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Biomedical subjects

F Emmrich

Publications and source records attributed to F Emmrich.

At least 127 records · Page 7Linked to original sources
PubMed1990

Suppression and prevention of adjuvant arthritis in rats by a monoclonal antibody to the alpha/beta T cell receptor.

Adjuvant arthritis (AA) in rats is an experimentally induced autoimmune disease mediated by T lymphocytes specific for Mycobacterium tuberculosis. We raised the question whether T cells carrying the gamma/delta T cell receptor (TcR), reactive or not to mycobacterial antigens, are involved in the pathogenesis of AA. For this purpose, T cells bearing the TcR alpha/beta were depleted from circulation by treatment with a monoclonal antibody against the rat TcR alpha/beta (R73). This treatment efficiently suppressed existing disease. Even more efficient was pretreatment with R73 from birth, which prevented AA induction completely. In these alpha/beta+ T cell-depleted animals an elevated level of alpha/beta- T cells (about 15% vs. 1% in normal rats) was evident, which was not significantly increased by Mycobacterium tuberculosis injection. We found no positive evidence that gamma/delta + T cells do contribute to AA induction. Moreover, treatment with an anti-TcR alpha/beta monoclonal antibody may be very efficient treatment of T cell-mediated autoimmune diseases.

Animals↗
PubMed1990

Imaging rheumatoid arthritis specifically with technetium 99m CD4-specific (T-helper lymphocytes) antibodies.

CD4 expressing T-lymphocytes are involved in the pathogenesis of rheumatoid arthritis, so the possibility of using radiolabelled CD4-specific antibodies to localise diseased joints was studied. Prospectively six patients with rheumatoid arthritis were investigated. Five of them received 200-300 micrograms of a 555 MBq technetium 99m CD4-specific antibody (MAX.16H5) and were examined with three phase bone scans. Max.16H5 (IgG1) was labelled according to the mercaptoethanol (Schwarz) method. Lymphocytes of one patient were isolated on a Ficoll-Hypaque gradient and labelled with the antibody in vitro. Scans were performed 1.5 h, 4 and 24 h post injection in anterior and posterior views. In all patients, diseased joints could be clearly imaged at as early as 1.5 h. The localisation of the diseased joints correlated (P less than 0.01) with the clinical signs, with the early methylene diphosphonate (MDP) scan (P less than 0.01) and only weakly with the late bone scan (P greater than 0.05). According to these data we conclude that 99mTc-labelled CD4-specific antibodies specifically image actively diseased joints in rheumatoid arthritis.

Antibodies, Monoclonal↗
PubMed1990

Expression of activation antigens on T cells in rheumatoid arthritis patients.

The aim of our study was to identify differences in cell surface marker expression between T cells taken from the peripheral blood (PB) of healthy individuals and T cells recovered from inflamed joints of rheumatoid arthritis (RA) patients. Out of 118 monoclonal antibodies (MoAbs) directed against activation antigens on haematopoietic cells, 12 MoAbs recognizing nine distinct surface molecules were selected after a screening procedure to study the expression of the corresponding antigens on T cells from the PB, synovial fluid and synovial tissue of RA patients, and also on T cells from PB and spleens of controls. Using two-colour flow cytometry and immunohistology we found the molecules B-C5, CD39, CD40, CD45 R0, CD54, CD76 and potentially 1D11 to be substantially up-regulated on T cells from various body compartments in RA patients. We thus could determine that the cell surface of T cells in RA patients not only differs in MHC class II expression, but also in a number of other activation-associated cell surface molecules from T cells in healthy individuals.

Adult↗
PubMed1990

Do carbohydrate antigens stimulate human T cells? Review article.

T cells fail to recognize free antigenic determinants. What the T-cell receptor recognizes is a complex consisting of a peptide fragment cleaved from antigen and self-MHC structures on the surface of antigen-presenting cells. While extensively investigated with protein antigens, only limited information is available on the capability of T cells to recognize carbohydrate antigens in a specific way. Therefore, we have investigated the specificity of human T-cell lines and clones reactive to streptococcal A (Strep A) vaccine. It was found that neither soluble streptococcal A carbohydrate (A-CHO) nor synthetic oligosaccharides deduced from bacterial carbohydrates could stimulate Strep A-reactive T cells, although A-CHO stimulates specific antibody production in B cells very effectively. In conclusion, Strep A-specific T cells seem to recognize other structures of the bacterial vaccine than A-CHO. This was confirmed by retained stimulation after removal of carbohydrate epitopes by periodate treatment. Such Strep A-reactive T cells are frequently (greater than 10(-3] found in CD4+ T cells of healthy donors. Implications of this finding with regard to anti-carbohydrate immune responses are discussed.

