the stimulants augmented the constitutive secretion of fibronectin or thymosin alpha 1 and HC inhibited thymosin alpha 1 secretion. TEC secretion of cytokines but not thymosin alpha 1 and fibronectin appear to be regulated in a more complex manner than heretofore recognized.

CD58 Antigens↗
PubMed1996

[Selenium levels in human bodies and environment in Qinghai province].

To study selenium level, its distribution in human bodies and environment and its effects on health, 3,035 specimens of human hair, blood, urine, and environmetal water, soil, food were collected from 91 sampling spots in 23 cities and counties of Qinghai Province and determined for selenium levels with fluorescence analysis. Results showed overall biological selenium level of human bodies in Qinghai Province was low and blood selenium level was lower than the normal reference value in 84.73% of the population, same as that in selenium-poor nations. Environmental selenium was poor or in a deficient status in Qinghai Province, 69.57% of the areas in the Province was in low, poor, or severely deficient selenium. Selenium level in vegetable food correlated closely with that in human blood, which indicated low selenium level in environment caused human selenium deficient in their internal environment via food chain. There were difference in biological selenium levels of human bodies in seven districts and six ethnic nationalities, which suggests selenium levels in human bodies correlate closely with economic development, selenium intake, geographical environment, living habits and customs, etc., and are nothing to do with the altitude above sea level.

Adolescent↗
PubMed1995

Tumor-specific granulocyte/macrophage colony-stimulating factor and interferon gamma secretion is associated with in vivo therapeutic efficacy of activated tumor-draining lymph node cells.

In this study, cytokine release by tumor-draining lymph node cells sensitized in vitro (IVS-TDLN) was examined and correlated with therapeutic efficacy in adoptive immunotherapy. Mice bearing immunologically distinct MCA 207 and MCA 205 sarcoma tumors were utilized in criss-cross experiments. IVS-TDLN obtained from mice bearing 10-day subcutaneous (s.c.) tumors mediated immunologically specific regression of established 3-day pulmonary metastases, but demonstrated non-specific cytolytic reactivity against both tumors in a 4-h 51Cr-release assay. By contrast, these IVS-TDLN cells were found specifically to secrete granulocyte/macrophage colony-stimulating factor (GM-CSF) and interferon gamma (IFN gamma) when restimulated in vitro with irradiated tumor cells. To determine the predictive value of tumor-specific cytokine release with in vivo therapeutic efficacy, a kinetic analysis of antitumor activities of TDLN obtained from animals bearing MCA 207 tumors for increasing lengths of time was performed. IVS-TDLN cells from mice bearing day-7, -10 and -14 s.c. tumors manifested tumor-specific release of GM-CSF and IFN gamma, and mediated significant antitumor reactivity in vivo. In contrast IVS-LN cells from day-0 and day-21 tumor-bearing animals did not release significant amounts of GM-CSF and IFN gamma, and were not therapeutically efficacious in vivo. Day-4 IVS-TDLN released high levels of GM-CSF and IFN gamma non-specifically, and were not therapeutic in adoptive immunotherapy at doses effective for day-7 and day-14 IVS-TDLN cells. In other experiments, IVS cells generated from different lymph node groups in animals bearing 10-day established s.c. tumors were examined and found to have unique profiles of cytokine release. In these studies, the ability of IVS cells to release specifically both cytokines as opposed to one was associated with greater therapeutic efficacy on a per cell basis. Our findings suggest that the tumor-specific releases of GM-CSF and IFN gamma are useful parameters to assess the in vivo therapeutic efficacy of immune lymphocytes.

Animals↗
PubMed1995

Adoptive immunotherapy of poorly immunogenic tumors with in vitro sensitized cells generated by intratumoral administration of biological response modifiers.

