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PubMed2003

CD3-specific antibody-induced active tolerance: from bench to bedside.

Although they were used initially as non-specific immunosuppressants in transplantation, CD3-specific monoclonal antibodies have elicited renewed interest owing to their capacity to induce immune tolerance. In mouse models of autoimmune diabetes, CD3-specific antibodies induce stable disease remission by restoring tolerance to pancreatic beta-cells. This phenomenon was extended recently to the clinic--preservation of beta-cell function in recently diagnosed patients with diabetes was achieved by short-term administration of a CD3-specific antibody. CD3-specific antibodies arrest ongoing disease by rapidly clearing pathogenic T cells from the target. Subsequently, they promote long-term T-cell-mediated active tolerance. Recent data indicate that transforming growth factor-beta-dependent CD4+CD25+ regulatory T cells might have a central role in this effect.

Animals↗
PubMed2006

Muromonab-CD3 (Orthoclone OKT3), methylprednisolone and cyclosporine for acute graft-versus-host disease prophylaxis in allogeneic bone marrow transplantation.

We report the results of a prospective non-randomized phase II study of Muromonab-CD3 (Orthoclone OKT3), an anti-CD3 monoclonal antibody, with methylprednisolone (MP) and cyclosporine (CSA) for acute GVHD (aGVHD) prophylaxis in 22 hematologic malignancy patients. OKT3 was given at 0.1 mg/kg/day with a maximum dose of 5 mg/day. Initial MP dose was 1000 mg before OKT3, with subsequent doses at 1 mg/kg/day before each OKT3 infusion with a planned taper beginning at day +28. CSA (3 mg/kg/day) was given as a continuous infusion at day -1 and adjusted to maintain serum levels between 250 and 399 ng/ml. Allogeneic BMT donors were HLA-matched siblings (n = 17), single HLA-mismatched-related (n = 1) and HLA-matched unrelated (n = 4). All patients achieved neutrophil engraftment at a median 11 days (range, 8-25 days). By intent-to-treat, the cumulative incidence of grade II-IV aGVHD was 33% (95% CI 13-53%) at a median 26 days post-BMT (range, 14-84 days). Chronic GVHD developed in 11/12 evaluable patients. Eight patients (36%) developed OKT3 first dose reactions; no cases of post-transplant lymphoproliferative disorder were observed. OKT3 depleted peripheral CD3+ cells in vivo as measured by flow cytometry. OKT3+MP+CSA combination is moderately effective aGVHD prophylaxis, however, it is unlikely to be superior to CSA+MTX.

Adolescent↗
PubMed1990

Subpopulations of CD4+ cells in lpr/lpr mice: differences in expression of T cell receptor/CD3 complex and proliferative responses.

CD4+ cells from autoimmune-prone C57BL/6 lpr/lpr mice contain two subpopulations, B220-CD4+ and B220+CD4+ cells. Highly purified B220-CD4+ cells from C57BL/6 +/+ and lpr/lpr mice were examined by comparing functional characteristics and expression of cell surface antigens and T cell receptor (TcR)/CD3 complex. Both lpr B220+CD4+ and B220+CD4-CD8- cells, most of which were PgP-1 positive, expressed TcR/CD3 complex on the cell surface at lower level as compared with B220-CD4+ cells of age-matched normal mice. In addition, the B2200-CD4+ cells were heterogeneous on the basis of surface expression of PgP-1 and CD3 antigens. Normal levels of TcR C alpha-, C beta- and V beta 8-specific mRNA were found in the B220-CD4+ cells and B220+CD4+ cells as compared with normal B220-CD4+ cells, while V beta 8-specific mRNA was preferentially expressed only by B220+CD4-CD8- cells. Either B220+CD4+ cells and B220+CD4-CD8- cells failed to respond to anti-CD3 monoclonal antibody (MoAb) as assessed by proliferative responses and production of interleukin-2 (IL-2). However, appreciable levels of reactivity to anti-CD3 MoAb were detected in the B220-CD4+ cells, although the responsiveness of this subset to such stimuli were reduced, compared with those of normal control. These results indicate that the B220-CD4+ cells in lpr mice are phenotypically and functionally distinct from normal B220-CD4+ cells.