Antigens↗
PubMed1990

Activation pathways of synovial T lymphocytes. Expression and function of the UM4D4/CDw60 antigen.

Accumulating evidence implicates a central role for synovial T cells in the pathogenesis of rheumatoid arthritis, but the activation pathways that drive proliferation and effector function of these cells are not known. We have recently generated a novel monoclonal antibody against a rheumatoid synovial T cell line that recognizes an antigen termed UM4D4 (CDw60). This antigen is expressed on a minority of peripheral blood T cells, and represents the surface component of a distinct pathway of human T cell activation. The current studies were performed to examine the expression and function of UM4D4 on T cells obtained from synovial fluid and synovial membranes of patients with rheumatoid arthritis and other forms of inflammatory joint disease. The UM4D4 antigen is expressed at high surface density on about three-fourths of synovial fluid T cells and on a small subset of synovial fluid natural killer cells; in synovial tissue it is present on more than 90% of T cells in lymphoid aggregates, and on approximately 50% of T cells in stromal infiltrates In addition, UM4D4 is expressed in synovial tissue on a previously undescribed population of HLA-DR/DP-negative non-T cells with a dendritic morphology. Anti-UM4D4 was co-mitogenic for both RA and non-RA synovial fluid mononuclear cells, and induced IL-2 receptor expression. The UM4D4/CDw60 antigen may represent a functional activation pathway for synovial compartment T cells, which could play an important role in the pathogenesis of inflammatory arthritis.

Adult↗
PubMed1990

The suppressive effect of an antibody to the alpha beta cell receptor in rat adjuvant arthritis: studies on optimal treatment protocols.

An antibody (R73) to the alpha beta T cell receptor (TCR) was able to dramatically suppress adjuvant arthritis (AA) in rats. The efficacy of R73 treatment was investigated with regard to antibody dosage, injection route and timing of injections. R73 was equally effective in reducing joint swelling throughout a wide dose range (80 to 2000 microgram/dose) when given on day 15, 18, and 21 after arthritis induction. Both i.p. and i.v. injection were able to suppress the pre-existing joint swelling to the same extent. However, R73 was only effective when given before or at the peak of joint swelling which occurred between day 18 to 24. Synovial membrane hyperplasia, mononuclear cell infiltration as well as cartilage and bone destruction were markedly reduced after therapy. The effect of R73 was associated with depletion of alpha beta+ T cells from the circulation even at low antibody doses. Only few alpha beta+ T cells were found in the pannus tissue. Late treatment on day 27, 30 and 33 after arthritis induction did not influence clinical scoring of the disease and histological examination thereafter did not show any difference between treated animals and controls. We conclude that antibody therapy directed at the TCR seems to be very effective even in pre-existing autoimmune diseases if the relevant T cell population is affected. However, inflammation and joint destruction may reach a state at which anti-TCR treatment is no longer effective.

Animals↗
PubMed1989

Lymphocyte stimulation by cell wall constituents.

T cells recognize peptides in association with self-MHC structures on antigen-presenting cells and become activated upon ligand binding to the T cell receptor. It is not known whether T cells are also able to recognize carbohydrate antigens. As a model system, we have investigated the human T cell immune response to the group-specific carbohydrate of A streptococci. This antigen stimulated specific antibody production in B cells very effectively, but was unable to stimulate proliferation in T cell lines or clones that reacted specifically to streptococcal A particles. Therefore, streptococcus A-specific T cells seem to recognize other structures of the particulate antigen than the carbohydrate, as was confirmed by the persistence of stimulation after periodate treatment.

Cells, Cultured↗
PubMed1988

Heterologous cross-linking of Lyt-2 (CD8) to the alpha beta-T cell receptor is more effective in T cell activation than homologous alpha beta-T cell receptor cross-linking.

