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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The enhancing effect of macrophages on interleukin-2 (IL-2)- and IL-4-induced murine lymphokine-activated killer (LAK) activity was investigated in this study. Peritoneal macrophages significantly enhanced LAK activity generated from accessory cell-depleted splenic lymphocytes in both IL-2 and IL-4 cultures. This effect was dependent on the number of macrophages and was not replaced by a factor derived from macrophages or lymphocytes. Macrophages enhanced IL-2- and IL-4-induced LAK activity against both natural killer (NK)-sensitive (YAC-I, P388D1) and NK-resistant (P815) tumor cells. Negative selection of cells with antibodies and complement showed no differences in surface markers between IL-2 LAK effectors and IL-4 LAK effectors generated in the presence of macrophages. These results suggest that the same LAK effector subsets can be enhanced by macrophages in either IL-2 or IL-4 cultures.
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PMID:Effect of macrophages on interleukin-2 (IL-2)- and IL-4-induced murine lymphokine-activated killer activity. 204 1

Cytotoxic T lymphocytes (CTL) are believed to play an important role in the regression of advanced malignancies in response to adoptive immunotherapy with interleukin-2 (IL-2) and lymphokine-activated killer cells or tumor-infiltrating lymphocytes. Because the current limitations to the use of adoptive immunotherapy are the IL-2 dose-dependent toxicities and the difficulty in expanding the effector cell population, recent investigations have focused on the development of newer methods for generating CTL in vitro. IL-1 and IL-6 have been shown to synergistically promote thymocyte proliferation; however, their effect on CTL development has not been studied. We investigated the ability of these two cytokines to induce CTL development from immature thymocytes. Thymocytes from 5-week-old BALB/c mice were cultured for 72 hours in the presence of Con A and recombinant IL-1, IL-6, or IL-1 plus IL-6. Cytotoxicity against 51Cr-labeled P815 target cells was then measured in the presence of submitogenic doses of PHA. Neither IL-1 nor IL-6 induced a significant number of CTL from immature thymocytes. However, these two cytokines synergistically induced maximal CTL development. The monoclonal antibody to IL-4 completely abrogated CTL development induced by IL-1 and IL-6, but antibody to the IL-2 receptor had no effect. The data suggest that IL-1 and IL-6 can provide an additional method for in vitro CTL generation in adoptive immunotherapy of advanced tumors.
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PMID:Induction of cytotoxic T lymphocyte development from murine thymocytes by IL-1 and IL-6. 205 98

The effect of interleukin 4 (IL-4) on expression of antitumor activity of blood monocytes purified by counter-flow centrifugal elutriation from healthy donors was examined. The blood monocytes were incubated for 24 h in medium with lipopolysaccharide, interferon gamma (IFN-gamma) or desmethyl muramyl dipeptide (norMDP) or with IFN-gamma and norMDP in the presence of IL-4, and then their tumoricidal activity was assayed by measuring 125IUdR release from human melanoma (A375) cells. Irrespective of activation stimulus, addition of IL-4 to cultures of monocytes and activators resulted in dose-dependent suppression of the tumoricidal activity of monocytes against parent A375 melanoma cells and the variant cells, A375-R resistant to IL-1 and tumor necrosis factor alpha. IL-4 suppressed the early induction phase of monocyte activation. Rabbit anti-IL-4 antisera completely blocked the IL-4-mediated suppression of monocyte activation to the tumoricidal state. These findings suggest that IL-4 is important in vivo in down-regulation of anti-tumor expression of monocytes.
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PMID:Suppression by interleukin 4 of activation of human blood monocytes to the tumoricidal state. 212 95

