Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P14784 (IL-2 receptor)
 3,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have earlier observed that 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU), a chemotherapeutic drug, cured 90-100% of mice bearing a syngeneic Ia- T-cell lymphoma (LSA) and furthermore, 100% of the BCNU-cured mice could reject homologous tumor rechallenge. In the present study, purified CD4+ and CD8+ T cells isolated from BCNU-cured mice were used to investigate the mechanism by which such T cells recognized and responded to the tumor-specific antigens. The responsiveness of CD4+ T cells to LSA was dependent on processing and presentation of tumor-specific antigens by syngenic Ia+ splenic antigen-presenting cells (APC). Such activated CD4+ T cells endogenously produced IL-2 but not IL-4 and only IL-2 acted as an autocrine growth factor inasmuch as anti-IL-2 receptor antibodies but not anti-IL-4 antibodies inhibited the CD4+ T cell proliferation. In contrast, the CD8+ T cells failed to produce endogenous growth factors when stimulated with LSA alone or with LSA plus APC, and therefore failed to proliferate. However, in the presence of exogenous recombinant IL-2 (rIL-2), CD8+ T cells could proliferate directly in response to LSA-stimulation, even in the absence of APC. Addition of exogenous rIL-4 alone to cultures induced CD4+ but not CD8+ T cells to proliferate. However, rIL-4 in the presence of rIL-2, could synergize and induce tumor-specific proliferation of CD8+ cells. These data suggested that for IL-4 to act as a T-cell growth factor, the presence of IL-2 was essential, either in the form of endogenously secreted IL-2 (CD4+ T cells) or exogenous IL-2 (for CD8+ T cells). In contrast to rIL-2 and rIL-4, rIL-6 failed to induce growth when used alone or in combination with rIL-2 or rIL-4. Furthermore, when tested individually, only rIL-2 but not rIL-4 or rIL-6 could support the cytotoxic differentiation of CD8+ T cells. The present study suggests that the early events in responsiveness to LSA tumor may involve activation of the IL-2-producing Th1 subpopulation of CD4+ helper cells which in turn activate IL-2 dependent CD8+ cytotoxic T cells. IL-4 if produced subsequently, may act synergistically with IL-2 to promote the growth of CD4+ and CD8+ T cells.
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PMID:Role of IL-2, IL-4 and IL-6 in the growth and differentiation of tumor-specific CD4+ T helper and CD8+ T cytotoxic cells. 197 41

Transmembrane signaling of normal human T cells was explored with mAbs directed at TCR, CD2, CD4, CD5, or CD8 antigens and highly purified CD4+ T cells and CD8+ T cells. Our experiments explicitly show that: (a) crosslinkage of TCR with the CD2 antigen, and not independent crosslinking of TCR and of CD2 antigen or crosslinking of either protein with the CD4 or CD8 antigen induces significant proliferation independent of co-stimulatory signals (e.g., accessory cells, recombinant lymphokines, or tumor promoter), (b) F(ab')2 fragments of mAb directed at the TCR and F(ab')2 anti-CD2, crosslinked with F(ab')2 fragments of rabbit anti-mouse IgG, promote the proliferation of highly purified T cells, (c) a prompt and sustained increase in intracellular free Ca2+ concentration results from crosslinkage of TCR with the CD2 antigen, (d) T cell proliferation induced by this novel approach is curtailed by EGTA and by direct or competitive inhibitors of PKC, (e) crosslinkage of TCR with the CD2 antigen results in the transcriptional activation and translation of the gene for IL-2 and in the expression of IL-2 receptor alpha (CD25), (f) anti-CD25 mAbs inhibit T cell proliferation initiated by crosslinkage of TCR with the CD2 antigen, and recombinant IL-2 restores the proliferative response. Our first demonstration that crosslinkage of TCR with the CD2 antigen induces proliferation of normal human CD4+ T cells and CD8+ T cells, in addition to revealing a novel activation mechanism utilizable by the two major subsets of T cells, suggest that the CD2 antigen might be targeted for the regulation of antigen-specific T cell immunity (e.g., organ transplantation).
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PMID:A novel model for antigen-dependent activation of normal human T cells. Transmembrane signaling by crosslinkage of the CD3/T cell receptor-alpha/beta complex with the cluster determinant 2 antigen. 197 76