Ag recognition of Lyt-2 (CD8)-positive T lymphocytes requires the presentation by APC of a suitably processed Ag in association with MHC class I molecules. In previous studies we have obtained evidence that, for optimal activation, both the alpha beta-TCR and Lyt-2 have to participate in this recognition process. In the current study we investigate the functional consequences of limited cross-linking of these cell surface molecules by using soluble, dimeric hetero- and homoconjugates of mAb to Lyt-2 and to the TCR beta-chain (F23.1). Heterologous cross-linking of Lyt-2 to the TCR induced a vigorous, selective Lyt-2+ T cell proliferative response. Functionally active cytotoxic cells were generated, and a high frequency of responding cells was observed in limiting dilution analyses. In contrast, homologous TCR cross-linking initiated a less pronounced proliferation with a relatively low frequency of response, whereas Lyt-2 cross-linking resulted in no cellular proliferation. Significant T cell activation occurred with exposure to anti-Lyt-2: F23.1 mAb dimers at concentrations an order of magnitude lower than those required for stimulation by F23.1:F23.1 mAb dimers. The induction of proliferation by mAb dimers occurred in the absence of Fc components and in rigorously APC depleted, purified T cell preparations. Effective stimulation of resting T cells could be induced also by heterodimers of monovalent Fab fragments. Heterologous cross-linking of Lyt-2 to the TCR was superior to homologous TCR cross-linking primarily with respect to proliferation in IL-2 containing media and to IL-2R expression, whereas proliferation in response to other lymphokines and the production of IL-2 itself were similar under both cross-linking regimens. Thus, when linked to the TCR, Lyt-2 contributed a strong, positive signal toward IL-2-dependent growth of resting T cells. We assume that in the case of Ag-driven T cell activation, the class I MHC molecule acts as the physiologic cross-linking ligand for Lyt-2 and the TCR.

Animals↗
PubMed1988

Human immune response to group A streptococcal carbohydrate (A-CHO). II. Antigen-independent stimulation of IgM anti-A-CHO production in purified B cells by a monoclonal anti-idiotopic antibody.

The paper describes the induction by a monoclonal anti-idiotopic antibody (anti-Id mAb) of specific antibody production to group A streptococcal carbohydrate (A-CHO) in purified human B cells of several unrelated individuals. The anti-Id mAb, designated 16F498 (anti-Id498), recognizes a recurrent idiotope (Id 498) associated with the combining site of human antibodies to N-acetyl-D-glucosamine (GlcNAc), the immunodominant group of A-CHO. Id498 is expressed on IgM anti-GlcNAc antibodies but does not occur on IgG antibodies with the same specificity. It occurs also on a minor population of IgM antibodies without specificity for A-CHO. Id498 was found in 19 of 27 sera from unselected healthy donors and thus seems to be frequently expressed within the adult B cell repertoire. The in vitro induction of anti-A-CHO antibodies was analyzed in human B cells extensively depleted for T cells. Specific antibody secretion required cross-linked anti-Id which was achieved by coupling the mAb to agarose beads. No antibody secretion could be induced by soluble anti-Id (1 and 10 micrograms/ml). An optimal response required soluble T cell-derived factors which were added as a mixture of recombinant interleukin 2 with a T cell hybridoma supernatant that augments B cell growth and differentiation. Under these conditions an antigen-independent specific increase of IgM anti-A-CHO production (2.6- to 10-fold, or up to 2000 ng/ml respectively) could be induced in blood B cell populations of four of six normal individuals expressing the Id498 at serum level.

Acetylglucosamine↗
PubMed1988

Selective stimulation of human T lymphocyte subsets by heteroconjugates of antibodies to the T cell receptor and to subset-specific differentiation antigens.

Ligand binding under conditions that generate microaggregates of the T cell receptor complex (Ti/CD3) with the membrane molecules CD4 or CD8 can induce activation of small resting T lymphocytes. We demonstrate this by using soluble dimeric heteroconjugates consisting of monoclonal antibodies to CD4/CD8 and of a novel anti-CD3 monoclonal antibody (BMA030) which even in aggregated form is not stimulatory on its own under limiting conditions in the absence of accessory cells. Using combinations of BMA030 with either anti-CD4 or anti-CD8, the corresponding T cell subpopulation could be selectively expanded in vitro. Selective expansion of T cell subpopulations in vitro or in vivo might be helpful for certain therapeutical manipulations. In addition, this finding may contribute to a better understanding of major histocompatibility complex-restricted T cell activation.

Antibodies, Monoclonal↗
PubMed1988

Human immune response to group A streptococcal carbohydrate (A-CHO). III. Comparison of the efficiencies of anti-idiotopic antibody and of nominal antigen in the induction of IgM anti-A-CHO-producing B cells.

