Nature and function of antigen-specific T-cell lines and their products.
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Animals↗
Biomedical subjects
E Mozes
Publications and source records attributed to E Mozes.
Antigen specific immune response potential and HLA typing of Israeli patients with thyroid autoimmune diseases (TAD).
The immune response potential to the synthetic polypeptide antigen (T,G)-A--L was studied in 35 patients with thyroid autoimmune diseases (TAD). For this purpose the ability of their antigen activated peripheral blood lymphocytes (PBL) to generate a (T,G)-A--L specific helper factor was tested. In addition, the patients were typed for their HLA determinants. The results of the study have shown that 20/35 (57%) patients responded to (T,G)-A--L, a similar proportion to that found among healthy donors that were tested as control. No significant difference was found in the rate of responses between patients with Graves' disease and Hashimoto's thyroiditis. The responses in these groups of patients were shown to be 13/22 (59%) and 7/13 (54%) respectively. HLA typing of 26 patients with TAD did not demonstrate any association of the disease or the immune response potential with any specific HLA determinant. It is proposed that unlike the general lack of regulation that we have previously observed in patients with systemic lupus erythematosus, the abnormal autoimmune reaction in TAD and probably in other organ-specific autoimmune diseases, is towards a specific organ without affecting other arms and functions of the immune system.
Autoimmune Diseases↗
Analysis of antigen specific T cell helper function in first degree relatives of patients with systemic lupus erythematosus (SLE).
Fourteen families with first degree relatives of patients with systemic lupus erythematosus (SLE) were studied for the ability of their members to respond to the synthetic polypeptide antigen (T,G)-A-L. The family members were also tested for their HLA determinants. All SLE patients tested responded to (T,G)-A-L as measured by the production of (T,G)-A-L specific T cell helper factors by their antigen activated T cells, confirming our previous findings that 100% of SLE donors responded to (T,G)-A-L in contrast to 50% responders in a control population of healthy donors. The general defect in the regulation of immune responses in SLE patients was further indicated by the demonstration that an SLE patient who is a daughter of non-responder parents to (T,G)-A-L, responded to this genetically regulated antigen. In contrast to our observations with SLE patients, the genetic regulation of the ability to respond to (T,G)-A-L was shown not to be impaired in healthy first degree family members of SLE patients and the segregation of the immune response potential in these families was as expected from an inherited dominant trait.
Animals↗
Association between HLA-DR4 and production of collagen-specific antibodies in Israeli patients with rheumatoid arthritis.
Antibodies to native human Type I + III collagen were measured by a radioimmunoassay in sera samples of 42 rheumatoid arthritis (RA) patients. Sixteen patients (38%) had significant antibody titers. Although the frequency of HLA-DR antigens of RA patients did not differ from that of the random Israeli population, there was a significant association (P less than 0.01) between the presence of collagen antibodies and HLA-DR4.
Adult↗
Antigen presentation by proliferating thymic macrophages to A (T,G)-A-L specific T cell line in an H-2 restricted manner.
Long-term cultures of murine homogeneous populations of Ia-bearing thymus-derived murine macrophages were tested for their ability to present antigen to a (T,G)-A-L specific IL-2-dependent continuous T cell line. Thymus-derived macrophages, with and without pretreatment for Ia induction, triggered efficiently antigen-specific T cell proliferation in an MHC restricted way. This experimental system, consisting of two normal proliferating homogeneous populations of macrophages and antigen specific T cells, provides an ideal tool for studying the mechanism of antigen presentation to T cells and for elucidation of the role of macrophages in T-B cell collaboration for antibody production.
Animals↗
Establishment and biological activity of a proliferative anti-idiotype-activated T cell line.
