Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to search for a new therapy that would maximize the effect of interleukin-2 (IL-2) in evoking antitumor immunity in vivo, the therapeutic effect of a combination of mitomycin-C(MMC)-treated tumor cells and recombinant IL-2 was examined for its induction of antitumor activity against established melanoma metastasis. In C57BL/6 mice intravenously (i.v.) injected with B16 melanoma cells on day 0, the combined treatment with an intraperitoneal (i.p.) injection of MMC-treated melanoma cells on day 6 and 2500 U rIL-2 (twice daily) on days 7 and 8 markedly reduced the number of pulmonary metastases. This antitumor activity was more effective than that in untreated controls and mice that were injected with MMC-treated melanoma cells alone or rIL-2 alone. When the i.p. injection of MMC-treated tumor cells was replaced by other syngeneic tumor cells, antitumor activity against metastatic melanoma was not induced. The antitumor activity induced by this treatment increased in parallel with an increase in the dose of rIL-2 injected. In contrast, an i.p. injection of soluble tumor-specific antigens alone could induce only a marginal level of antitumor activity, and this activity was not augmented by subsequent i.p. injections of rIL-2. In vivo treatment with anti-CD8 monoclonal antibody (mAb), but not with anti-CD4 mAb or anti-asialo-GM1 antibody, abrogated the antitumor activity induced by this combined therapy. This suggests that the antitumor effect was dependent on CD8+ T cells. Lung-infiltrating lymphocytes from mice that had been i.v. injected with melanoma cells 11 days before and were treated with this combined therapy, showed melanoma-specific cytolytic activity. This combined therapy also showed significant antitumor activity against subcutaneously inoculated melanoma cells. These results demonstrate that the combined therapy of an i.p. injection of MMC-treated tumor cells and subsequent and consecutive i.p. administration of rIL-2 increases antitumor activity against established metastatic melanoma by generating tumor-specific CD8+ CTL in vivo.
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PMID:Generation of tumor-specific cytotoxic T lymphocytes in vivo by combined treatment with inactivated tumor cells and recombinant interleukin-2. 816 15

We have previously shown that an intact immune system was essential to the increase in survival time of IFN-alpha/beta-treated mice injected i.v. with an IFN-alpha/beta-resistant line of Friend erythroleukemia cells (FLC) highly metastatic to the liver and spleen. Here, we have investigated the early interactions of IFN alpha/beta with host cells prior to the development of the immune response. IFN alpha/beta treatment resulted in 50- to 100-fold inhibition of FLC multiplication in the liver and spleen of normal DBA/2 mice shortly after tumor inoculation, as evaluated by colony formation in agarose. IFN treatment was far less effective in inhibiting the multiplication of FLC in the livers of NK-cell-deficient DBA/2 beige mice, or in immunocompetent DBA/2 mice treated with antibody to asialo GMI, or silica, or in mice subjected to sub-lethal irradiation. Injection of antibody to CD4 or CD8 did not affect the early inhibitory action of IFN alpha/beta on FLC multiplication but did decrease survival time. Light- and electron-microscope examination of the livers of IFN-treated, FLC-injected mice confirmed the early inhibition of FLC multiplication in the liver and spleen. Our results indicate that IFN alpha/beta inhibits the development of FLC visceral metastases by acting first on host cells, such as NK cells and macrophages, and then continues to act in consort with the developing immune response.
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PMID:Interaction of IFN alpha/beta with host cells essential to the early inhibition of Friend erythroleukemia visceral metastases in mice. 818 64