We investigated the efficacy of intratumoral administration of biological response modifiers (BRM) in induction of in vitro sensitized (IVS) cells for adoptive immunotherapy of the poorly immunogenic MCA 102 sarcoma and B16-BL6(BL6) melanoma. We used the bacterial immunoadjuvant Nocardia rubra cell wall skeleton (N-CWS), and a streptococcal preparation, OK-432, for MCA 102 and BL6, respectively. After C57BL/6(B6) mice were inoculated subcutaneously (s.c.) with viable MCA 102 or BL6 tumor cells in the foot-pad, mice were injected intratumorally (i.t.) with N-CWS ranging from 10 to 400 micrograms or OK-432 ranging from 1 to 100 micrograms. Draining popliteal lymph nodes (LN) were harvested 7 days after i.t. administration of BRM, and LN cells were cultured with irradiated tumor cells in the presence of IL-2 for 11 days. These IVS cells (7.5 x 10(6) or 2 x 10(6)) were transferred intravenously (i.v.) to B6 mice with 4 day pulmonary metastases established by i.v. injection of viable MCA 102 cells (1 x 10(6)) or viable BL6 cells (3 x 10(5)). The mice were also received intraperitoneally 4 x 10(4) IU/day of IL-2 for 4 days after adoptive transfer. The transfer of IVS cells from mice immunized by i.t. injection of 100 micrograms of N-CWS 1 week after inoculation of tumor cells significantly reduced MCA 102 pulmonary metastases, compared with control IVS cells without administration of N-CWS. Moreover, the transfer of IVS cells from mice immunized by i.t. injection of 10 micrograms of OK-432 3 days after inoculation of tumor cells significantly reduced BL6 pulmonary metastases compared with control IVS cells without administration of OK-432. The administration of N-CWS resulted in no enhancement of in vitro cytotoxicity. Although the administration of 10 micrograms of OK-432 augmented in vitro cytotoxicity of IVS cells against BL6, cytotoxic activity was lower than that of IVS cells immunized with N-CWS. The major phenotype was CD8+ cells in IVS cells immunized with N-CWS or OK-432. These results suggest that i.t. administration of N-CWS and OK-432 facilitates the production of sensitized T-cells, and this administration route of BRM may be useful in the adoptive immunotherapy of human cancer.

Adjuvants, Immunologic↗
PubMed1995

Generation of therapeutic T-lymphocytes after in vivo tumor transfection with an allogeneic class I major histocompatibility complex gene.

In an effort to enhance the generation of tumor-reactive T-lymphocytes for adoptive immunotherapy, we examined the effects of in vivo transfection of an allogeneic major histocompatibility complex (MHC) class I gene (H-2Ks) of the poorly immunogenic B16BL6 (BL6) melanoma of H-2b origin. Cells from lymph nodes (LNs) draining these tumors after transfection were assessed in adoptive immunotherapy experiments for tumor reactivity after sequential activation with anti-CD3 monoclonal antibody (mAb) followed by culture in interleukin (IL)-2. H-2Ks lipofection of progressively growing BL6 subcutaneous tumors did not reduce tumorigenicity. However, in vivo lipofection of BL6 by intratumor inoculation or admixture of H-2Ks cDNA/liposome complexes and tumor cells prior to inoculation resulted in enhanced development of sensitized T-lymphocytes in the draining LN, which mediated the reduction of the numbers of established 3-day parental lung metastases in six of six experiments. In subsequent studies, in vivo transfection of BL6 with naked H-2Ks cDNA was found to be more effective than lipofection in eliciting sensitized T-cells in the draining LN. Admixture of liposomes alone or control plasmid DNA did not have an adjuvant effect similar to H-2Ks cDNA. Relative tumor transfection efficiency was assessed by an indirect assay with the chloramphenicol acetyltransferase (CAT) reporter gene. BL6 tumors were more efficiently transfected by intratumor inoculation with naked cDNA compared with lipofection. In summary, in vivo allogenization of the poorly immunogenic BL6 tumor resulted in enhanced generation of therapeutic T-cells effective in the treatment of parental tumor.

Adjuvants, Immunologic↗
PubMed1994

Characteristics and in vivo homing of long-term T-cell lines and clones derived from tumor-draining lymph nodes.