Animals↗
PubMed2000

Osteopontin augments CD3-mediated interferon-gamma and CD40 ligand expression by T cells, which results in IL-12 production from peripheral blood mononuclear cells.

Osteopontin is an RGD-containing bone matrix protein with cytokine-like functions that is associated with early stages of Th1-mediated diseases. Although the function of osteopontin in these responses is unknown, it is expressed by activated T cells and macrophages and can costimulate T cell proliferation. Studies have demonstrated that early IL-12 and IFN-gamma expression is required to induce a protective response to many intracellular pathogens. Herein, we demonstrate that osteopontin stimulation augments the ability of anti-CD3 monoclonal antibody to induce CD40 ligand (CD40L) and IFN-gamma expression on human T cells, resulting in CD40L- and IFN-gamma-dependent IL-12 production in vitro. These findings suggest a functional role for osteopontin in early Th1 responses, namely regulation of T cell-dependent IL-12 production. Further, osteopontin up-regulation of CD40L provides mechanistic support for the association of osteopontin with polyclonal B cell proliferation and humoral autoimmune disease.

Adult↗
PubMed2001

Dynamic recruitment of human CD2 into lipid rafts. Linkage to T cell signal transduction.

CD2 mediates T cell adhesion via its ectodomain and signal transduction utilizing its 117-amino acid cytoplasmic tail. Here we show that a significant fraction of human CD2 molecules is inducibly recruited into lipid rafts upon CD2 cross-linking by a specific pair of mitogenic anti-CD2 monoclonal antibodies (anti-T11(2) + anti-T11(3)) or during cellular conjugate formation by CD58, the physiologic ligand expressed on antigen-presenting cells. Translocation to lipid microdomains is independent of the T cell receptor (TCR) and, unlike inducible TCR-raft association, requires no tyrosine phosphorylation. Structural integrity of rafts is necessary for CD2-stimulated elevation of intracellular free calcium and tyrosine phosphorylation of cellular substrates. Whereas murine CD2 contains two membrane-proximal intracellular cysteines, partitioning CD2 into cholesterol-rich lipid rafts constitutively, human CD2 has no cytoplasmic cysteines. Mapping studies using CD2 point mutation, deletion, and chimeric molecules suggest that conformational change in the CD2 ectodomain participates in inducible raft association and excludes the membrane-proximal N-linked glycans, the transmembrane segment, and the CD2 cytoplasmic region (residues 8-117) as necessary for translocation. Translocation of CD2 into lipid rafts may reorganize the membrane into an activation-ready state prior to TCR engagement by a peptide associated with a major histocompatibility complex molecule, accounting for synergistic T cell stimulation by CD2 and the TCR.

Amino Acid Sequence↗
PubMed1991

Accessory receptors regulate coupling of the T-cell receptor complex to tyrosine kinase activation and mobilization of cytoplasmic calcium in T-lineage acute lymphoblastic leukemia.

T-lineage acute lymphoblastic leukemia (T-ALL) cells have abundant cytoplasmic CD3/Ti but express low amounts on the cell surface and are deficient in CD3/Ti-mediated signal transduction. Nevertheless, plating T-ALL cells on dishes containing immobilized anti-CD3 monoclonal antibodies with a source of growth factors induced the expression of CD25 (interleukin-2 receptor alpha chain) and stimulated the formation of blast colonies in 12 of 14 cases studied. The proliferative response to CD3 ligation was modulated by the presence of antibodies to the CD2, CD4, or CD8 accessory T-cell receptors. The effect of these accessory receptors on signal transduction mediated by CD3/Ti was next investigated by monitoring cytoplasmic calcium concentration [( Ca2+]i) and by measuring tyrosine phosphorylation after stimulation. Crosslinking CD3, CD2, CD4, or CD8 alone did not induce cytoplasmic calcium mobilization in T-ALLs, but crosslinking the accessory receptors with CD3/Ti induced calcium responses in three of the T-ALLs and enhanced calcium responses in three of the T-ALL cell lines, including HPB-ALL, MOLT-4, and CEM. Crosslinking CD4 but not CD2 with CD3/Ti greatly enhanced tyrosine phosphorylation of multiple substrates in comparison with crosslinking either CD4 or CD3/Ti separately on both normal mature T cells and the CEM T-ALL cell line. Thus, CD4 regulates CD3/Ti signal transduction in T-ALL cells through the tyrosine phosphorylation of substrates whereas CD2 may regulate [Ca2+]i signal transduction through a separate mechanism.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1998