Small cell lung cancer (SCLC) is the most malignant of the pulmonary neoplasms and is associated with a poor local cellular immune response. 16 patients with non small cell lung cancer (NSCLC) and 11 patients with SCLC underwent bronchoalveolar lavage (BAL) in the lung which harbored the tumor in order to investigate the lymphocyte surface antigens utilizing the immunoperoxidase technique. Analysis of blood lymphocytes was performed in parallel. 8 patients with previous sarcoidosis in complete remission who underwent BAL and 10 normal blood donors served as controls. Among blood lymphocytes the CD3+, CD4+ and CD16+ cell populations were elevated significantly and the T4/T8 ratio was elevated in NSCLC patients, but only CD16+ were augmented in SCLC. Cell populations expressing the activation markers transferrin (TF) receptor, interleukin-2 (IL-2) receptor and the very late antigen VAL-1 were also increased in NSCLC, while SCLC was associated with antigen distributions similar to controls. No differences between the cohorts were seen in the expression of human leukocyte antigen (HLA)-DR. In BAL the population of CD3+ and CD4+ cells were reduced in SCLC and the T4/T8 ratio was diminished in contrast to controls and NSCLC patients, whereas these two latter groups did not differ from each other. The distribution pattern of CD16, TF receptor and IL-2 receptor in the study groups resembled that of cells of the blood stream, but CD16+ natural killer cells were additionally down regulated to control values in SCLC. No differences were seen in the distribution of VLA-1. HLA-DR+ cells were clearly elevated in both cancer groups.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Assessment of local cellular immunity in lung cancer by bronchoalveolar lavage. 197 83

A functional analysis of tumor-infiltrating lymphocytes (TILs) from renal cell carcinoma (RCC) and malignant melanoma was performed. TILs were expanded in recombinant interleukin-2 (50 U/ml) in Iscoves medium. Phenotypic and functional (cytolytic vs regulatory) analyses were carried out with the fresh and expanded TIL populations after 4 weeks in culture. Only one TIL population from an RCC case (out of six cases studied) was CD8+ and demonstrated MHC class I-restricted tumor-specific cytotoxicity against the autologous RCC target. TIL populations from the other five cases became predominantly CD4+ and they neither killed the respective autologous tumor cells nor killed the NK-sensitive target K-562 cells. When studied for other functions, two CD4+ TIL populations were found to suppress the lymphokine-activated killer cell response by peripheral blood lymphocytes (PBL) in coculture. Of these two, a TIL population from an RCC case (MJ TIL) was used to study the cellular and molecular mechanisms of suppression. The MJ TIL synthesized a supernatant factor that blocked activation of resting PBL as measured by the induction of high-affinity IL-2 receptor (IL-2R) when stimulated by phytohemagglutinin but did not down-regulate the fully expressed IL-2R on activated T cells. The suppression of high-affinity IL-2R induction on T cells did not result from tumor necrosis factor-alpha and beta or from transforming growth factor-beta as these cytokines were not detected in the cell-free supernatant from the MJ TIL culture. The supernatant factor also suppressed IL-2-mediated enhancement of cytotoxicity by natural killer (NK) cells without demonstrating direct toxic effect on the NK cells. Thus, when TIL are used for adoptive immunocytotherapy, it may be useful to fully characterize them functionally, in vitro.
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PMID:Suppression of lymphokine-activated killer cell generation by tumor-infiltrating lymphocytes. 202 93

