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Query: UNIPROT:P06889 (Mol)
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The biochemical structure of CD69 early activation antigen has been characterized by means of two newly isolated mAb, namely C1.18 and E16.5. Upon analysis by SDS-PAGE, C1.18-reactive molecules immunoprecipitated from 125I-surface labeled PMA activated PBL consisted of a 32 + 32 kD dimer, a 32 + 26 kD dimer, a 26 + 26 kD dimer and a 21 + 21 kD dimer. E16.5-reactive molecules consisted of a 26 + 26 kD dimer and a 21 + 21 kD dimer. Cross absorption experiments showed that E16.5 mAb reacts with an epitope of the CD69 molecule distinct from the one recognized by C1.18 mAb and present only on a subpopulation of the CD69 molecular pool. The patterns of migration of C1.18- and E16.5-reactive molecules in two-dimensional gel-electrophoresis, under reducing conditions before and after treatment with Endoglycosidase F enzyme suggest that the two mAb recognize the same glycoprotein structure, but in two distinct glycosylation forms, both expressed on the cell surface membrane. Finally, p32, p26 and p21 of CD69 complex obtained from three distinct normal donors did not show appreciable structural polymorphism, by two-dimensional peptide mapping, not only among single subunits within the same individual, but also among homologous subunits in distinct individuals. Further, it was found that CD69 complex is expressed at the cell surface of resting PBL, although at a very reduced level in comparison to PMA activated cells. C1.18 and E16.5 mAb induced comparable cell proliferation and IL-2 production in PBL in the presence of PMA. C1.18 mAb increased intracellular free calcium concn in PMA activated PBL after cross-linking with goat anti mouse Ig, while the effect induced by E16.5 mAb after cross-linking was consistently lower. Finally, it was found that Sepharose-linked C1.18 mAb, in the presence of rIL-2 or PMA, did not induce TNF release from 6 NK cell clones.
Mol Immunol
PMID:Structural analysis of the CD69 early activation antigen by two monoclonal antibodies directed to different epitopes. 170 36

The role of cytokines in vivo has been difficult to assess. This difficulty is due, in part, to the limited number of producer cells and the strict regulation of cytokine production. In order to address this situation, we have developed assays which allow us to quantitate both protein production and steady state mRNA levels from specific in vivo sites. In this report, we present data utilizing these assays on cells obtained from draining LN following specific sensitization with antigen in vivo. In order to determine the relative quantities of cytokine mRNA, we modified the reverse transcriptase-polymerase chain reaction which had been previously described. The modified assay is (1) linear over a large concn range of input template (2) demonstrates a high degree of reproducibility (SE approximately 13%) and (3) is very sensitive. Utilizing this assay, we have measured a constitutive mRNA (DHFR), quantitated both the presence of lymphokine mRNA (IL-2) and the induction of cytokine mRNA (TNF alpha). In this report we have examined the kinetics of TNF alpha mRNA expression and have demonstrated that following epicutaneous sensitization with picryl chloride, there is rapid induction (within 24 hr) of TNF alpha mRNA in the draining LN and that the levels of mRNA remain detectable through d7. In addition, we determined the time course of production of TNF protein by the draining LN cells and found that it was similar to that of the mRNA levels. A potential pathologic role for immune response generated TNF alpha is also discussed. We believe these experiments demonstrate that cytokine production following antigen-specific sensitization in vivo can be analyzed at both the cellular and molecular level. The data suggests that this approach can be used to study cytokine regulation in vivo.
Mol Immunol
PMID:Quantitation of cytokine mRNA levels utilizing the reverse transcriptase-polymerase chain reaction following primary antigen-specific sensitization in vivo--I. Verification of linearity, reproducibility and specificity. 171 71