Characterization of human fibroleukin, a fibrinogen-like protein secreted by T lymphocytes.

We have recently cloned the human homologue of the murine pT49 cDNA (hpT49h), a transcript encoding a protein homologous to the beta- and gamma-chains of fibrinogen. Here, we report the identification of the hpT49h gene product using mAbs generated against a peptide corresponding to the carboxyl-terminal end of the deduced protein and a recombinant protein fragment expressed in Escherichia coli. mAbs 23A6, 7B12, and 3F4 specifically recognized a protein of 70 kDa in reducing SDS-PAGE in the culture supernatant of 293T cells transiently transfected with the full length hpT49h cDNA and freshly isolated PBMC. Under nonreducing conditions, the material migrated with a molecular mass of 250 to 300 kDa, indicating that the 70-kDa protein forms a disulfide bonded complex. Because of its homology with fibrinogen, we have termed this protein fibroleukin. Fibroleukin is spontaneously secreted in vitro by freshly isolated CD4+ and CD8+ T lymphocytes. RT-PCR analysis revealed preferential expression of fibroleukin mRNA in memory T lymphocytes (CD3+/CD45R0+) compared with naive T lymphocytes (CD3+/CD45RA+). Fibroleukin production by PBMC was rapidly lost in culture. Production could be partially maintained in the presence of IFN-gamma, while T lymphocyte activation had no effect. To demonstrate fibroleukin production in vivo, we analyzed colon mucosa by immunohistology. Fibroleukin staining was detected in the extracellular matrix of the T lymphocyte-rich upper portion of the lamina propria mucosa. While the exact function of fibroleukin remains to be defined, these data suggest that fibroleukin may play a role in physiologic lymphocyte functions at mucosal sites.

Amino Acid Sequence↗
PubMed2000

Induction of the IL-10 gene via the fas receptor in monocytes--an anti-inflammatory mechanism in the absence of apoptosis.

Death receptors play an important role in controlling cell numbers and immune responses. In contrast to TNF receptors, little is known about non-apoptosis functions of the Fas receptor (CD95, APO-1). Here we demonstrate that Fas receptor engagement results in the induction of the IL-10 gene in monocytes, but not in lymphocytes or dendritic cells. In contrast, TNF-alpha stimulated IL-10 production in dendritic cells but not monocytes. Fas receptor-mediated transcriptional activation of the IL-10 gene was followed by the release of large amounts of the cytokine in cell cultures and occurred in the absence of apoptosis induction. Since caspase activation did not occur in monocytes following Fas receptor engagement, it is unlikely that caspases are involved in IL-10 gene activation. Monocyte-derived IL-10 suppressed T cell proliferation induced by anti-CD3 monoclonal antibody without affecting CD3-mediated transmembrane signal transduction. In conclusion, we report about a novel pathway initiated via the Fas receptor leading to transcriptional activation of at least one cytokine gene. Fas ligand-induced IL-10 production in monocytes might represent an important anti-inflammatory mechanism in secondary immune responses.

Apoptosis↗
PubMed1993

Modification of the anti-CD3-induced cytokine release syndrome by anti-interferon-gamma or anti-interleukin-6 antibody treatment: protective effects and biphasic changes in blood cytokine levels.