In this study the efficiencies of a monoclonal anti-idiotopic (Id) antibody (anti-Id498) and of various preparations of nominal antigen in the induction of an antigen-specific human B cell response in vitro were compared. Anti-Id498 recognizes a recurrent, binding site-related Id present on IgM antibodies with specificity for N-acetyl-D-glucosamine, the immunodominant group of streptococcal group A carbohydrate (A-CHO). We have previously shown that anti-Id498 induces IgM anti-A-CHO secretion from B cells of donors that possess Id-498+ antibodies in their serum. A-CHO was presented to B cells either in soluble or insoluble form, i.e. coupled to beads or as intact bacteria. Purified blood B cell populations from three Id+ healthy donors with high numbers of circulating anti-A-CHO B cells were used and antibody-producing B cells are enumerated in a single-cell assay (spot ELISA). The data show that anti-Id498 was superior in the induction of IgM anti-A-CHO-secreting B cells in two donors (factor 4.6 and 13.5 as compared to the most efficient antigenic stimulation). In the third donor antigen stimulation was slightly more efficient than anti-Id but only with Sepharose-bound A-CHO and not with soluble A-CHO or intact bacteria. The increase of specific B cells induced after stimulation with anti-Id498 could be abolished after addition of autologous T cells in two donors. On the contrary, an enhancement of the specific response was observed after addition of autologous T cells in antigen-stimulated cultures. Neither suppression nor enhancement were induced by addition of irradiated T cells.

Antibodies, Anti-Idiotypic↗
PubMed1988

Selective induction of T-cell subsets by antibodies to the T-cell antigen receptor and to the subset-specific differentiation antigens CD8 and CD4.

This report shows that small, resting T lymphocytes from mouse and man can be activated to proliferation and function by submitogenic concentrations of antibodies to T-cell antigen receptor in combination with antibodies to either CD8 or CD4. The combined antibodies can be applied either in solid phase condition or as soluble dimeric heteroconjugates. Activation is more efficient than by high concentrations of anti-T-cell-receptor antibody alone. Most importantly, activation is subset-specific such that the antibody to CD8/CD4 determines which T-cell subset will be induced.

Animals↗
PubMed1988

Activation of human T lymphocytes: differential effects of CD3- and CD8-mediated signals.

T cells are activated physiologically by triggering the T-cell receptor-CD3 complex. There is evidence that invariant accessory molecules on the T-cell membrane (CD8 and CD4) are involved in the major histocompatibility complex-restricted recognition process. Moreover, binding and crosslinking of these accessory molecules to the T-cell receptor-CD3 complex exerts a positive synergistic signal, as has been shown by stimulation with crosslinked antibodies. Here we demonstrate that stimulation mediated by immobilized anti-CD3/CD8 antibodies differs from stimulation mediated solely by anti-CD3. Whereas interleukin 2 receptor expression and interferon gamma production are seen to a similar extent in both cases, a second signal provided by the additional involvement of CD8 seems to be essential for interleukin 2 production and full interleukin 2 responsiveness in CD8+ T cells. This second signal is much more sensitive to inhibition by 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine, an inhibitor of protein kinase C and cGMP/cAMP-dependent kinases. Our results also show that substantial modulation of the T-cell receptor complex and most likely CD3 phosphorylation are not essential for initiating the activation of resting T cells. Instead, we found a 22- to 24-kDa phosphoprotein whose strong phosphorylation correlated reliably with T-cell activation.

Adult↗
PubMed1987

Enumeration of T cells reactive with Mycobacterium tuberculosis organisms and specific for the recombinant mycobacterial 64-kDa protein.

The major goal of the present study was to develop a limiting dilution system for the enumeration of T cells which respond to mycobacterial antigens. Purified T cells from M. tuberculosis-immune mice were restimulated with mycobacterial antigens and accessory cells, and after 4 days expanded with antigen, accessory cells and T cell growth factor. After another 3 days, proliferative responses were determined. Similar cultures performed without antigen served as controls. Limiting dilution analysis revealed that approximately 1/2000 to 1/3000 T cells from M. tuberculosis-immune mice responded to whole M. tuberculosis organisms while T cells from normal mice did not respond. Similar T cell numbers reacted with several mycobacterial strains indicating expression of shared T cell antigens. Using a semi-purified recombinant 64-kDa protein from M. bovis the frequency of T cells generated after immunization with M. tuberculosis which reacted with a single mycobacterial protein could be estimated. We found that approximately 1/5 of the M. tuberculosis-reactive T cells recognized this particular antigen. Immunization with the recombinant 64-kDa protein in an adjuvant containing trehalose dimycolate, monophosphoryl lipid A and mycobacterial cell wall skeleton stimulated an equally high number of M. tuberculosis-reactive T cells (1/2000). These findings demonstrate that a high proportion of tuberculosis-responsive T cells are directed against the 64-kDa protein and that immunization with this antigen in an appropriate adjuvant system is capable of stimulating high numbers of M. tuberculosis-reactive T cells. Limiting dilution analysis with a panel of mycobacterial proteins or peptides may allow their ranking from immunodominant to immunosilent and facilitate identification of antigens or epitopes relevant to protection.