A chimeric mouse/human MAb against the human p55 IL-2R was constructed from Ig genes isolated from a mouse hybridoma cell line, designated AHT107. AHT107 binds to a different epitope on p55 than IL-2, and similar to observations made for other rodent anti-IL-2R antibodies that do not recognize the same or spatially related epitope as IL-2, murine AHT107 did not efficiently inhibit proliferation of T-lymphocytes in mitogen and MLR PBMC stimulation assays. In contrast, the chimeric AHT107 antibodies containing a human IgG-1 constant region had substantially more anti-proliferative activity than their murine IgG-I counterparts. Our results indicated that the human constant region of the chimeric antibodies interacted more efficiently than the murine constant region with effector components present in the PBMC cultures. This conclusion was supported by our observation that F(ab')2 generated from the chimeric antibodies did not efficiently inhibit proliferation in the PBMC assays, and the chimeric antibodies did not inhibit proliferation of an antigen specific, IL-2 dependent human T-cell clone stimulated in the absence of PBMC.
Mol Immunol 1992 Jan
PMID:A chimeric mouse/human anti-IL-2 receptor antibody with enhanced biological activities. 173 Nov 87

Glycosphingolipids added to the cell culture medium can be incorporated into the plasma membrane and interfere with the growth of certain cell types. In the past years, previous reports have shown that gangliosides, a class of glycosphingolipids bearing sialic acid can inhibit antigen or mitogen induced T cell proliferative responses in vitro. We report here that the inhibition of PHA induced proliferation by the trisialoganglioside GT1b was not reversed by addition of exogenous IL-1, IL-2, TPA and calcium ionophore. Furthermore, GT1b did not affect IL-2 production by activated T cells. In addition, GT1b ganglioside could also decrease strongly the expression of the T cell antigens CD3, CD2, CD4, CD8 and the alpha/beta T cell receptor antigenic complex whereas it did not affect HLA-class I antigens. By contrast, GT1b modulated only partially membrane expression of activation antigens such as CD25 (Tac) and transferrin receptor and increased the expression of HLA-class II antigens. Moreover CD25 messenger RNA induction was not affected by GT1b treatment of PHA-stimulated T cells. Our results demonstrate that gangliosides, in spite of their anti-proliferative capacity and their modulation effect on T cell antigen membrane expression, do not prevent the progression of T cells into early stages of the activation process.
Mol Immunol 1991 Nov
PMID:Analysis of phenotypic and functional changes during ganglioside-induced inhibition of human T cell proliferation. 183 57

We have evaluated the effect of Interleukin-2 [IL-2] after Cyclophosphamide (C) chemotherapy in 41 patients with metastatic cancer. IL-2 was given as a continuous infusion priming cycle 36 hours after C at 1 gm/m2 intravenously. In 39 evaluable patients, there were no complete remissions [CR], 2 partial remissions [PR], and 1 had a minor response [MR]. Stable disease for 30 days was seen in 16 patients whereas 20 progressed. The durations of partial and minor responses were brief, ranging from 1-6 months. Grade 3-4 neutropenia was seen in 41%. This was more severe than seen with IL-2 alone or IL-2 combined with lower doses of C. The marrow suppression was due to the chemotherapy. This combination of IL-2 and C appears to be reasonably well tolerated by patients, but toxicity is greater and the response rate is no better than results achieved by IL-2 alone. Responses of 26 patients with renal cancer appear to be inferior to our historical data using IL-2/LAK cells without C. Immune monitoring demonstrated changes expected with C chemotherapy (i.e., a non-selective decline in immune function). C induced no further differences in IL-2 induced changes in immune function.
Mol Biother 1991 Jun
PMID:Continuous infusion of interleukin-2 and cyclophosphamide as treatment of advanced cancers: a National Biotherapy Study Group Trial. 191 Jun 23