Anti-interferon-gamma (IFN-gamma) antibodies were found to protect mice against pathological changes induced by injection of anti-CD3 antibody: incidence of diarrhea, severity of hypothermia and mortality rates were dramatically reduced. In anti-IFN-gamma antibody-treated mice, IFN-gamma blood levels were significantly reduced at 1.5 h post anti-CD3 challenge, but more elevated levels were found from 4 to 24 h. This rebound-like IFN-gamma response coincided with more profound hypoglycemia. Tumor necrosis factor and interleukin (IL)-6 levels were not affected by anti-IFN-gamma treatment. Exogenous IFN-gamma, administered within 3 h (but not later) of the anti-CD3 challenge made the syndrome worse. Furthermore, inter-mouse strain differences in sensitivity to the anti-CD3 syndrome correlated with the ability of the strain to produce IFN-gamma. Anti-IL-6 antibodies provided only marginal protection against hypothermia and mortality, but did markedly reduce hypoglycemia. Levels of biologically active IL-6 in serum were not influenced by anti-IL-6 antibody treatment during the first few hours after anti-CD3 challenge, but were significantly increased at later times. The data provide evidence that endogenous IFN-gamma is a critical element in the early phase of the anti-CD3 syndrome; endogenous IL-6, while possibly being involved in hypoglycemia, seems of lesser importance for the outcome of the syndrome.

Animals↗
PubMed1991

OKT3 prophylaxis in liver transplantation.

In a randomized prospective study of liver transplant recipients, we compared prophylaxis with OKT3, steroids, and azathioprine to cyclosporine, steroids, and azathioprine. Seventy-two percent of patients receiving OKT3 prophylaxis were rejection free in the first 14 days compared to 41% in the cyclosporine group (P = 0.02). However, after 14 days through a mean of 6.3 months, the overall incidence of rejection did not differ between the two groups (74% for the cyclosporine group and 48% for the OKT3 group). There was no increase in the rate of infectious complications noted in the OKT3-treated group. Thirty-nine percent of the OKT3-treated patients developed anti-OKT3 antibodies. Eight patients in the OKT3 group required reuse of OKT3 for rejection. Six of these continued to have greater than 10% CD3-positive cells with retreatment. Five were rescued successfully. With a mean survival of greater than 674 +/- 209 days in the OKT3-treated group and 626 +/- 242 days in the cyclosporine-treated group, no overall differences in graft and patient survival, liver function, renal function, late rejection incidence, or infectious complications were evident between the two groups. We conclude that OKT3 offers no long-term benefit compared to cyclosporine prophylaxis and should be reserved for treatment of rejection in patients in whom cyclosporine may be contraindicated.

Adult↗
PubMed1985

Phytohemagglutinin-induced proliferation and cytolytic activity in T3+ but not in T3- cloned T lymphocytes requires the involvement of the T3 antigen for signal transmission.

Proliferation and the cloning efficiency of T3+ but not T3- T cells are increased by the addition of lectins (phytohemagglutinin; PHA) to the culture medium. In contrast to that of T3+ cloned cell lines, the cytolytic activity of T3- clones is not enhanced by PHA, as we report here. We have investigated the effects of anti-T3 monoclonal antibody (MAb) and PHA on the proliferative capacity and cytolytic activity of various T3+ and T3- clones and cells to determine the possible involvement of the T3 receptor in these processes. We found that, in addition to inhibition of allospecific cytotoxicity, anti-T3 MAb can induce and/or enhance nonspecific cytolytic activity against particular target cells in cloned allospecific cytotoxic T cells (CTL) following preincubation of the effector cells with PHA or anti-T3. This enhancement of cytolytic activity is seen in T3+ but not T3- activated killer (AK) clones or fresh T3- natural killer (NK) cells and depends on the concentrations of anti-T3 MAb or PHA used. We conclude that the T3-Ti antigen-receptor complex is involved in the transmission of the activation signals by anti-T3 and PHA.

Antibodies, Monoclonal↗
PubMed1995

Polymorphonuclear neutrophils enhance suppressive activities of anti-CD3-induced CD4+ suppressor T cells.

