Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CD4+ autoreactive T cells are a major cell population in regulating immune responses to altered autologous neoplastic cells. Normal autoreactive T cells recognize major histocompatibility complex (MHC) class II molecules in association with self-peptides on antigen-presenting cells, such as macrophages (M phi). Tumor-bearing hosts (TBH) have decreased autoreactivity partly because tumors increase M phi secretion of suppressor molecules like prostaglandin E2 (PGE2) and decrease M phi MHC class II expression. Because interleukin (IL)-10, a cytokine produced by T cells, M phi, and tumor cells, inhibits production of most M phi suppressor molecules, we determined if IL-10 could reverse tumor-induced murine splenic M phi-mediated suppression of autoreactive T cell proliferation. Tumor growth enhanced activated M phi production of PGE2, nitric oxide, and tumor necrosis factor-alpha (TNF-alpha). IL-10 strongly reduced or inhibited M phi production of these molecules. When added to pure normal host (NH) CD4+ T cells, NH syngeneic splenic M phi stimulated autoreactive T cell proliferation more than did TBH splenic M phi. Exogenous IL-10 or M phi preincubation with IL-10 restored TBH M phi-stimulated autoreactivity to normal levels. IL-10 treatment had little or no effect on NH M phi-stimulated autoreactivity. IL-10 inhibited TBH M phi secretion of suppressor molecules in T cell proliferation assays because supernatants from IL-10-pretreated TBH M phi-syngeneic NH T cell cultures had decreased levels of suppressor molecules. When endogenous IL-10 activity was neutralized with anti-IL-10 monoclonal antibody, autoreactive T cell proliferation stimulated by NH or TBH M phi was slightly, but significantly decreased. Although IL-10 is known to inhibit M phi foreign antigen-presenting cell-dependent T cell proliferation, this study shows that IL-10 restores autoreactive T cell functions during tumor growth by counteracting M phi production of inhibitory molecules. These data suggest that IL-10 up-regulates anti-cancer autoreactive T cell responses by down-regulating suppressor M phi activity.
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PMID:Promotion of macrophage-stimulated autoreactive T cell proliferation by interleukin-10: counteraction of macrophage suppressor activity during tumor growth. 778 92

P-glycoprotein (P-gly) is the transmembrane efflux pump responsible for multidrug resistance in tumor cells. Functional P-gly activity can be conveniently assessed microfluorometrically using the fluorescent dye rhodamine 123 (Rh123), which is an artificial substrate for the P-gly transporter. Here we assess P-gly activity in subsets of mouse peripheral T lymphocytes using the Rh123 efflux assay. Our data indicate that virtually all CD8+ cells extrude Rh123 efficiently, whereas only a subset of CD4+ cells exhibit P-gly activity. Correlation of P-gly activity in CD4+ cells with the expression of a panel of surface markers revealed that cells bearing an "activated/memory" phenotype (CD45RB-, CD44hi, CD62L-, CD25+, CD69+) were exclusively found in the fraction that can extrude Rh123. In contrast "naive" phenotype CD4+ cells (CD45RB+, CD44lo, CD62L+, CD25-, CD69-) could be further subdivided into two major subsets based on P-gly activity. In functional studies of sorted cell populations the Rh123-extruding subset of "naive" CD4+ cells proliferated more strongly and secreted higher levels of interleukin (IL)-2 than its Rh123-retaining counterpart when activated by a variety of polyclonal stimuli. Furthermore, this subset produced detectable levels of interferon (IFN)-gamma upon stimulation but no IL-4 or IL-10. As expected, the Rh123-retaining "naive" subset produced only IL-2 after stimulation, whereas the "memory" subset produced IFN-gamma, IL-4 and IL-10 in addition to low levels of IL-2. Collectively, our data indicate that P-gly activity is a novel parameter that can be used to distinguish a subset of "preactivated" CD4+ cells that would be considered as naive on the basis of their surface phenotype.
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PMID:Heterogeneity in P-glycoprotein (multidrug resistance) activity among murine peripheral T cells: correlation with surface phenotype and effector function. 780 24

