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PubMedDate not supplied

Positive and negative immunoregulation through CD4 depends on the concentration of the specific ligand and on the state of activation of the responding cells.

In order to better define the functional role of the interaction of CD4 polypeptide with the T-cell receptor (TCR) complex, we analysed the effect of an anti-CD4 monoclonal antibody (mAb) on T-cell activation and on the modulation of expression of CD3, CD4 and TCR variable (V) regions. The results presented here demonstrate that both positive and negative modulation of CD3 and TCR V regions can be obtained with different concentrations of the same anti-CD4 mAb and that these effects are functionally directly related to differences in IL2-receptor expression. Moreover, our data show that the dose of anti-CD4 mAb required for modulating CD3- and CD4-molecule expression on activated E+ peripheral blood mononuclear cells is at least 30 times higher than that required to obtain the same effect on resting cells. Thus, our results demonstrate that the interaction of CD4 molecule with its ligand can result in both up and downregulation of TCR and IL2-receptor expression, and that this differential modulation is strictly dependent on the concentration of available ligand as well as on the activation state of the responding cells.

Adult↗
PubMed1996

Cure of disseminated xenografted human Hodgkin's tumors by bispecific monoclonal antibodies and human T cells: the role of human T-cell subsets in a preclinical model.

Cure of a single established human Hodgkin's tumor growing subcutaneously in severe combined immunodeficient (SCID) mice can be achieved with a complex protocol using two bispecific monoclonal antibodies (Bi-MoAb) directed against the Hodgkin's associated CD30 antigen and the T-cell triggering molecules CD3 and CD28, respectively, together with human T cells prestimulated in vitro with Bi-MoAbs in the presence of CD30+ cells. To adapt this model to the clinical situation, disseminated tumors were established in SCID mice by intravenous injection of 2 x 10(7) cells of the Hodgkin's derived cell line L540CY. Treatment of SCID mice bearing disseminated CD30+ Hodgkin's tumors with the combination of CD3/CD30 and CD28/CD30 Bi-MoAbs and naive (ie, not in vitro prestimulated) human T cells resulted in the cure of all appropriately treated animals. T lymphocytes obtained from patients with advanced stage untreated Hodgkin's disease were as effective as lymphocytes from healthy controls. Treatment was effective even when delayed until 2 weeks after tumor inoculation, and application of Bi-MoAbs into SCID mice with circulating human T cells was as effective as injecting the Bi-MoAbs before the lymphocytes. Treatment results with isolated CD4+ and CD8+ human T cells suggest that both subsets are necessary for the Bi-MoAb mediated cure of xenografted human tumors in vivo. The efficacy and practicability of this preclinical immunotherapy protocol support and form the basis for the clinical evaluation of this approach in patients with Hodgkin's disease resistant to standard therapy.

Animals↗
PubMed1993

Development of clinical standards for flow cytometry.

Flow cytometers are instruments that can determine multiparameter data simultaneously and have a great potential in providing unique information about cells. To transfer this potential to the clinical laboratory, the development and the proper use of standards and calibrators are required to ensure comparability and reproducibility of data from different flow cytometers. Although there are a number of types of standards for flow cytometry, each has its specifically designed purpose to ensure that data from this complex instrument are accurate, precise, and reproducible among instruments over time.

CD3 Complex↗
PubMed1991

Target cell-induced T cell activation with bi- and trispecific antibody fragments.

Previously we proposed a concept for tumor immunotherapy in which two different bispecific antibody conjugates, an anti-target x anti-CD3 and an anti-target x anti-CD28 conjugate, induce the activation of resting human T cells upon binding to the respective tumor target cells. After in vivo application of these reagents, this model of a "target cell-induced T cell activation" envisages the destruction of target cells by in situ activated T cells. Obviously however, for in vivo application, the use of Fc-free antibody fragments is mandatory to prevent binding of the conjugates to Fc receptor-positive cells which would lead to Fc-mediated T cell activation. Here we report a simplification of published procedures for the generation of bispecific Fab-hybrid fragments, univalent for each antigen. We demonstrate that an anti-target x anti-CD3/anti-target x anti-CD28 combination of such hybrids, as well as an identical combination of covalently coupled F(ab')2 fragments, mediate "target cell-induced T cell activation" in an in vitro test system. Thus, these reagents may be capable of inducing an in situ activation of human T cells upon systemic in vivo application according to the concept outlined above. A trispecific conjugate with anti-target, anti-CD3- and anti-CD28 specificity appears to be unsuitable for this purpose because it activates resting T cells in soluble form without requiring immobilization through binding via its anti-target portion.