In recent years there has been considerable discussion of possible cross-regulatory mechanisms involving the immune system and the neuroendocrine system. Certainly, evidence of hormonal communication between these two systems would provide at least a partial explanation for the many anecdotal observations of physical and mental stress affecting disease course. In previous studies of a neoplastic lymphokine-responsive B cell clone, BCL1-3B3, we noted that these cells produced a lymphokine which could affect normal B cell growth and viability. Physical characterization of this lymphokine indicated that its molecular weight was identical to that of the neuroendocrine hormone adrenocorticotropin (ACTH). Since Blalock and colleagues had reported the production of ACTH by virally-infected B cells, we have investigated whether ACTH can functionally mimic the BCL1-3B3-derived lymphokine. The neuroendocrine hormone adrenocorticotropin (ACTH) can increase in vitro murine B lymphocyte proliferation when added at physiologically relevant concentrations between 10(-9) to 10(-11) M. ACTH does not mimic the action of any lymphokine known to be required for B cell proliferation such as IL-2, IL-4, or IL-5. ACTH requires the presence of one or more of these known B cell stimulatory factors for its action and the most marked increase in B cell proliferation were noted in assays for IL-5 activity where 10(-10) M ACTH increased thymidine incorporation up to five-fold. Using two-stage assays, we determined that ACTH acts during the latter stages of B cell activation (i.e., 3-4 days after initial stimulation with either the combination of IL-4, GAMIg-Sepharose, and IL-1 or the combination of DxS and IL-5). These data indicate a direct role for a stress-induced neuroendocrine hormone in modulating the course of a humoral immune response.
J Mol Cell Immunol 1990
PMID:Adrenocorticotropin (ACTH) functions as a late-acting B cell growth factor and synergizes with interleukin 5. 196 84

Although interleukin (IL)-2 may in part be responsible for lymphocyte accumulation to sites of active sarcoidosis, other cytokines that control such recruitment are not well characterized. Similarly, the pathogenic rationale for the ability of sarcoid macrophages to produce 1,25-dihydroxycholecalciferol (calcitriol) is not understood. We studied the release of chemokinetic lymphokines from human nylon wool-non-adherent tonsillar lymphocytes (HNTLs) employing a standard in vitro lymphocyte migration assay. If mitogen-stimulated HNTL supernatants were fractionated by high-performance liquid chromatography, five positive and one negative chemokinetic factors could be identified. The five lymphocyte chemoattractant factors (LCFs) ranged in mol wt from 5 to 35 kD and stimulated the in vitro migration of nonsensitized human lymphocytes by 200 to 500%. The LCFs appeared distinct from IL-2, IL-1, or gamma-interferon. Co-incubation of HNTLs with mitogen and 1 nM calcitriol prevented the production or release of two of the LCFs and significantly decreased the quantity of a third LCF. Calcitriol also resulted in the appearance of a second negative chemokinetic factor, lymphocyte migration inhibitory factor (LyMIF). Combined with our previous studies demonstrating that calcitriol interferes with IL-2-induced lymphocyte migration, these results provide a rationale for an anti-inflammatory role for calcitriol in sarcoidosis and other granulomatous disorders. These experiments also demonstrate that the control of lymphocyte recruitment to inflammatory foci is multifactorial.
Am J Respir Cell Mol Biol 1991 Jan
PMID:Lymphocyte chemokinetic factors derived from human tonsils: modulation by 1,25-dihydroxyvitamin D3 (calcitriol). 198 77

Two murine T cell lines (C30.1 and Line 1) were used to study the expression of the p55 interleukin-2 receptor gene. C30.1 is an IL-2-dependent T cell line that can be stimulated for a short period of time by IL-4. Line 1 cells are propagated in IL-4 but they also proliferate in response to IL-2. In both cell lines stimulation by IL-2 leads to a strong induction of p55 IL-2 receptor mRNA while stimulation by IL-4 leads only to a very moderate increase in expression of this mRNA. The induction of p55 IL-2 receptor mRNA by IL-4 is comparable to that of beta-actin mRNA. These data confirm that IL-2 upregulates p55 IL-2 receptor gene expression while IL-4, which also activates T cells, does not lead to specific induction of this gene. We have also determined the transcription initiation sites utilized by the p55 IL-2 receptor gene in C30.1 and Line 1 cells. Seven sites were identified, one of which predominates. Resting cells, or cells stimulated with IL-2 or IL-4, display the same pattern of transcription site utilization.
Mol Immunol
PMID:Induction of mouse p55 interleukin-2 receptor gene expression by IL-2 and IL-4 and characterization of its transcription initiation sites. 201 Nov 31