Antisera were raised in rabbits against a monoclonal antibody (McAb 103) of C3H.SW origin which is specific to the synthetic polypeptide (T,G)-A-L and was shown to express the major idiotypic determinants of conventional anti-(T,G)-A-L antibodies. Antibodies were purified and were shown in a binding assay to recognize McAb 103 as well as C3H.SW anti-(T,G)-A-L antibodies. C57BL/6 mice were immunized with the purified rabbit anti-McAb 103 (Ra 103) and their lymph nodes were studied in a proliferation assay. Proliferation was observed in the presence of both Ra 103 and (T,G)-A-L, although the latter stimulated the cells to a lesser extent, suggesting the induction in vivo of (T,G)-A-L-specific clones in low frequency. A T cell line was established from these lymph node cells. The line is kept in continuous growth in the presence of IL-2 and periodic triggering with Ra 103. A significant proliferative response was obtained with Ra 103 only. This proliferation could be almost completely inhibited by either McAb 103 or by conventional anti-(T,G)-A-L antibodies of C3H.SW origin, indicating the cross reaction between the idiotypes expressed on the T cell line and the (T,G)-A-L-specific antibodies. No proliferation could be detected in the presence of either normal rabbit IgG or rabbit anti-mouse IgG. Thus, the T cell line TId 103 allows the analysis of the role of idiotype in T cell recognition and regulation.
Animals↗
HLA-linked immune responsiveness to (T,G)-A-L: a family study.
The heredity of the immune response potential to the synthetic polypeptide poly(LTyr,LGlu)-poly(DLAla)-poly(LLys) [(T,G)-A-L] and its possible linkage to the major histocompatibility complex of man were studied in 24 families. Peripheral blood lymphocytes (PBL) obtained from 174 donors belonging to 24 unrelated families were educated to (T,G)-A-L on autologous antigen-pulsed adherent cells. The supernatants obtained from these activated PBL were tested for their antigen-specific helper activity in an in vitro antibody production system. All donors were typed for their HLA haplotypes. The results obtained indicated that the ability to respond to (T,G)-A-L by production of an antigen-specific T cell helper factor is inherited as an autosomal dominant trait linked to the responder HLA haplotype.
Alleles↗
(T,G)-A-L specific immune response potential and HLA typing of Israeli patients with systemic lupus erythematosus.
Thirty-three Israeli patients with systemic lupus erythematosus (SLE) were studied for their ability to respond to the synthetic polypeptide poly (Tyr,Glu)-poly (DLAla)-poly(Lys) [( T,G]-A-L) as measured by the production of a T cell helper factor by their antigen activated T cells. Twenty-seven of the patients were typed for their HLA phenotypes. Nineteen patients were with more active disease and 14 with a milder non-active disease. All the patients of the two groups responded to (T,G)-A-L by the production of an antigen specific helper T cell factor, in contrast to only 50% responders among healthy donors. Thus, lack of normal regulation of T cell helper function was observed among all patients with SLE, independently of their disease activity and/or treatment. A higher frequency of DR5 (75%) was observed in patients with a milder non-active disease (vs 46.6% in normal healthy control individuals) while 53.3% of patients with active disease possessed DR7 (21.8% in controls). These findings may suggest a possible association between the severity of the disease and a specific DR determinant.
Antibody Formation↗
An improved microculture-hemolytic spot assay for the study of carrier-specific antibody responses.
A microculture system based on limiting dilution and a hemolytic spot assay was adapted for study of the carrier-specific anti-hapten response in vitro. Spleen or lymph node cells from normal mice or mice immunized with NIP-ovalbumin (NIP-OVA) or NIP-human thyroglobulin (NIP-Tg) were cultured for 5 days by the microculture technique. The anti-hapten (anti-NIP) response was measured by assaying the supernatants of the microcultures in a hemolytic spot test with NIP coupled to sheep red blood cells. A micro-ELISA reader was adapted to read the degree of lysis in the spot assay which gives an objective quantitation of the degree of lysis and thus reduces the number of culture replicates. In vivo induced specific helper cells in mice immunized with the carrier protein, human thyroglobulin, as well as carrier-specific T cell factors, gave rise to carrier-specific anti-NIP responses. The microculture system may enhance the expression of T-cell helper function when suppressor cells or their precursors are present in the initial cell preparation.
Animals↗
Induction of acetylcholine receptor-specific suppression. An in vitro model of antigen-specific immunosuppression in myasthenia gravis.