The autologous mixed lymphocyte reaction (AMLR) is an in vitro measure of autoreactivity, a key mechanism in immune homeostasis. In this system, macrophages (M phi) act as accessory cells to autoreactive L3T4+ T cells by presenting self-Ia and releasing soluble modulators. During tumor growth, changes occur in M phi and T cells. Tumor-bearing host (TBH) M phi have a reduced ability to act as accessory cells. In fact, TBH M phi suppressed autoreactivity by 60-70%. The decrease in TBH M phi or T-cell abilities was not due to differences in cell numbers or incubation time. Because tumor growth causes increased prostaglandin E2 (PGE2) production by M phi, indomethacin was used to assess the contribution of prostaglandins. Normal and TBH T-cell reactivity increased nearly 50% when stimulated by normal host M phi, while normal and TBH T-cell reactivity increased nearly 100% when stimulated by TBH M phi. Thus increased prostaglandin production is partly responsible for the increased TBH suppressor M phi activity and in the normal host, suppressor M phi may be responsible for maintaining immune regulation. To assess the direct role of prostaglandins in T-cell hyporesponsiveness, PGE2 was titrated into the cultures. PGE2 suppressed normal and TBH T-cell responsiveness in a dose-dependent manner. Normal host T cells were suppressed to a greater extent than TBH T cells by PGE2 (66% versus 42% suppression, respectively). Reduced Ia expression and active suppressor mechanisms are not the only mechanisms mediating hypoautoreactivity during tumor growth. TBH autoreactive L3T4+ T cells were less responsive to self-Ia; they were only 60-80% as reactive as their normal counterparts. To address whether the helper T (TH)-cell defect involved cytokines, T cells were treated with interleukin (IL)-1, IL-2, and IL-4. In all cases, the TBH T-cell response to the factors was decreased (only 60-75% as reactive as normal T cells). Because TBH M phi-mediated suppression can override the addition of IL-1, IL-2, and IL-4, indomethacin was also added with the exogenous interleukins. This coaddition significantly enhanced normal host autoreactivity above control levels while TBH autoreactivity (the combination of TBH T cells and TBH M phi) only returned to normal host unstimulated levels. Tumor growth modulates the immune response at least by (i) decreasing the accessory cell abilities of TBH M phi through decreased Ia expression and increased production of suppressive molecules such as prostaglandins; and (ii) decreasing the responsiveness to immune enhancing factors by TH cells.
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PMID:Tumor modulation of autoreactivity: decreased macrophage and autoreactive T cell interactions. 213 15

Autoimmune-susceptible, MRL-lpr/lpr (lpr) mice develop a profound lymphadenopathy resulting from the accumulation of CD4-CD8- (double-negative, DN) cells in peripheral lymphoid organs. The source and the mechanism of this abnormal accumulation of cells is still unknown. Recently, we reported that a significant number (approximately 35%) of the CD4-CD8- cells expressed J11d, a marker expressed by immature thymocytes but not by mature functional peripheral T cells. In the present study, we investigated the phenotype, growth requirements, and functional properties of purified J11d+ and J11d- subpopulations. Using the mAb, F23.1, which recognizes a TCR determinant encoded by the V beta 8 gene family, it was observed that approximately 30% of the J11d+ and J11d- DN cells expressed this determinant. Further studies on the thymus revealed that J11d+ DN cells from lpr thymus also contained F23.1+ cells (approximately 25%), whereas, similar cells from normal MRL(-)+/+mice were all F23.1-, consistent with earlier reports in other normal strains. Further phenotypic studies revealed that the peripheral J11d+ and J11d- cells from lpr mice were similar in expressing CD3, Ly-5 (B220), and Ly-24 (Pgp-1) determinants. When stimulated with phorbol myristic acetate (PMA) and recombinant IL-2 (rIL-2), only J11d- cells but not J11d+ cells responded by proliferation. However, in the presence of calcium ionophore (A23187) and PMA, both J11d+ and J11d- subpopulations proliferated by producing and responding to endogenous IL-2 but not IL-4. The lymph node T cells from 1-month-old MRL-lpr/lpr mice responded strongly when stimulated with PMA + rIL-4 or PMA + rIL-6. In contrast both J11d+ and J11d- subpopulations failed to respond when similarly stimulated. The J11d+ but not J11d- cells demonstrated spontaneous cytotoxic activity against the NK-sensitive YAC-1 tumor targets. The J11d- cells did not exhibit cytotoxic potential in spite of culture with PMA + rIL-2. Even after repeated culture in vitro with PMA + A23187 or PMA + rIL-2, both J11d+ and J11d- subpopulations failed to express the mature phenotype bearing CD4 and/or CD8 antigens. The present study demonstrates the expansion of unique J11d+, alpha beta-TCR+, DN T cells with cytotoxic potential in lpr mice and further suggests the existence of phenotypic and functional heterogeneity among the abnormal lpr DN cells.
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PMID:Evidence for the existence of distinct heterogeneity among the peripheral CD4-CD8- T cells from MRL-lpr/lpr mice based on the expression of the J11d marker, activation requirements, and functional properties. 213 66