Lymph nodes draining a progressively growing tumor contain T-cells which can be activated sequentially by anti-CD3 and IL-2 to differentiate into tumor-specific effector cells. In this study, long-term cultured T-cell lines were established from activated MCA 106 tumor-draining lymph node cells by periodic stimulation with irradiated tumor cells in the presence of low concentrations of IL-2 (< or = 60 International units/ml). Such long-term cultured cell lines maintained therapeutic effects when transferred to tumor-bearing mice. Although the initial anti-CD3/IL-2-activated T-cells displayed a broad distribution of T-cell antigen receptor beta chain variable region (V beta) usages, long-term cultured cells were dominated by T-cells expressing a few V beta elements. Of six cell lines, only three V beta phenotypes (V beta 5, 11, 13) were identified, and individual cell lines frequently expressed a single V beta gene product. Despite restricted V beta expression, each cell line mediated tumor-specific reactivity in adoptive immunotherapy. Many T-cell clones were isolated from long-term cell lines. Three V beta 13 T-cell clones demonstrated specific in vivo antitumor effects, whereas two V beta 11 and two V beta 5 clones revealed a significant degree of cross-reactivity against the antigenically distinct MCA 205 tumor. Although the initial anti-CD3/IL-2-activated cells lacked demonstrable cytotoxic reactivity, T-cell clones derived from them exhibited cytotoxic effects to the MCA 106 tumor cells. The specificity of the cytotoxicity mediated by each clone reflected its in vivo antitumor effects. Furthermore, studies of in vivo localization of cloned T-cells demonstrated tumor-specific infiltration of the 5A2 (V beta 13) clone to the MCA 106 tumor metastases, whereas clone 9H6 (V beta 5) revealed some accumulation in the MCA 205 tumor. Again, the in vivo antitumor effects of the 9H6 clone correlated with its in vivo infiltration into the specific MCA 106 and the nonspecific MCA 205 metastases. Taken together, the long-term culture of anti-CD3/IL-2-activated tumor-draining lymph node cells resulted in selective expansion of a few T-cells as evidenced by the limited T-cell receptor V beta expression. Our results also demonstrated that systemically administered antitumor T-cell clones gained access and accumulated at metastatic tumor sites, and the degree of infiltration correlated with the specificity of the in vivo antitumor effect as well as the in vitro cytotoxic activity.

Animals↗
PubMed1994

Stimulation of tumor-draining lymph node cells with superantigenic staphylococcal toxins leads to the generation of tumor-specific effector T cells.

In animal studies, lymph nodes (LN) draining progressive tumors contain immunologically sensitized but functionally deficient T cells. These preeffector cells can differentiate into mature effector cells on stimulation in vitro with anti-CD3 and IL-2. However, anti-CD3 react with all T cells and the activated cell population expressed a broad but normal distribution of V beta phenotypes. In this study, we examined the feasibility of using bacterial superantigens to stimulate tumor-draining LN cells. Because of their TCR V beta restriction, superantigen activation may afford a means to identify T cell subsets that are important in the antitumor immune response. Stimulation of draining LN cells with staphylococcal enterotoxins A (SEA) or B (SEB) followed by culture in IL-2 resulted in selective activation and expansion of V beta 3 and V beta 11 or V beta 3 and V beta 8 T cells, respectively. However, in adoptive immunotherapy, SEB- but not SEA-activated cells mediated the regression of established pulmonary metastases. To define the relative antitumor effects of V beta 3 and V beta 8 T cells, SEB-activated cells were depleted of either V beta 3 or V beta 8 T cells with mAb and magnetic beads. The antitumor effects were demonstratably diminished after V beta 8 cell depletion but enhanced after V beta 3 cell depletion. Using antigenically distinct MCA 205 and 207 sarcomas, tumor regression mediated by the activated cells was found to be immunologically specific for the tumor that stimulated the draining LN. Furthermore, the SEB-activated cells were virtually all T cells consisting of approximately equal proportions of CD4+ and CD8+ cells and the collaboration of the two T cell subsets was required for in vivo antitumor effects. However, the helper function of CD4+ cells could be facilitated by the administration of exogenous IL-2. Despite their in vivo antitumor reactivity, SEB-activated cells did not exhibit tumor cytotoxicity in the 4-h 51Cr release assay. However, they secreted IFN-gamma on specific stimulation with tumor cells. Taken together, these results provide for the first time clear evidence of the functional significance of superantigen interactions with immunologically committed T cells and suggest a preferential V beta use that might be associated with the T cell immune response to progressively growing tumors.

Animals↗
PubMed1994

Activation of T lymphocytes for the adoptive immunotherapy of cancer.