T-cell adjuvancy involves the use of agents to stimulate preferentially delayed type hypersensitivity (DTH). Traditional adjuvants like Alum, Freunds, muramyl peptides, and endotoxins are not selective. Natural infection (e.g. vaccinia) may yield selective DTH. Low dose cyclophosphamide (CY) with mycobacteria was the first experimental T-cell adjuvant. New adjuvant formulations (ISCOMS, MAPS, etc.) with synthetic T-cell epitopes offer improved formulations. Upregulation of TH-1 helper cells and their actions with interleukins like IL-2, IL-12, and gamma IFN or antibodies to IL-4 and IL-10 may augment potently pathogen and tumor resistance. Similarly, transfection of tumor target cells with genes for IL-2, IL-12, gamma IFN, etc., offers novel vaccine treatment approaches. Finally, "thymomimetic" peptides like thymosin alpha 1 or drugs like levamisole or isoprinosine alone or in conjunction with interleukins may augment TH-1 and DTH responses. These approaches are seeing increasing emphasis in new treatment strategies for cancer and infections like HIV.
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PMID:T-cell adjuvants. 780 29

Hairy-cell leukemia (HCL) is a B-cell leukemia, but many factors argue for a T-cell dysfunction and/or involvement in this disease. Hairy cells typically home in the spleen, and become circulating only late in the disease. As it is assumed that the T-cell abnormalities are caused by specific interactions with the hairy cells, we studied the immunophenotype in 17 cases (CD3, CD4, CD8, CD45R0, TCR gamma delta) and cytokine gene expression in four cases (IL-1 beta, IL-2, IL-3, IL-4, IL-6, IL-7, IL-10, IFN-gamma, TNF-alpha, GM-CSF and the receptors of IL-1 and IL-2, using the cDNA-PCR technique) of purified T-cell fractions from hairy-cell spleens. By Northern blot analysis, mRNA for IFN-gamma, GM-CSF, IL-10 and TNF-alpha was measured in purified T cells and hairy cells from three HCL spleens. The results of the immunophenotype and cDNA-PCR data were compared with ten normal spleens. Compared to blood, splenic T cells showed a reversed CD4/CD8 ratio, a normal percentage of memory T cells, and an increase in CD3+TCR gamma delta + cells. Without specific induction spontaneous cytokine gene expression of IL-2, IL-4, IFN-gamma, and GM-CSF was seen in the purified T-cell fractions without signals in the purified hairy-cell fractions. mRNA expression of IFN-gamma and GM-CSF in the T cells, and of IL-10 and TNF-alpha in the hairy cells was confirmed by the Northern blot technique. From these data we suggest that splenic T cells in HCL should not be considered as residual or recirculating T cells, but rather as tumor-infiltrating lymphocytes.
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PMID:Abnormally activated T lymphocytes in the spleen of patients with hairy-cell leukemia. 780 97

In vitro and in vivo expressions of cytokine mRNAs by four transplantable murine B lymphocytic malignancies designated A20, MOPC 315, 2PK-3, and RAW 8.1 were determined using sensitive reverse-transcribed (RT)-PCR. Despite significant differences in both the stage of B cell differentiation represented by each cell line and the method used to induce the original B lymphocytic tumors, IL-6 and IL-10 mRNAs were detected in each of the cultured cell lines. Whereas IL-2, IL-4, IL-5, and IL-12 mRNAs were not detected in cultured cells, expression of cytokine mRNAs in solid tumor tissue was quite different. RT-PCR of poly(A)+ RNA isolated from each of the four solid tumors demonstrated the presence of IL-4, IL-5, IL-6, IL-10, TGF-beta 1, and TNF-alpha mRNAs. There was a noticeable lack of significant IL-2 mRNA expression in any of the solid tumors. Using RT-PCR, it was clear that each of the malignant B lymphocytes expressed IL-6, IL-10, TGF-beta 1, and TNF-alpha, with limited expression of IL-4 and IL-5. To explore the mechanisms that might contribute to the lack of IL-2 mRNA in these solid tumors, quantitative competitive (QC)-RT-PCR was used to quantify expression of IL-10 mRNA. MOPC 315 tumor expressed the most IL-10 mRNA (23.2 pg/micrograms of poly(A)+ RNA), whereas 2PK-3, A20, and RAW 8.1 tumors expressed 7.4, 2.6, and 0.6 pg/micrograms of poly(A)+ RNA, respectively. Secretion of IL-10 into culture supernatants or into sera and ascitic fluid of tumor-bearing animals correlated with mRNA expression. This dysregulated IL-10 production in animals with B lymphocytic tumors suggested a mechanism that may account for the lack of IL-2 mRNA expression in solid tumors, and suggested a possible mechanism by which malignant B lymphocytes may limit cell-mediated antitumor responses.
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PMID:Lymphokine mRNA expression by transplantable murine B lymphocytic malignancies. Tumor-derived IL-10 as a possible mechanism for modulating the anti-tumor response. 781 78