Despite recent advances in the understanding of normal T lymphocyte immunobiology, there has been little progress in characterizing the non-HTLV cutaneous T-cell lymphomas and leukemias (CTCL) Mycosis Fungoides and Sezary syndrome. The two major impediments to in vitro studies of these malignancies have been the contamination of CTCL cells with normal T cells and the inability to induce a vigorous proliferative response or establish long-term cultures with standard T-cell mitogens. The ideal reagent for identifying CTCL cells in a given patient would be tumor specific. Although a monoclonal antibody to the clonotypic antigen receptor on CTCL cells would approach this ideal, it is not currently feasible to generate such antibodies for each CTCL patient. As a compromise, we chose to test an "almost clonotypic" reagent by examining whether monoclonal antibodies directed at the variable (V) region of the T-cell antigen receptor could be applied to CTCL. We identified three Sezary patients, who by standard T-cell phenotype and Southern blot analysis for clonality had a virtually pure peripheral blood population of leukemic cells (PBL). We then screened the PBL of these patients with a panel of seven commercially available monoclonal anti-V region antibodies and found one patients' cells reacted greater than 99% with alpha V beta 5. The other patients' cells were non-reactive. In addition, we utilized a solid-phase system to cross-link V beta 5 on the one CTCL patients' PBL cells, and found that they proliferated vigorously in the presence of 10 units of IL-2 and IL-4. Parallel cultures have been maintained for one month by restimulation twice a week. These findings suggest that anti-V region antibodies should prove useful for investigating the immunobiology of CTCL.
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PMID:Anti-V region antibodies as "almost clonotypic" reagents for the study of cutaneous T cell lymphomas and leukemias. 214 26

We have utilized cultured Langerhans cells to activate and expand hapten- and protein-specific T-helper cells from nonsensitized mice. The generation of these lines was strongly dependent on eliminating all autologously reacting cells from the responder T-cell population. Primary in vitro sensitization was not uniquely induced with cultured Langerhans cells as splenic dendritic cells could subserve the same function. Despite its ability to induce strong allogeneic T-cell responses as well as hapten-specific secondary responses, M12c cells, a class II-bearing B-cell lymphoma line, could not activate hapten-specific T-helper cells in vitro. After primary or secondary in vitro stimulation, the T-helper cells which are generated secrete IL-2 and are able to adoptively transfer hapten-specific contact sensitivity, thus stimulating Type-1 T-helper cells. The T-helper cell lines which were generated after repeated cycles of stimulation stimulated type-2 T-helper cells in that they produced IL-4 and depended on this cytokine for autocrine growth. As well, when cultured with syngeneic, hapten-modified, small resting B cells, these T-helper cells caused specific IgE production. Thus, the studies reported herein demonstrate that it is possible to activate and expand T-helper cells with desired specificity from nonsensitized animals in vitro. Previous studies have demonstrated that expansion and adoptive transfer of effector T cells with specificity for tumor-associated antigens may be useful in the control of certain tumors; T-helper cells generated by in vitro sensitization should also be useful in adoptive immunotherapy.
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PMID:Generation and characterization of T-helper cells by primary in vitro sensitization using Langerhans cells. 214 19

We have recently demonstrated that nitrosoureas such as 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) and chlorozotocin (CLZ) can cure almost 100% of mice bearing LSA tumor, syngeneic to C57BL/6 mice. In contrast, similar or higher doses of streptozotocin (STZ) completely failed to cure LSA-bearing mice. Further studies revealed that the efficacy of nitrosoureas may depend on their immunomodulating properties. In the current study, therefore, we investigated the effect of these nitrosoureas on the immune system of normal mice. Treatment of C57BL/6 mice with 5 intraperitoneal injections of 20 mg/kg body weight of BCNU or CLZ caused an increase in the percentage of CD4(-)CD8- T cells and a decrease in the percentage of CD4(+)CD8+ T cells in the thymus. In addition, such treatment also caused an increase in the percentage of CD4+ T cells without significantly affecting the CD8+ T cells in the thymus. However, when total cellularity of the thymus was studied, BCNU and CLZ were found to decrease the total number of CD4(+)CD8+ T cells without significantly affecting the other subsets. In contrast, similar or higher (100 mg/kg body weight) doses of STZ had no significant effect on the total number and percentages of T cell subsets in the thymus. Also BCNU and CLZ but not STZ treatment caused a 50% decrease in the total number of CD4+ and CD8+ T cells in the spleen. When T cells in the spleens of nitrosourea-treated mice were functionally analysed, it was observed that BCNU and CLZ caused a dramatic decrease in the T cell responsiveness to ConA, anti-CD3 and phorbol myristate acetate plus calcium ionophore stimulation. In contrast, STZ treatment failed to significantly inhibit the T cell responsiveness to these activation signals. Using the accessory cell-dependent and -independent assays, BCNU and CLZ were found to suppress the functions of both T cells and macrophages. Also, addition of growth factors such as IL-1, IL-2, IL-4 and IL-6 failed to reconstitute the defective responsiveness of BCNU- and CLZ-treated T cells and macrophages. Together our data suggest that nitrosoureas have varying immunomodulating properties and this may in turn determine their efficacy in the treatment of cancer.
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PMID:Immunomodulatory effects of nitrosoureas on the phenotype and functions of T cells in the thymus and periphery. 214 19