Antibodies, Monoclonal↗
PubMed2001

Dexamethasone modulates TCR zeta chain expression and antigen receptor-mediated early signaling events in human T lymphocytes.

Dexamethasone is a potent anti-inflammatory and immunosupressive agent that has complex, yet incompletely defined, effects on the immune response. Here, we explored the effect of dexamethasone on the expression of TCR zeta chain and TCR/CD3-induced early signaling events in human T lymphocytes. Immunoblotting studies using TCR zeta chain specific mAb showed a dose-dependent biphasic effect of dexamethasone on TCR zeta chain expression, that is, it was increased when cells were incubated with 10 nM, whereas the expression was decreased when incubated with 100 nM dexamethasone. The dose-dependent biphasic effect of dexamethsone on the TCR zeta chain expression was also revealed by FACS analysis of permeabilized cells. Time course studies showed that upregulation of the TCR zeta chain at 10 nM dexamethasone reached maximum levels at 24 h and remained elevated up to 48 h. Other subunits of the TCR/CD3 complex were minimally affected under these conditions. The increased expression of the TCR zeta chain following treatment with 10 nM dexamethasone correlated with increased anti-CD3 antibody-induced tyrosine phosphorylation of the TCR zeta chain and downstream signaling intermediate ZAP-70 and PLC gamma with faster kinetics. Similarly, the induction of TCR zeta chain expression at 10 nM dexamethasone correlated with increased and more sustained TCR/CD3-mediated [Ca(2+)](i) response. Reporter gene assays using TCR zeta chain promoter-driven luciferase gene constructs in Jurkat cells showed that treatment with 10 nM dexamethasone increased TCR zeta chain promoter activity and that the region between -160 and +58 was responsible for the observed effect. These results suggest that dexamethasone primarily acts at the transcriptional level and differentially modulates TCR zeta chain expression and antigen receptor-mediated early signaling events in human peripheral T lymphocytes.

Adolescent↗
PubMed1991

Anti-tumor X anti-lymphocyte heteroconjugates augment colon tumor cell lysis in vitro and prevent tumor growth in vivo.

Cross-linking an anti-tumor antibody, specific for tumor cell surface antigens, and an anti-lymphocyte antibody, specific for the T lymphocyte receptor complex (TCR/CD3), produces a heteroconjugate that can direct T cells to lyse tumor cells. We tested the ability of anti-tumor X anti-lymphocyte (CD3) heteroconjugates to redirect human peripheral blood lymphocytes (PBLs) to lyse human colon cancer cells in cytotoxicity assays and in a murine colon tumor model. We demonstrated in vitro, that cultured human PBLs alone produced low levels of tumor lysis, but PBLs treated with anti-tumor X anti-CD3 heteroconjugates produced significantly greater tumor cell lysis (P less than 0.0025). Similarly, nude mice injected with LS174T human colon cancer cells and treated with cultured human PBLs and anti-tumor X anti-CD3 heteroconjugates survived significantly longer than saline control mice (P less than 0.01), or mice treated with PBLs alone (P less than 0.01), or heteroconjugates alone (P less than 0.05). F(ab')2 heteroconjugates were equally as effective in prolonging animal survival, but irrelevant heteroconjugates and monoclonal anti-tumor antibodies showed no therapeutic benefit. Anti-tumor X anti-CD3 heteroconjugates may represent an effective approach to tumor-specific cellular immunotherapy.

Animals↗
PubMed1994

Different use of T cell receptor transducing modules in two populations of gut intraepithelial lymphocytes are related to distinct pathways of T cell differentiation.