We investigated the effects of polymorphonuclear neutrophils (PMN) on the suppressive activities of CD4+ suppressor T cells induced by immobilized mAb to the CD3 molecular complex in order to explore the role of PMN in the regulation of humoral immune responses. CD4+ T cells that had been treated with mitomycin C induced the IgM production from highly purified B cells in cultures stimulated with immobilized anti-CD3. Addition of CD4+ T cells that had not been treated with mitomycin C (control T4 cells) suppressed the IgM production induced by immobilized anti-CD3-stimulated T4 mito. PMN enhanced the degree of suppression of the IgM production by anti-CD3-stimulated control T4 cells. The capacity of PMN to enhance the suppressive activity of anti-CD3-stimulated control T4 cells was restored when PMN were fixed with paraformaldehyde (PFA), suggesting that direct interactions between PMN and CD4+ T cells, but not soluble factors secreted by PMN, were involved in the enhancement of suppression. Fresh PMN as well as PFA-fixed PMN enhanced the endogenous IL-2 production by immobilized anti-CD3-stimulated CD4+ T cells. Moreover, neither fresh PMN nor PFA-fixed PMN significantly augmented the suppressive activity of anti-CD3-stimulated control T4 cells in the presence of exogenous IL-2. These results indicate that PMN enhance the suppressive activity of anti-CD3-stimulated control T4 cells through direct interactions between PMN and CD4+ T cells. The enhancement of the suppressive activity of CD4+ suppressor T cells by PMN is accounted for by the enhancement of the endogenous IL-2 production by anti-CD3-stimulated CD4+ T cells. Thus, the data demonstrate that PMN influence the magnitude of humoral immune responses by regulating the production of IL-2 through direct interactions with T cells.

Adult↗
PubMed1991

A subunit common to an IgG Fc receptor and the T-cell receptor mediates assembly through different interactions.

The zeta subunit is a component of the Fc gamma receptor of natural killer cells (Fc gamma RIII or CD16), as well as the multimeric T-cell receptor/CD3 complex, and is required for assembly of both native receptors. The role of the zeta subunit in human Fc gamma RIIIA assembly differs from its role in T-cell receptor/CD3 complex assembly. The transmembrane domain of the Fc gamma RIIIA alpha subunit forms noncovalent interactions with the comparable domain of the zeta subunit and is sufficient for surface expression of the Fc gamma RIIIA complex. In the absence of these interactions, sequences in the transmembrane domain of the Fc gamma RIIIA alpha subunit signal its degradation. Leu-46, present in the transmembrane domain of the human zeta subunit, is important for assembly with the Fc gamma RIIIA alpha subunit. Substitution of this leucine with an isoleucine, as found in the mouse zeta subunit, significantly reduces this interaction. In contrast, the mouse and human zeta subunits interact with the pentameric T-cell receptor/CD3 complex, resulting in surface expression of this receptor.

Amino Acid Sequence↗
PubMed1995

In vivo studies using bispecific antibodies (anti-CD3 x anti-idiotype) and CD28-induced costimulation in the BCL1 lymphoma.

We previously reported the successful treatment of the BCL1 lymphoma in Balb/c mice using bispecific (anti-CD3 x anti-idiotype) antibodies (BsAb). The in vivo effect was dependent on the bridging of tumor cells and CD3-positive cells. This direct CD3/TCR cross-linking induced targeted cytolytic and cytotoxic activity toward the tumor cells. Definitive proof of an underlying T cell-mediated mechanism was obtained, as the therapeutic effect was completely lost when animals were T cell depleted before treatment. In all these experiments, animals were injected intraperitoneally (i.p.) with 5000 tumor cells (day 0) and treated with one single intravenous (i.v.) injection of 5 micrograms BsAb (day 9). At a higher tumor load, the therapy lost its effectiveness. We evaluated repeated injections of bispecific antibodies (BsAb) to treat mice with a higher tumor burden (10(5) tumor cells). However, a dose-related immunosuppression (even with 5 micrograms BsAb) was induced. Therefore, this approach was only beneficial if the immune system could recover from the previous injection of BsAb. To prevent this induction of anergy, costimulation with bivalent anti-CD28 has been proposed, but despite the high in vitro T cell proliferation using BsAb + anti-CD28 versus BsAb alone, we were repeatedly unsuccessful in improving our in vivo results using immunologically naive animals. Only when T cell preactivation was induced was a significantly better outcome observed when the animals were treated with a mixture of BsAb + anti-CD28 compared with BsAb or anti-CD28 alone. The potency of the BsAb + anti-CD28 combination was demonstrated by the fact that 10 times less BsAb was necessary to cure animals with a 20 times higher tumor burden.