BACKGROUND: Adoptive immunotherapy of malignancy involves the passive transfer of antitumor-reactive cells into a host in order to mediate tumor regression. Based on animal models, the transfer of immune lymphoid cells can eradicate widely disseminated tumors and establish long-term systemic immunity. Critical for successful adoptive immunotherapy is the ability to isolate large numbers of immune cells. For clinical therapy, it will require the development on in vitro methods to promote the sensitization and propagation of tumor-reactive cells. However, this is a formidable task since human cancers are postulated to be poorly immunogenic because of their spontaneous origins. RESULTS: Human lymphoid cells for ex vivo activation and subsequent adoptive transfer have been derived from different sources, including peripheral blood, tumor, and lymph nodes. Peripheral blood lymphocytes can be incubated with interleukin 2 to generate lymphokine-activated killer (LAK) cells, which nonspecifically lyse autologous and allogeneic tumor cells in vitro. LAK cell therapy represented the earliest attempt to treat advanced human cancers, with encouraging results documented in patients with renal cell cancer and melanoma. From that experience, the use of more immunologically specific cellular agents with potentially greater therapeutic efficacy has been investigated. One approach uses tumor-infiltrating lymphocytes, which have been characterized experimentally to be more specific in tumor reactivity compared with LAK cells. Other techniques have involved the use of lymphoid cells derived from lymph nodes draining tumors or primed by tumor vaccines. In vitro activation of these cells with tumor antigen or anti-CD3 monoclonal antibody results in the generation of T cells that mediate the rejection of poorly immunogenic tumors in animal studies. These alternate methods are currently being evaluated in clinical studies. CONCLUSIONS: Experimentally, cellular therapy is a potent method to eradicate progressive tumors. Initial clinical studies have demonstrated that this form of therapy is technically feasible and can result in meaningful antitumor responses. Advances in this area will require improved methods to sensitize, isolate, and expand tumor-reactive T cells for adoptive transfer.

Animals↗
PubMed1994

Adoptive immunotherapy of murine intracerebral tumors with anti-CD3/interleukin-2-activated tumor-draining lymph node cells.

We have recently identified a source of potent antitumor effector cells that can be generated by the sequential culture of tumor-draining lymph node (TDLN) cells with anti-CD3 monoclonal antibody (anti-CD3) and interleukin-2 (IL-2). In this study the therapeutic efficacy of these immune effector cells in the treatment of experimentally induced brain metastases was evaluated. With use of the MCA 205 sarcoma, TDLN cells were harvested from syngeneic B6 mice 9-10 days after subcutaneous inoculation with 10(6) tumor cells. These TDLN cells were activated in vitro by exposure to anti-CD3 for 2 days followed by expansion with IL-2 (10 U/ml) for 3 days. In a neutralization assay, anti-CD3/IL-2-activated cells admixed with MCA 205 tumor cells at an effector/tumor cell ratio of 10 effectively suppressed the growth of tumor cells after intracranial inoculation. In mice with 3-day established brain tumors, multiple intracranial administrations of activated TDLN cells resulted in prolonging survival for which a 50-fold increase in number of cells given intravenously did not. However, the therapeutic effectiveness of systemically (intravenously) administered activated TDLN cells in the treatment of 3-day brain tumors was achieved if tumor-bearing mice were sublethally whole-body irradiated (500 cGy). In two experiments irradiated animals that were not treated or received therapy with IL-2 alone had median survival times (MSTs) of 16 and 17 days, respectively. By contrast, in irradiated animals that received TDLN cells plus IL-2, MST was not reached beyond the observation period of 90 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Enhancement of immune reactivity in the lymph nodes draining a murine melanoma engineered to elaborate interleukin-4.

The adoptive transfer of immune T cells has been demonstrated to mediate regression of established tumors in animals, with encouraging results in human clinical trials. In animal studies, lymph nodes (LN) draining a progressively growing immunogenic tumor contain tumor-sensitized but functionally deficient T cells. These "preeffector" cells can be activated in vitro by sequential stimulation with anti-CD3 and interleukin (IL)-2 to differentiate into mature effector cells capable of mediating the regression of disseminated tumor. However, the preeffector cell response is weak during the growth of poorly immunogenic tumors such as the B16-BL6 melanoma. In this study, a clone of B16-BL6, A9, was transfected with the cDNA encoding for murine IL-4, in an attempt to enhance tumor immunogenicity. IL-4 secreting clones grew significantly slower than controls after intradermal (i.d.) inoculation, but all animals eventually succumbed to the progressive tumor. The ability of IL-4-secreting tumor cells to stimulate a preeffector cell response was then investigated. LN draining the IL-4-secreting tumors for 10 days were activated by the anti-CD3/IL-2 method. The resulting lymphocytes were adoptively transferred into animals bearing 3-day established parental pulmonary metastases. The transfer of cells derived from sensitization with the IL-4-secreting tumors was capable of significantly reducing the numbers of pulmonary metastases more effectively than cells sensitized to the parental tumor. Thus, genetic modification of tumor cells to secrete IL-4 can stimulate an increase in the preeffector cell response in the tumor-draining LN, suggesting an enhancement in T-cell-mediated immune function against the parental tumor.