These studies investigate the effects of exogenously administered recombinant human IL-7 (rhIL-7) on mouse leukocyte subsets in vivo in normal and tumor-bearing mice. The administration of rhIL-7 to normal mice caused a pronounced leukocytosis (three- to fivefold increase over background) in the spleen and lymph nodes, with B-lineage and T cells, NK cells, and macrophages all being increased. CD8+ T cells increased disproportionately, such that the CD4 to CD8 ratio decreased dramatically. The rhIL-7-induced effects were dose-dependent, increased with duration of treatment, and were reversible after cessation of rhIL-7 administration. T cell number increases after rhIL-7 treatment were primarily a result of an expansion of the peripheral T cell population. Importantly, splenocytes from rhIL-7-treated mice have enhanced proliferative responses to various T cell stimuli in vitro and were able to potentiate an allogeneic CTL response in vivo. The rhIL-7-induced changes in T cell number and the CD4 to CD8 ratio also were observed in mice bearing early Renca renal adenocarcinoma pulmonary metastases, and these changes coincided with up to a 75% reduction in pulmonary metastases. Overall, these results demonstrate that the administration of rhIL-7 to mice profoundly increases the number of B and T cells, and reduces the number of pulmonary metastases. The results also suggest that IL-7 may be useful for restoring lymphoid subsets in immunosuppressed hosts and in enhancing T cell-mediated immune responses. Such effects may be useful in the treatment of microbial diseases and cancer.
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PMID:Administration of recombinant human IL-7 to mice alters the composition of B-lineage cells and T cell subsets, enhances T cell function, and induces regression of established metastases. 820 7

Two cases of true histiocytic lymphoma of the small intestine occurred in middle-aged patients, manifesting as tumors causing intestinal obstruction. One of the patients died of uncontrollable local and metastatic disease, 16 months after surgery and polychemotherapy, and the other patient is alive 12 months after surgery and chemotherapy. The histologic characteristics of the tumor cells, namely complex nuclear outlines and abundant variably eosinophilic cytoplasm, suggested histiocytic differentiation. Both cases had negative results for B-cell and T-cell markers but stained for the histiocytic markers lysozyme, CD68, and HLA-DR and had positive results for S-100 protein and vimentin. Acetone-fixed frozen sections of one case showed positive results for several histiocytic markers, including CD11c, CD14, CD33, CD68, and BerMac3 (unclustered monoclonal antibody). CD4, a T-cell antigen present in a subset of histiomonocytic cells, had positive results in the cytoplasm. The tumor cells had negative results for CD1a, CD15, and CD30. Immunoglobulin and T-cell receptor gene probes showed germline configuration in one case studied. These results indicate the tumors are true histiocytic lymphomas, which have immunophenotypic features of both ordinary histiocytes and interdigitating reticulum cells.
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PMID:True histiocytic lymphoma of small intestine. Analysis of two S-100 protein-positive cases with features of interdigitating reticulum cell sarcoma. 837 37

Effective adoptive immunotherapy of immunocompetent DBA/2 mice challenged i.v. with the highly metastatic ESb T-cell lymphoma required the combined treatment of recipient mice with tumor-sensitized spleen cells and IFN-alpha/beta. In contrast, immune spleen cells and IFN-alpha/beta treatment did not increase the survival time of ESb-injected DBA/2-nu/nu mice, DBA/2-bg/bg mice, or normal DBA/2 mice injected with antibody to CD4. Treatment of immunocompetent DBA/2 mice with antibody to asialo-GM1, silica, dichloromethylene diphosphonate-containing liposomes, or 500 rads whole-body gamma-irradiation did not diminish the antimetastatic action of ESb-immune cells and IFN-alpha/beta. These results indicate that adoptively transferred immune T lymphocytes and IFN-alpha/beta act together with host CD4+ T lymphocytes/factors to inhibit ESb visceral metastases. Combined treatment with ESb-immune cells together with interleukin-1 beta (IL-1 beta), IL-2, tumor necrosis factor-alpha, or granulocyte-macrophage colony-stimulating factor did not increase the survival time of normal DBA/2 mice challenged with ESb cells. In contrast, IL-12, which had only a slight antimetastatic effect when administered alone, did synergize with ESb-immune spleen cells and increased the survival time of ESb-challenged mice to a similar extent as did IFN-alpha/beta and immune spleen cells. Treatment of DBA/2 mice with potent antibody to IFN-alpha/beta did not abrogate the capacity of IL-12 and ESb-immune spleen cells to inhibit ESb metastases. Unlike immunotherapy with ESb-immune cells and IFN-alpha/beta, ESb-immune cells together with IL-12 inhibited ESb metastases in immunodeficient DBA/2-bg/bg mice.
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PMID:Host CD4+ T lymphocytes are required for the synergistic action of interferon-alpha/beta and adoptively transferred immune cells in the inhibition of visceral ESb metastases. 852 4