IL-10 inhibits Langerhans cell (LC) Ag presentation to Th1 clones. As LC are capable of presenting tumor-associated Ags (TAA) for primary and secondary tumor immune responses, we examined the effect of IL-10 on LC Ag presentation in a model of immunity to the S1509a spindle cell tumor (H-2a). Because induction of immunity to S1509a requires exposure of LC to granulocyte-macrophage (GM)-CSF, this system also allowed us to study the regulatory interactions of GM-CSF and IL-10 on LC. Naive CAF1 (H-2a/d) mice could be immunized against S1509a by injection with GM-CSF-exposed and TAA-pulsed epidermal cells (EC) as assessed by inhibition of the growth of inoculated tumor cells. Incubation of EC in IL-10 before GM-CSF exposure completely inhibited Ag presentation in this system. Significantly, neither co-incubation of EC in IL-10 and GM-CSF (without preincubation in IL-10) nor IL-10 treatment after GM-CSF incubation was able to exert a down-regulatory effect. The ability of IL-10 to modulate EC presentation of TAA for a secondary immune response was also examined. EC were pulsed with TAA in vitro and then injected into a hind footpad of tumor-immune mice with 24 h swelling assessed as a measure of delayed-type hypersensitivity. Preincubation in IL-10 before TAA exposure significantly inhibited elicitation of delayed-type hypersensitivity with or without subsequent exposure to GM-CSF. Co-incubation of EC in IL-10 and GM-CSF or exposure to IL-10 after GM-CSF led to a normal response. These data indicate that IL-10 may serve as an important regulator of LC Ag-presenting function for tumor immune responses. IL-10 appears to specifically prevent the GM-CSF-induced maturation of LC Ag-presenting function when treatment with IL-10 occurs before exposure to GM-CSF but does not reverse the established mature state.
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PMID:IL-10 inhibits tumor antigen presentation by epidermal antigen-presenting cells. 782 97

Inadequate co-stimulation of tumor reactive T cells may contribute to the fact that antigenic tumors are not normally rejected by the immune system. We recently reported that the induction of profound unresponsiveness in a T cell clone by melanoma cells expressing MHC class II antigens may provide a mechanism for these tumor cells to escape immunosurveillance. Here we demonstrate that two T cell clones (sTC3 and sTS5) produced high amounts of IL-10 after being rendered anergic by autologous melanoma cells. Co-culture of these T cell clones with melanoma cell transfectants expressing B7, which failed to induce anergy, resulted in a significantly lower production of IL-10. IL-10 production by the anergic T cell clones correlated with an impaired ability to produce IL-2 in response to TCR mediated activation. Neutralization of IL-10 reduced the duration of T cell unresponsiveness from 14 to only 4 days, but inhibition of IL-10 production during initiation of anergy showed no effect on it. Induction of the unresponsive state, as well as the subsequent IL-10 production in sTC3 cells, could be prevented by the addition of cyclosporin A to the primary co-culture of sTC3 and the autologous melanoma. Taken together, these results indicate that IL-10 is important for maintenance of T cell anergy induced by contact with nonprofessional antigen presenting cells such as MHC class II+ melanoma cells. Furthermore, we were able to detect IL-10 in serum from melanoma patients and IL-10 mRNA in tumor infiltrating lymphocytes isolated from melanoma metastases, suggesting an in vivo relevance of our in vitro findings.
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PMID:Maintenance of clonal anergy by endogenously produced IL-10. 782 50

EBV-immortalized B-lymphoblastoid cell lines (LCL) inoculated s.c. into T-cell-deficient nude mice regress completely after a short initial growth period. We tested whether the putative host response underlying this phenomenon might also be directed against progressively growing Burkitt's lymphoma (BL) tumors in nude mice. Outgrowth of BL tumors was suppressed when cells of the highly tumorigenic BL cell line BL 60 were mixed with cells of the autologous LCL IARC 277 before s.c. inoculation into nude mice. Even when the cells were inoculated separately and simultaneously into contralateral flanks of the mice, regression of initially growing BL tumors could be observed, albeit with reduced frequency and dependent on the dose of LCL cells. Tumor growth of BL 60 cells could also be suppressed by co-inoculation with the non-autologous LCL IARC 174 and IARC 277 cells could suppress growth of the non-autologous BL cell line Eli. Pronounced infiltration with murine (m)CD-11b-positive mouse macrophages and mCD-8a-positive mouse lymphoid cells, most probably natural killer cells, was seen in histological tissue sections of regressing BL 60 tumors when LCL cells were inoculated contralaterally. In regressing BL tumors, these mouse cells were present not only in necrotic areas but also in vital BL tissue, indicating that infiltration of mouse cells had taken place before the development of necrosis. Since tumor-infiltrating mouse cells can be activated at least by some human cytokines, we measured cytokine production of BL 60 and IARC 277. High amounts of IL 6 and IL 10 were produced by the LCL cells, whereas IL-6 and IL-10 production by the BL 60 cells was beyond or close to the detection threshold. In addition, IL 8 was secreted up to 5-fold more by the LCL than by the BL cells. The results presented here thus suggest a host response of the nude mouse, which is triggered by cytokines released from the LCL but, once induced, is directed also against BL cells.
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PMID:Suppression of Burkitt's lymphoma tumorigenicity in nude mice by co-inoculation of EBV-immortalized lymphoblastoid cells. 782 68