Most gut intraepithelial cells (IEL) of the mouse are T cells that bear CD8 molecules, present either as alpha-beta chain heterodimers (CD8 beta+) or as alpha chain homodimers (CD8 beta-). All CD8 beta+ IEL bear alpha/beta T cell receptors (TCR); CD8 beta- IEL bear either alpha/beta or gamma/delta TCR and are considered to be a thymus-independent (TI) population, probably arising locally from a small fraction of CD3- IEL containing the recombinant activating gene RAG proteins. Here we report that TI CD8 beta- IEL, whether bearing alpha/beta or gamma/delta TCR, contain, in normal mice, mRNAs for both zeta and Fc epsilon RI gamma chains. These chains are present in their CD3-TCR complexes as homo- or heterodimers. In contrast, only zeta chain mRNA and homodimers are found in gut CD8 alpha/beta+ IEL and in peripheral T lymphocytes. Intestinal CD3- precursor cells contain only gamma chain, and CD3- IL-2R+ thymocyte precursors only zeta chain mRNAs. Only very primitive thymocyte precursors contain detectable gamma chain mRNA, and it thus appears that Fc epsilon RI gamma chain use is switched off at a very early stage during thymocyte differentiation. Thus, T cell differentiation in the gut epithelium differs from that occurring in the thymus, from which CD8 beta+ IEL appear to derive. Use of different TCR transducing modules and CD8 accessory molecules between the TI and the thymus-derived T cell populations provides an explanation for their difference in reactivity to antigenic stimulations and thus in selection of repertoires.

Animals↗
PubMed1999

[The role of vav protein in TCR-mediated signaling with MHC/peptide complexes leading to positive or negative selection of thymocytes].

On the basis of recent reports we discuss the role of Vav in TCR-dependent signaling pathways. The Vav protein is GDP/GTP exchange factor for Rac, which initiates transduction of signals in JNK pathway. Upon stimulation of TCR by antigenic peptides, Vav associates with Zap-70 in TCR/CD3 signaling complex and becomes phosphorylated on Tyr-174 by tyrosine kinase Lck. The function of Vav is modulated by substrates and products of PI3-kinase activated by interaction of CD28 on thymocytes with B7 on antigen presenting cells. The PI3-kinase substrates inhibit activation of Vav, while the products enhance phosphorylation and activation of Vav by Lck. It seems that Vav functions in key point of TCR-mediated signaling pathway, which is regulated by costimulatory molecule (CD28) necessary for negative selection. The Vav-mediated integration of signals results in positive or negative selection of thymocytes.

Animals↗
PubMed1991

Co-stimulation of T cell proliferation by transforming growth factor-beta 1.

Transforming growth factor-beta (TGF-beta) exhibits diverse regulatory roles in the immune system and has been described as a potent inhibitor of lymphocyte and hemopoietic progenitor cell growth. The present studies investigated the effects of TGF-beta 1 on murine T cell proliferation triggered through the T cell receptor/CD3 complex. In contrast to previously reported T cell growth inhibition, TGF-beta 1 costimulated splenic T cell proliferation in the presence of immobilized anti-CD3 antibody 2C11, with maximal effect at anti-CD3 concentration of 50 micrograms/ml. Although TGF-beta 1 induced a modest increase in IL-2R display, TGF-beta 1 co-stimulated proliferation was largely independent of IL-2 and/or IL-4. Anti-IL-2 and/or anti-IL-4 antibody did not significantly block the TGF-beta 1 co-stimulated T cell growth, and no IL-2 or IL-4 bioactivity was detected in TGF-beta 1 co-stimulated cultures. TGF-beta 1 did not enhance IL-2 mRNA expression beyond control levels. However, TGF-beta 1 co-stimulation caused an accelerated evolution of a memory or mature T cell population phenotype. Both CD4+ and CD8+ T cell subsets were significantly enriched for cells of the mature CD45RBloPgp-1hi phenotype, in comparison with T cells stimulated by anti-CD3 alone or with PMA, and CD8+ T cells predominated. These results thus provide initial evidence that TGF-beta 1 is capable of bifunctional T cell growth regulation, which occurs largely via an IL-2- and IL-4-independent pathway.