Murine liver contains alpha beta T cells with intermediate TCR (TCRint) as well as alpha beta T cells with bright TCR. Liver TCRint cells express NK1.1 Ag (NK1+ TCRint) and IL-2 receptor beta chain, both of which are NK cell markers and are not expressed on conventional T cells. Liver NK1+ TCRint cells consist of CD4-8- double negative T cells and CD4+ T cells and have V beta 8+ T cell preponderance. They are dependent on class Ib or CD1 molecules of APC for their development. They can also develop thymus independent manner, because athymic nude mice have this population. These NK1+ TCRint cells in the livers of both euthymic and athymic mice were found to be activated by systemic administration of IL-12 and increased NK1 expression (NK1high TCRint) and cytotoxicity against various NK-sensitive and resistant tumors. Cytotoxicity assays after treatment of IL-12 stimulated hepatic MNC with respective Abs and C revealed that CD4+ NK1high TCRint cells are responsible for IL-12 induced cytotoxicity. Although NK1+ TCRint cells were normally few in the lungs, a significant proportion of NK1high TCRint cells with strong cytotoxicity was also induced in the lung by IL-12. Interestingly, adoptive transfer of IL-12 stimulated hepatic MNC into other mice, which were pre-injected with tumors, inhibits hepatic metastases of EL4 cells and pulmonary metastases of 3LL cells as similarly as IL-12 administration. Transfer experiments after treatment of IL-12 stimulated hepatic MNC with respective Ab and C revealed that depletion of either NK1+ cells, CD3+ cells or CD4+ cells but not CD8+ cells greatly impaired antimetastatic effect in both organs. Thus, CD4+ NK1high TCRint cells are a major antimetastatic population, especially, against hematogenous metastases.
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PMID:[The function and role of extrathymic T cells]. 853 54

We demonstrate herein evidence that IL-12-activated alpha beta T cells with intermediate TCR (NK1+ TCRint cells) in the liver inhibit metastases in the lung as well as in the liver metastases of i-v. injected tumors. IL-12 administration enhanced NK1 expression of NK1+ TCRint cells (NK1high) and increased CD4 weakly positive (CD4low) TCRint cells, while both CD4+ TCRint cells and double-negative TCRint cells were proportionally diminished. Accordingly, the major parts of NK1high TCRint cells are CD4low cells, and most of these cells are V beta 8+ cells. The cytotoxic assays of IL-12-stimulated hepatic mononuclear cells after treatment with respective Abs and complement in vitro and after sorting revealed that CD4low NK1high TCRint cells are cytotoxic effectors. When IL-12-stimulated hepatic mononuclear cells (but not splenocytes) were transferred into tumor-preinjected mice, EL-4 cell metastases in the liver as well as 3LL cell metastases in the lung were inhibited. The antimetastasis of hepatic mononuclear cells transfer was abrogated by the depletion of NK1+ cells, CD3+ cells, or CD4+ cells but not CD8+ cells before transfer. Moreover, transfer of these cells of nude mice into tumor-preinjected mice also inhibited metastases in both organs. Although NK1+ TCRint cells are nearly absent in the hepatic vein blood, a significant proportion of NK1high TCRint cells appeared by IL-12 administration. These results demonstrate that IL-12-stimulated liver NK1high TCRint cells, including extrathymic ones, are major effectors against tumor metastasis and suggest that the cells migrate and inhibit lung metastases.
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PMID:Liver NK1.1+ CD4+ alpha beta T cells activated by IL-12 as a major effector in inhibition of experimental tumor metastasis. 861 62