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

Peripheral blood lymphocytes, regional lymph node lymphocytes or malignant effusion lymphocytes from cancer patients were incubated with crude IL-2 (cIL-2) for 13 days. These effectors, which frequently expressed IL-2 receptor (IL-2R), proliferated well and possessed augmented killing activity against fresh autologous tumor cells and K562. However, when recombinant IL-2 (rIL-2) was added for the last 4 days of culture instead of cIL-2, IL-2R expression and killing activity against fresh autologous tumor cells decreased significantly (P less than 0.05). Phenotypic analysis indicated that cIL-2 significantly promoted the expansion of the cytotoxic population (CD8+.11b-)(P less than 0.05). The decreases in killing activity and IL-2R expression were restored by 0.004% PHA plus rIL-2, but not in the presence of rIFN-gamma, rIL-1 alpha, rIL-1 beta, rIL-4 or rIL-6. PHA-free cIL-2 maintained killing activity, but not IL-2R expression. We conclude that some factors in cIL-2 and a low dose of PHA-P are necessary for the maintenance of killing activity and IL-2R expression of cultured lymphocytes in the late phase of culture.
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PMID:Comparison between crude interleukin-2 and recombinant interleukin-2 in maintaining killing activity of cultured lymphocytes. 211 1

Immunohistochemical study with various monoclonal antibodies to the mononuclear cell surface antigens was carried out on the regional lymph nodes in patients with cervical cancer to assess the augmentative effect of lentinan. Zero, 2, 4, or 6 mg of lentinan was administered i.v. one day prior to surgery to patients with cervical cancer (14 cases with FIGO stage 0 and 19 with FIGO stage Ib) and those with benign gynecologic tumors (8 cases with myoma uteri and 6 with ovarian tumor). Frozen sections of fresh pelvic lymph nodes obtained from these patients during surgery were stained by the ABC (avidin-biotin-peroxidase complex) method using several monoclonal antibodies to define the surface phenotype of mononuclear cells. The results were as follows: 1. Pelvic lymph nodes in patients with benign disease: In the absence of lentinan, lymphocytes stained with Leu 3a antibody were more numerous than those stained with Leu 2a, and both were observed mainly in the paracortical area (PC). The number of lymphocytes stained with Leu 4 antibody was practically equal to the sum of those stained with Leu 3a and Leu 2a. HLA-Dr positive lymphocytes were present in moderate numbers in PC and sinus. The above findings were not changed by the administration of lentinan. Cells stained with monoclonal antibodies including Leu 7, 11, M3, and IL-2 receptor (IL-2R) were very few or absent. 2. Pelvic lymph nodes in patients with cervical cancer receiving no lentinan: The findings obtained in these cases were much the same as those in patients with benign tumors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Antigenic phenotype of the lymphocytic component of regional lymph nodes in patients with cervical cancer and its modulation by lentinan]. 213 55

Synergistic and cooperative effects in vitro of OKT3, interleukin 2 (IL-2), and tumor necrosis factor alpha (TNF) as stimuli in generating effectors with lymphokine-activated killer activity were studied. Activation of human peripheral blood mononuclear cells with OKT3 (10 ng/ml) for 48 h, followed by culture in low concentrations of IL-2 (10 units/ml) and TNF (250 units/ml) resulted in higher cell recovery (50- to 3300-fold) compared to the number of cells in the initial culture and enhanced lytic activity against both Raji and fresh lung tumor targets (mean 100-fold) by day 30 compared to those expanded with higher concentrations of IL-2 (100 units/ml) alone. Immunofluorescence analysis of peripheral blood mononuclear cells initiated with OKT3 and expanded with IL-2 plus TNF revealed a selective increase in CD8+ cells and a decrease in CD4+ by day 28; the opposite effect was observed when cells were incubated with 100 units/ml of IL-2 alone, resulting in a greater proportion of CD4+ cells. Almost all cells were CD3+. Studies of cytokine receptor expression indicated that OKT3 plus IL-2 plus TNF caused an earlier up-regulation of the IL-2 receptor beta chain (Tac) and higher TNF receptor expression by day 6 compared to 100 units/ml IL-2 alone. Significant TNF levels (greater than 17 units/ml) were measured in culture supernatants from peripheral blood mononuclear cells initiated with OKT3 alone. Collectively, our data demonstrate that induction of lymphokine-activated killer activity with OKT3, followed by culture in low concentrations of IL-2 plus TNF is an alternative to the use of high-dose IL-2 alone and suggest that this combination may provide potential advantages in long-term generation of cytolytic cells.
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PMID:Characterization of OKT3-initiated lymphokine-activated effectors expanded with interleukin 2 and tumor necrosis factor alpha. 216 Mar 21