Animals↗
PubMed1994

Mouse antibody-coated lymphocytes during OKT3 therapy in liver transplantation.

Flow cytometry has been a technique in search of a use in transplantation. With each new monoclonal antibody, it has been hoped that the secrets of rejection would be unlocked. The usefulness of CD3+ T-lymphocyte counts to predict successful treatment of organ transplant rejection has been called into question. CD2+, CD3+, and mouse antibody-coated CD3 lymphocytes were followed by flow cytometry in 44 liver transplant patients during OKT3 therapy for induction or rejection. CD3+ lymphocyte counts did not predict successful management of rejection by OKT3. When expressed as percentages of the total lymphocyte count, an increasing trend in CD2+ and mouse antibody-coated CD3+ lymphocytes after day 7 of OKT3 therapy portended persistent or recurrent rejection within 2 months of treatment. It is uncertain if the increasing population of mouse antibody-coated CD3 cells is due to an immune phenomen or decreased clearance by an ailing liver. Care should be taken when using CD3 lymphocyte counts as indicators of adequate OKT3 therapy in liver transplantation.

Animals↗
PubMed1993

Coactivation with anti-CD28 monoclonal antibody enhances anti-CD3 monoclonal antibody-induced proliferation and IL-2 synthesis in T cells from autologous bone marrow transplant recipients.

Recent studies show that costimulation of T cells with anti-CD28 Mab (anti-CD28) enhances anti-CD3 Mab (anti-CD3)-induced proliferative responses and cytokine production. This study determines if coactivation with anti-CD3 and anti-CD28 corrects defects in proliferation and IL-2 secretion in peripheral blood lymphocytes (PBL) from bone marrow transplant (BMT) recipients. PBL or T cells from 5 of 16 autologous and 5 of 22 allogeneic recipients increased their anti-CD3-induced proliferation responses by > 50% after coactivation. In short-term (< 180 days after BMT) autologous recipients, the group mean response increased after anti-CD3 activation from 62,900 to 97,800 cpm after coactivation. In long-term (> 180 day after BMT) autologous recipients, the group mean response after anti-CD3 activation increased from 62,600 to 78,400 cpm after coactivation. The long-term autologous recipient group had costimulated responses from PBL that were significantly higher than the paired anti-CD3-induced responses (p < 0.01); in contrast, such differences were not seen in allogeneic recipient groups. After anti-CD3 stimulation, the mean response of 88,000 cpm for PBL from short-term allogeneic recipients and the mean response of 83,600 cpm for PBL from long-term allogeneic recipients were higher than those in PBL from autologous recipients were higher than those in PBL from autologous recipient groups. The amount of IL-2 secreted by T cells from three autologous and three allogeneic recipients was enhanced 0.9-25-fold by coactivation. Coactivation of PBL from selected recipients increased proliferation into the normal range and increased IL-2 secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

In vitro OKT3-induced mitogenesis in selenium-deficient patients on a diet for phenylketonuria.

Patients with phenylketonuria (PKU) are frequently deficient in the essential trace element selenium (Se), because of their very low protein diet. Using two approaches to investigate T-cell response to proliferative signaling, viz, mitogenesis caused by the monoclonal antibody OKT3 and the plant lectin phytohaemagglutinin (PHA), we demonstrated significantly reduced responses to optimal concentrations of OKT3 in a group of PKU patients with reduced serum Se compared with a normal group (p = 0.0005) and with a group of PKU patients whose serum Se was normal (p = 0.0023). The response of the Se-deficient group to optimal levels of PHA did not differ from that of the normal controls or from that of Se-normal PKU patients. A dose-dependent relationship between serum Se levels and mitogenic response was evident for OKT3 (r = 0.34, p = 0.0154), but not for PHA (r = -0.02, p = 0.9086). We suggest that the reduced response to OKT3 mitogenesis in Se-deficient PKU patients is possibly the consequence of impaired Se-dependent metabolic activity, which affects mitogenic signaling via the T cell antigen receptor (TCR/CD3) complex.

Adolescent↗