Animals↗
PubMed2005

Construction and characterization of a humanized anti-human CD3 monoclonal antibody 12F6 with effective immunoregulation functions.

12F6 is a murine anti-human CD3 monoclonal antibody, which competes with OKT3 for binding to human T cells and possesses more effective T-cell suppression and activation properties compared to OKT3. It thus exhibits the potential to be developed as an immunoregulation agent for manipulating T-cell functions and preventing acute allograft rejection. In an attempt to minimize the immunogenicity of murine 12F6 (m12F6) for potential clinical application, a humanized version of 12F6, denoted as hu12F6, was successfully constructed by complementary determining region (CDR) grafting and shown to maintain both T-cell activation and suppression activities similar to m12F6. Furthermore, in order to reduce the first dose reaction syndrome caused by T-cell activation following the first administration of anti-CD3 antibodies, two amino acid mutations were introduced into the Fc region of hu12F6, resulting in the Fc-mutated 12F6 humanized antibody (hu12F6mu). This Fc-mutated version displayed a similar antigen-binding affinity and specificity compared with hu12F6 and m12F6 but with much weaker FcR binding activity. hu12F6mu was shown to be much less potent in the induction of T-cell proliferation, cytokine release (tumour necrosis factor-alpha, interferon-gamma and interleukin-10) and early activation marker expression on the cell surface (CD69 and CD25) than parental 12F6 and OKT3 did. In contrast, hu12F6mu was effective in modulating T-cell receptor/CD3 and inhibiting mixed lymphocyte reaction with a similarity as compared to m12F6 and OKT3. In conclusion, the resultant hu12F6mu was much less mitogenic to T cells but retained potent immunosuppression, suggesting it might be an alternative to OKT3 as an immunosuppressive drug with less immunogenicity and toxicity for clinical application.

Amino Acid Sequence↗
PubMedDate not supplied

Human cytotoxic effector cells: definition and analysis of activity.

Studies have indicated that the complexity of NK and LAK activities goes beyond the question of which effector cell mediates most of this activity. Examination of Nk activity reveals that numerous effector phenotypes can mediate spontaneous, non-MHC-restricted cytotoxicity. These effector cells are predominantly the CD3-, Leu19 (NKH1)+ and the CD3+, Leu19 (NKH1)+ lymphocytes. However, the existence of other effector cells capable of mediating NK activity and the relative contribution of each type of effector cell in vivo situations requires further study. In addition, LAK activity has been attributed to numerous cell types, and an indepth examination of the regulation and recognition events involved in LAK activity indicates a greater degree of heterogeneity than was initially anticipated. The preliminary data presented above support the contention that although NK and LAK activities are quite similar with regard to their lytic properties (e.g. effector phenotype, target selection), their mechanisms of targets cell recognition and lytic attack appear to be quite different. Our investigation of recognition events indicated that IL-2-activated effector cells do not recognize the same structure that is recognized by freshly isolated NK cells. These data suggest that a recognition event occurs on activated cells that can be dissociated from the events involved in NK binding by fresh CD3- LGL. With regard to CD3+ effectors, the role of the TcR and the nature of the receptor mediating LAK activity require further study to determine whether multiple receptors or a single, unique receptor class are expressed after IL-2 stimulation. In addition, the role of IFN gamma and other regulatory cytokines must be further examined to determine their importance in human LAK activity.

Animals↗