Animals↗
PubMed1994

[Effect of indirect fluorescent antibody test for the diagnosis of amoebiasis].

Indirect fluorescent antibody test (IFAT) was performed by the method of [symbol: see text] (1971) with some slight modifications for the diagnosis of amoebiasis. The antigen used was prepared from 48-hour culture of Entamoeba histolytica (strains G2, G3, and G5) in LAS diphasic medium and only those amoebae clinging the culture were collected. The serum samples or blood drops on filter paper were positive by the improved IFAT in all of the 54 cases of amoebic liver abscess and the positive reactions of most cases were very marked. Of 23 cases of acute amoebic dysentery, 19 were positive, the positive rate being 82.6%. The results also show that 42 cases of other diseases and 40 healthy persons were all negative.

Animals↗
PubMed1994

Adoptive immunotherapy mediated by anti-TCR/IL-2-activated tumour-draining lymph node cells.

The adoptive immunotherapy of cancer with sensitized T lymphocytes is well documented in several animal models. These studies indicate the existence of precursor lymphocytes, in the tumour-bearing animals, which can acquire therapeutic efficacy after in vitro manipulations. To generate immune effector cells, these precursor lymphocytes have to be antigenically stimulated in vitro by the tumour of origin. Using the weakly immunogenic MCA 205 and MCA 203 murine sarcomas, we demonstrate here that this in vitro antigenic stimulation can be achieved by sequential activation with anti-T-cell receptor (TCR) monoclonal antibody and interleukin-2 (IL-2). The culture of tumour-draining lymph node (TDLN) cells with anti-TCR/IL-2 resulted in an up to eightfold increase in cell numbers. The adoptive transfer of these activated cells mediated a significant reduction of 3-day established pulmonary metastases. Although this antibody could activate all of the TCR alpha beta-bearing T cells non-specifically, the therapeutic efficacy mediated by anti-TCR/IL-2-activated cells was tumour specific. Treatment of MCA 205 advanced pulmonary metastases resulted in prolongation of survival, and 30% of treated mice were tumour free for more than 90 days. These tumour-free mice rejected a challenge of MCA 205 but not MCA 203, indicating the development of long-lasting systemic tumour immunity. In spite of their in vivo anti-tumour efficacy, the anti-TCR/IL-2-activated TDLN cells did not exhibit detectable in vitro cytotoxicity. These results demonstrate that this activation method could be an alternative way to generating potent anti-tumour effector T cells.

Animals↗
PubMed1993

Direct gene transfer with DNA-liposome complexes in melanoma: expression, biologic activity, and lack of toxicity in humans.

Direct gene transfer offers the potential to introduce DNA encoding therapeutic proteins to treat human disease. Previously, gene transfer in humans has been achieved by a cell-mediated ex vivo approach in which cells from the blood or tissue of patients are genetically modified in the laboratory and subsequently returned to the patient. To determine the feasibility and safety of directly transferring genes into humans, a clinical study was performed. The gene encoding a foreign major histocompatibility complex protein, HLA-B7, was introduced into HLA-B7-negative patients with advanced melanoma by injection of DNA-liposome complexes in an effort to demonstrate gene transfer, document recombinant gene expression, and determine the safety and potential toxicity of this therapy. Six courses of treatment were completed without complications in five HLA-B7-negative patients with stage IV melanoma. Plasmid DNA was detected within biopsies of treated tumor nodules 3-7 days after injection but was not found in the serum at any time by using the polymerase chain reaction. Recombinant HLA-B7 protein was demonstrated in tumor biopsy tissue in all five patients by immunochemistry, and immune responses to HLA-B7 and autologous tumors could be detected. No antibodies to DNA were detected in any patient. One patient demonstrated regression of injected nodules on two independent treatments, which was accompanied by regression at distant sites. These studies demonstrate the feasibility, safety, and therapeutic potential of direct gene transfer in humans.

Aged↗