Animals↗
PubMed1987

Cross-linking of the T cell receptor complex with the subset-specific differentiation antigen stimulates interleukin 2 receptor expression in human CD4 and CD8 T cells.

Nonpolymorphic interactions between the T cell differentiation antigens CD4 or CD8 and major histocompatibility complex (MHC)-encoded molecules have been postulated to participate in antigen recognition of MHC-restricted T cells. This would imply simultaneous binding of CD4/8 and of the T cell receptor complex (Ti/CD3) to MHC molecules on the stimulator or target cell. In this report experimental evidence is provided that simultaneous binding by antibodies of Ti/CD3 and of CD4 or CD8 leads to the expression of interleukin 2 (IL 2) receptors in resting human T cells and to their subsequent proliferation in the presence of recombinant IL 2 (rIL 2). This could be shown by using a novel anti-CD3 monoclonal antibody (BMA 030) which alone only marginally stimulates highly purified human T cells even when applied in cross-linked form. However, human T cell subpopulations could be stimulated to grow in the presence of rIL 2 when BMA 030 was fixed to a solid support in combination with antibodies to either CD4 or CD8. In limiting dilution experiments, the frequencies of CD4 and CD8 T cells activated by the antibody combinations were similar to those activated by phytohemagglutinin in the presence of irradiated adherent cells. No stimulation was achieved if both or one antibody was applied in soluble form. In contrast, soluble antibodies inhibited activation by solid-phase antibodies. Taken together, cross-linking of Ti/CD3 with CD4/8 seems to be essential for T cell activation in cases of ligands that bind but do not activate T cells on their own--a situation that may reflect the interaction of T cell receptors with MHC-encoded molecules in association with antigen.

Antibodies, Monoclonal↗
PubMed1987

Effective activation of resting mouse T lymphocytes by cross-linking submitogenic concentrations of the T cell antigen receptor with either Lyt-2 or L3T4.

We studied the activation of small resting mouse T lymphocytes by antibodies to the T cell antigen receptor in combination with antibodies to other T cell surface antigens. Solid-phase but not soluble antibodies KJ16-133 and F23.1, both directed to beta chains of the V beta 8 family, activate T cells to proliferate in the presence of growth factors, in a dose-dependent fashion. Antibodies to Lyt-2 and to L3T4 had no activating effect at any concentration. However, submitogenic concentrations of KJ16-133 and of F23.1 synergized with a wide range of concentrations of anti-Lyt-2 and anti-L3T4 to cause T cell proliferation similar or greater in magnitude to that caused by high concentrations of anti-T cell receptor antibody. Synergistic activation was also observed with antibodies to Lyt-1, LFA-1 and H-2 class I antigens but to a significantly lower degree. This was particularly clear in limiting dilution experiments in which the corrected frequencies of T cells proliferating in response to low amounts of anti-T cell receptor antibody together with anti-Lyt-2 were 1/4 to 1/7 for BALB/c T cells. The frequencies of BALB/c T cells responding to high concentrations of anti-T cell receptor antibody alone were between 1/14 and 1/126 and still lower frequencies of T cells proliferated in synergistic responses with anti-LFA-1 or anti-Lyt-1. Synergistic activation leads to the induction of functional cytotoxic cells. We interpret these data as suggestive that cross-linking of the T cell antigen receptor with either Lyt-2 (CD8) or L3T4 (CD4) represents an optimal activating signal for resting T cells. We think that, in physiological T cell activation, cross-linking of the T cell receptor to CD8 or CD4 is induced by their simultaneous binding to major histocompatibility complex (MHC) class I (for CD8) or MHC class II (for CD4) molecules on stimulator cells. We consider the possibility that similar cross-linking requirements may also exist during T cell repertoire selection in ontogeny, thus accounting for the strict coexpression of MHC class I and class II-restricted T cell receptors with CD8 and CD4 molecules, respectively.

Animals↗