Tumor infiltrating (TIL) and peripheral blood lymphocytes (PBL) were isolated from 18 patients with non-small cell lung cancer undergoing radical surgery. Surface marker analysis revealed that TILs and PBLs mainly consisted of CD3+ T cells and that TILs generally displayed a lower CD4/CD8 ratio. Differences were found in the expression of CD25 (IL-2 receptor) and DR (MHC class II) antigens, which were increased in TILs, and in the percentage of CD16+ natural killer (NK) cells, which was reduced in TILs as compared to PBLs. Accordingly, the NK activity of TILs was lower than that of PBLs, whereas neither TILs nor PBLs expressed spontaneous cytolytic activity against fresh autologous tumor cells, melanoma cells and the "NK-resistant" A549 lung carcinoma cell line. After 4 days of culture in medium with recombinant-interleukin-2 (rIL-2), TILs and PBLs acquired cytolytic activity against all cell targets, but TILs expressed higher levels of cytotoxicity than autologous PBLs only in 3 patients out of 16 tested. More importantly, both TILs and PBLs displayed similar levels of cytotoxic activity against autologous tumor cells. TILs and PBLs from 8 patients were also analyzed by a limiting dilution microculture system. Cloning efficiency was remarkably lower in TILs, and surface marker analysis of T cell clones confirmed that an accumulation of CD8+ lymphocytes, which displayed cytolytic activity in a lectin-dependent assay, occurred at the tumor site. The non-MHC-restricted cytolytic activity of TIL- and PBL-derived T cell clones against K562, A549, and allogeneic melanoma cells and the cytolytic activity against autologous tumor cells showed no significant differences. Only 53% of TIL clones released IL-2 in response to PHA + TPA stimulation, whereas 68% of PBL-derived clones were IL-2 producers. Moreover, most PBL- and TIL-derived clones released tumor necrosis factor alpha in response to mitogen stimulation.
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PMID:Peripheral blood and tumor infiltrating lymphocytes in non-small cell lung cancer: analysis at the population and clonal level. 217 60

Recent data from studies of experimental murine tumors and certain human tumors (primarily melanoma) suggest that tumor-infiltrating T-lymphocytes (T-cell TILs) represent a highly potent and specific host antitumor response. We conducted an immunohistochemical analysis of the T-cell TIL subpopulations in frozen tissue sections taken from 82 consecutive B-cell diffuse large cell lymphoma (DLCL) patients. Initially, we analyzed the relationship in these patients between relapse-free survival (RFS) and their T-cell TIL characteristics. Nineteen patients had a low percentage (less than 6% of Leu-2+ (suppressor/cytotoxic) T-cell TILs, and 63 patients had a high percentage (greater than 6%) of Leu-2+ TILs. We found that a low percentage of Leu-2+ TILs correlated with a reduction in RFS: at 20 mo follow-up, all 19 low Leu-2+ patients had relapsed, whereas 70% of the 63 high Leu-2+ patients remained relapse-free (P = 0.008). No significant correlations appeared between patients' T-cell TIL subsets and overall survival. The percentage of newly diagnosed tumors with low counts of Leu-4+ (pan-T) TILs was marginally greater among interleukin-2 (IL-2) receptor-positive tumors than among IL-2 receptor-negative tumors (50 versus 28%, P = 0.098), which suggests that specific phenotypic characteristics of B-cell DLCL may modulate the host T-cell TIL response. Our results indicate that the host's T-cell TIL response in B-cell DLCL can be quantitated from frozen tissue sections and that this response may be related to disease course. Further related TIL studies may lead to new immunorestorative therapeutic approaches for patients with deficient or aberrant cytotoxic T-lymphocyte host responses.
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PMID:Tumor-infiltrating T-lymphocytes in B-cell diffuse large cell lymphoma related to disease course. 219 16


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