Undifferentiated nasopharyngeal carcinoma (NPC) is tightly associated with the Epstein-Barr virus (EBV) and very heavily infiltrated with T lymphocytes. We demonstrated recently that NPC epithelial cells produce immuno-regulatory molecules, including the Blast-2/CD23 antigen, which is induced in B lymphocytes upon infection by EBV. We demonstrate here that CD23 expression is a non-constant but highly specific feature of epithelial cells from NPC. The C15 and C17 NPC tumor cells express mainly the b form of CD23, which is known to be non-lineage-specific and IL-4-inducible. C17 cells were found also to weakly express the a form of CD23, which has been described as B cell-specific. In addition, several factors potentially released in vivo by tumor infiltrating lymphocytes (TILs) are able to regulate CD23 expression in NPC cells. In particular, we found that IL-4 was a potent inducer of CD23 expression in C15 cells, as shown at both the protein and the mRNA levels. These results, together with the already reported expression of class II MHC antigens and the release of IL-1 by NPC cells, suggest that the interactions between TILs and malignant cells are a key factor in NPC pathogenesis and development.
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PMID:Structure and regulation of the blast-2/CD23 antigen in epithelial cells from nasopharyngeal carcinoma. 215 Oct 25

Systemic interleukin 2 (IL-2) and IL-2-activated lymphocytes have induced tumor regression in some cancer patients. The IL-2-activated cells have usually been generated by obtaining peripheral blood mononuclear cells (PBMC) from cancer patients shortly after systemic IL-2 therapy and culturing them with IL-2 in vitro. In an effort to augment the ex vivo generation of such cells preactivated in vivo, we examined the proliferative responses of PBMC from IL-2-treated cancer patients to several proliferative signals including IL-2, interleukin 4 (IL-4), and mitogenic antibodies to CD3 and CD28. Although much is known about the response of normal PBMC to these signals, the possibility was considered that the response of lymphocytes preactivated by IL-2 in vivo might differ from that of normal PBMC. Accordingly, PBMC obtained from ten normal, healthy controls and from 17 patients with advanced cancer 1 to 3 days after systemic IL-2 therapy were cultured for 4 days with IL-4 (1000 units/ml) and/or IL-2 (10 units/ml or 1000 units/ml) or with combinations of IL-4 and anti-CD3 +/- anti-CD28, and they were then tested for proliferation by [3H]thymidine incorporation. IL-4 failed to induce proliferation of normal PBMC and inhibited IL-2-induced proliferation, whereas IL-4 alone induced proliferation in PBMC from five of 11 IL-2-treated patients and did not inhibit but augmented the proliferation induced by IL-2 (10 units/ml and 1000 units/ml) in PBMC from six of nine patients and five of 11 patients, respectively. Anti-CD3 induced proliferation in PBMC from eight of nine patients, and the proliferation was consistently augmented by coculture with anti-CD28. Finally, IL-4 significantly augmented the proliferative responses of PBMC from IL-2-treated patients to anti-CD3, as well as to the combination of anti-CD3 and anti-CD28. Thus, in PBMC from IL-2-treated cancer patients, IL-4 enhanced the in vitro proliferation induced by IL-2 or by anti-CD3 +/- anti-CD28. The results suggest that IL-4 and/or mitogenic antibodies may be useful in augmenting the ex vivo generation of lymphocytes for clinical adoptive immunotherapy.
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PMID:Enhancement by interleukin 4 of interleukin 2- or antibody-induced proliferation of lymphocytes from interleukin 2-treated cancer patients. 215 52


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