The peptide regulatory factors (PRFs), variously termed cytokines, lymphokines, interleukins, colony stimulating factors, interferons, etc., play a key role in the quantitative and qualitative regulation of protective responses--both in initiating immunological and inflammatory responses and in mediating and controlling the effector mechanisms that protect the body against micro-organisms. The process of immunization--involving antigen-presentation, lymphocyte-activation and clonal proliferation--depends on the action of a variety of PRFs. The function of accessory cells--the dendritic cells, macrophages, etc.--is stimulated by PRFs such as interferon-gamma, IL-1, TNF, GM-CSF and IL-4. The activation and expansion of T-lymphocytes requires IL-1, IL-2, IL-4, interferon-gamma, IL-6 and probably IL-7. Likewise, the activation and expansion of B-lymphocytes is regulated by PRFs such as IL-1, IL-2, IL-4, IL-5, IL-6, IL-7 and interferon-gamma. It is likely, although unproven, that PRFs also regulate the differentiation of B-cells to memory cells. Successful vaccination requires the immune system to be primed in such a way that natural challenge with a micro-organism or its products evokes an immune response that has the qualitative and the quantitative characteristics of both the humoral and cellular responses. Antibody class is critically influenced by particular PRFs, e.g. interferon-gamma regulates IgG2a; IL-4, IgE and IgG1; IL-5 and TGF-beta, IgA. PRFs are both produced by and regulate the T-lymphocytes which have key roles in protective responses--either directly, viz. the cytotoxic T-lymphocytes important in protection against certain viruses, or indirectly through the secretion of PRFs that regulate the speed, magnitude and quality of antibody cellular responses. The recruitment and enhanced production and function of granulocytic and phagocytic cells involves a number of T-lymphocyte PRFs including GM-CSF, IL-3, IL-5, IL-4, and IL-6. We do not have a good understanding of the fine-tuning of cellular responses nor of how infection with different pathogens results in different types of inflammatory responses; it is clear, however, that certain cellular responses are due to the action of specific PRFs, e.g. IL-3 induces a mastocytosis and IL-5 an eosinophilia. There is increasing evidence that the relative levels of different PRFs are important determinants of the effectiveness of responses.(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Immunol 1991 Mar
PMID:Peptide regulatory factors and optimization of vaccines. 201 99

Murine T and B lymphocytes can be induced to release soluble interleukin 2 receptors (sIL2R). This receptor is believed to be a truncated form of the p55 chain of the cell membrane-associated receptor. It has been speculated that this receptor may play an immunoregulatory role via competition for IL-2 with the high-affinity (p55/75 heterodimer) IL-2 receptor. Of crucial importance to this hypothesis are both the concentration of the receptor and its affinity of binding for interleukin 2. We report the measurement of the affinity of sIL2R derived from stimulated normal murine splenocytes for IL-2. We also report the quantification of an enzyme linked immunosorbent assay (ELISA) for sIL2R via measurement of the sIL2R concentration in normal murine splenocyte conditioned medium using a radioimmunometric assay and Scatchard analysis. This method of sIL2R quantification is preferable to sIL2R purification and subsequent concentration estimation as used by previous investigators as any purification process risks destruction of some epitopes. Using the above conditioned medium as a standard we have tested supernatants from several cell lines and sera from several different mouse strains for sIL2R. As would be expected this method of quantification yielded a markedly different value for serum sIL2R levels in normal mice than that obtained by previous investigators. Our results indicate that it is very unlikely that sIL2R competes with the high-affinity form of the IL-2 receptor for IL-2. However, it is possible that it competes for IL-2 with the medium-affinity p75 form of the IL-2 receptor and as such is important in restricting unwanted non-specific (bystander) activation of p75 expressing cells. Evidence from both our previous work as well as from the literature is presented to support this hypothesis.
J Mol Cell Immunol 1990
PMID:A regulatory role for the soluble IL-2 receptor via competition with the p75 cell-surface form of the receptor for IL-2. 208 Sep 85


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