The purpose of this study was to investigate the relationship between changes in density and distribution of dendritic cells, both in epidermis and in peritumoral infiltrate, and lymphocyte subset variations in malignant melanomas (MM) of patients belonging to different risk groups. The collective immunoreactive expression of six markers (S100 protein, CD1-a, HLA-DR, CD4, CD8 and CD25) was analyzed in 13 cutaneous malignant melanomas. Changes were observed in density and distribution of Langerhans cells (LC) (S100+, CD1-a+) in the epidermis overlying the tumor, as well as in peritumoral and intratumoral locations, independently of the tumor-invasion level. A decrease was recorded in LC (S100+, CD1-a+) in the epidermis overlying six tumors, whereas most of the MM studied showed an increase of LC (S100+, CD1-a+) in peritumoral infiltrate. The expression of HLA-DR in tumor cells was controversial; it was observed in three moderate-risk MM, but it was negative in high-risk tumors. The percentage of CD4+ cells was in most cases greater than that of CD8+ in the peritumoral infiltrate, irrespective of the degree of histopathological malignancy. The concomitant expression of the lymphocytic activation marker CD25 (receptor for interleukin 2) in lymphocytic infiltrate was variable. Peritumoral infiltrate in three high risk MM contained few CD25+ cells, and a concomitant decrease was recorded in LC. This preliminary report shows that alterations in the density and distribution of LC may be responsible for determining the degree or T lymphocyte activation, and this may be critical for the development of effective tumor-directed immunity. Further studies are required to demonstrate these hypothetical interrelations.
Invasion Metastasis 1995
PMID:Immunophenotype analysis of dendritic cells and lymphocytes associated with cutaneous malignant melanomas. 862 Dec 68

The FACS-analysis of diseases as different as cancer, autoimmune disorders and chronic (retro)viral infections, including HIV-infection, shows -at least temporarily- a common feature of lymphocyte hyperactivation, characterized by cellular activation markers (HLA-DR, CD26, CD38, CD69, CD2R and/or CD30), as well as by solubilized membrane structures, such as beta-2m, sICAM-I, sIL-2R/sCD25, sCD8, and by some oversecreted immunocyte products (e.g. neopterin, lysozyme and/or cathepsin D). We tested two potential approaches to down-regulate the pathologically elevated CD8+ and HLA-DR+ T cells: (a) In animal model, we tested the sensibility of these, disease inducing and maintaining T cell subsets to in vitro pretreated (cell death preprogrammed) semi-syngeneic and allogeneic donor T cells in tumor-bearing mice. (b) In the first clinical study, we used a novel combination of FDA-approved drugs which inhibits Ca(2+)-influx and concomitantly down-regulates cytosolic cAMP in patient's overstimulated immunocompetent cells. We could achieve a 94.6-100% long-term survival in tumor-bearing mice. In patients, large primary tumors and large metastases shrinked by 80-85% and small metastases disappeared completely. Since in HIV-infected persons, the increased number of HLA-DR+ CD38+T (T8) cells is associated with a fall in CD4-level and with development of AIDS, we are looking for the elimination of these HLA-DR+ targets by our novel technique in two AIDS-simulating (FIV/FeLV and SIV) animal models.
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PMID:Treatment of solid tumors should obligatorily be combined with the in vivo codepletion of tumor-protecting, CD8+/HLA-DR(+)-suppressor T cells by alloreactive donor T cells whose preprogrammed cell death allows a high GvL-effect before GvHD can be established. Results of animal experiments, including more than 6000 mice. 873 48

A number of traditional Chinese medicinal herbs have become extremely interesting in the search for potential BRMs in the international medical community, especially in the United States and Japan. Naturin, a new Chinese medical herb produced by XingYa Pharmaceutical Co., Ltd., has enhanced immune response, inhibited tumor metastases and retroviral infection in animal models as well as in clinical studies. The results demonstrated that the inhibition of Natural Killer (NK) and Lymphokine-activated Killer (LAK) cell activity and lymphocyte proliferation was compromised by tumor metastases and retrovirus infection (Murine AIDS), even immunosuppression induced by surgical amputation can be restored by Naturin. It is also shown that Naturin can protect the mice from lethal total body irradiation. These studies indicated that Naturin possesses immunomodulatory effects in vivo for a broad range of stresses. The results of the clinical studies on Naturin have demonstrated: (a) significantly improved symptoms of patients, including MDS, acute and chronic leukemia, aplastic anemia, lung cancer, and association with the increased number and percentage of CD4 (Helper T-cell) which have been reduced in some patients, (b) Lymphocyte proliferation and NK cell activity which were suppressed in cancer patients can be significantly restored by Naturin treatment, (c) the addition of Naturin treatment to patients receiving radiotherapy and chemotherapy augments immune response and reduces radiation and chemotherapy injury, and (d) no cytotoxic side effects were found in patients given Naturin treatment for up to eight months.
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PMID:Naturin: a potent bio-immunomodifier in experimental studies and clinical trials. 874 1


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