Tumor growth causes macrophages (M phi) to suppress T-cell proliferation by inducing M phi production of soluble suppressor molecules. Because interleukin (IL)-10 inhibits production of most M phi-derived molecules, we investigated the effects of IL-10 on murine M phi suppressor function during tumor growth. When acting as accessory cells during alloantigen-induced CD4+ T-cell proliferation, syngeneic tumor-bearing host (TBH) peritoneal M phi suppressed normal host (NH) T-cell proliferation more than their normal counterparts. Exogenous IL-10 suppressed alloantigen-stimulated CD4+ T-cell proliferation in the absence of accessory M phi, but it blocked TBH M phi-mediated suppression. IL-10 pretreatment of M phi reversed suppression mediated by TBH M phi but did not affect NH M phi activity. Supernatant transfer experiments showed that IL-10 blocked TBH M phi-mediated suppression by inhibiting soluble suppressor molecule production. Activated TBH M phi produced greater quantities of the suppressor molecules tumor necrosis factor-alpha, nitric oxide, prostaglandin E2, and granulocyte-macrophage colony-stimulating factor than NH M phi did. Exogenous IL-10 reduced production of these molecules by TBH M phi more than by NH M phi. Activated TBH M phi produced more IL-10 than NH M phi, suggesting that endogenous IL-10 contributes to increased TBH M phi sensitivity to exogenous IL-10's inhibitory action. The antibody-mediated neutralization of endogenous IL-10 activity relieved NH, but not TBH, M phi-mediated suppression of T-cell proliferation. This result supports the idea that TBH M phi are more sensitive to the inhibitory action of IL-10 on suppressor molecule production. IL-10 is known to inhibit M phi antigen-presenting cell-dependent helper T-cell proliferation. We report here that IL-10 restores TBH helper T-cell functions by blocking accessory M phi production of inhibitory molecules. This restoration suggests that IL-10's M phi deactivating activity provides an upregulatory role in immunocompromised individuals where suppressor M phi are abundant.
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PMID:Increased sensitivity of tumor-bearing host macrophages to interleukin-10: a counter-balancing action to macrophage-mediated suppression. 784 45

The effect of recombinant human IL-4, IL-10, and IL-13 on the chemotaxis and antitumor activity of human blood monocytes induced by monocyte chemotactic and activating factor (MCAF) was examined. MCAF alone did not induce monocyte-mediated cytotoxicity against human melanoma (A375-M) cells whereas it significantly enhanced the cytotoxicity by norMDP-stimulated monocytes. MCAF, unlike IFN-gamma, had no priming effect on monocyte activation by norMDP. MCAF acted with norMDP or LPS to enhance the production of both IL-1 beta and TNF-alpha. Enhanced cytotoxicity of monocytes stimulated with MCAF plus norMDP was reduced by IL-1 receptor antagonist and anti-TNF-alpha antibody. IL-4, IL-10, and IL-13 suppressed the generation of antitumor activity and cytokine production (IL-1 beta and TNF-alpha) of monocytes stimulated with MCAF plus norMDP or LPS. Chemotaxis of monocytes induced by MCAF was not affected by norMDP or any of the anti-inflammatory cytokines (IL-4, IL-10, and IL-13). Moreover, the pretreatment of monocytes with anti-inflammatory cytokines did not suppress monocyte-chemotaxis. These findings suggest that in vivo recruitment and anti-tumor expression of blood monocytes induced by MCAF may be differently regulated by anti-inflammatory cytokines in vivo.
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PMID:Differential effects of anti-inflammatory cytokines (IL-4, IL-10 and IL-13) on tumoricidal and chemotactic properties of human monocytes induced by monocyte chemotactic and activating factor. 785 46


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