This report describes the in vivo and in vitro induction of murine (AChR)-specific suppressor T cells (Ts) and T cell factors (TsF), and the development of an appropriate assay system for their measurement. The assay described is based on the in vitro Mishell-Dutton culture system. Using this assay, it was shown that the AChR-specific helper cell is an Lyt-2- radiosensitive T cell. Moreover, the proliferating cell measured in the lymphocyte transformation assay was shown to provide AChR-specific T cell help. In vivo induction of Ts cells is achieved by injection of soluble AChR; potent AChR-specific suppression is found in the spleen 1 wk later. In vitro induction of Ts cells involves the primary education of naive splenocytes by culturing them with high concentrations of AChR. Both the in vivo- and in vitro-induced Ts cells were shown to secrete AChR-specific factors that mediate their suppressive effects. The possibility of specifically suppressing the AChR-immune response may be of a particular clinical importance since the AChR is the target autoantigen in the neuromuscular autoimmune disease myasthenia gravis.
Animals↗
Serological analysis of idiotypic determinants on monoclonal antibodies specific to poly(Tyr,Glu)-poly(DLAla)--poly(Lys) and its ordered analogue (Tyr-Tyr-Glu-Glu)-poly(DLAla)--poly(Lys).
Anti-idiotypic sera (aIds) were raised in C57BL/6 mice against monoclonal antibodies (McAbs) which bind poly(Tyr,Glu)-poly(DLAla)--poly(Lys)--abbreviated to (T,G)-A--L--and (Tyr-Tyr-Glu-Glu)-poly(DLAla)--poly(Lys)--abbreviated to (T-T-G-G)-A--L--(nos. 103 and 160) and McAbs which react only with (T-T-G-G)-A--L (nos. 100 and 114). Anti-Id antibodies against 103 McAb reacted with (T,G)-A--L specific antibodies and specifically inhibited their binding to iodinated antigen. Similarly, conventional antibodies against the major idiotypes of (T,G)-A--L-specific antibodies inhibited the binding of 103 McAb to antigen. It is therefore suggested that 103 McAb shares major idiotypes with (T,G)-A--L-specific polyclonal antibodies of C3H.SW origin. Anti-Ids against 114 McAb also inhibited the binding of (T,G)-A--L-specific antibodies to antigen, but the binding of 114 McAb could not be inhibited by conventional aIds. Therefore, idiotypes of 103 and 114 McAbs define idiotypic determinants expressed on two different subpopulations of (T,G)-A--L-specific antibodies: those that carry major idiotypes and those which express idiotypic determinants other than the major one (minor Ids). Anti-idiotypic sera against McAbs nos. 100 and 160 reacted with the homologous idiotypes and not with the major idiotypes of (T,G)-A--L-specific antibodies. In addition to the aforementioned specificities we could define cross-reactive idiotypes (private) shared by McAbs nos. 100, 103 and 114 McAbs nos. 160 and 114. The analysis of idiotypes expressed on anti-(T,G)-A--L McAbs enabled the detection of new antigen binding site related idiotypic determinants in addition to the major idiotypes which were immunodominant in the polyclonal anti-(T,G)-A--L antibodies.
Animals↗
The use of synthetic antigens for the analysis of T cell recognition units and cellular interactions leading to immune reactions.
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Animals↗
Cellular sensitivity to collagen in thromboangiitis obliterans.
We studied 39 patients with thromboangiitis obliterans to determine their cellular and humoral immune responses to native human collagen Type I and Type III, which are constituents of blood vessels. Cell-mediated sensitivity to these collagens was measured by an antigen-sensitive thymidine-incorporation assay. The mean stimulation index--the ratio of thymidine incorporation in the presence of antigen to that in its absence--with both Type I and Type III collagens used as antigens was significantly higher in patients with thromboangiitis obliterans than in patients with arteriosclerosis obliterans or in healthy male controls. Lymphocytes from 77 per cent of the patients with thromboangiitis obliterans exhibited cellular sensitivity to human Type I or Type III collagens (or both). Furthermore, in 17 of 39 serum samples from the patients with thromboangiitis obliterans a low but significant level of anticollagen antibody activity was detected, whereas there was no antibody activity in serum samples from controls. These results suggest that there is a distinct etiologic factor in this disease and also raise the possibility of differentiating between thromboangiitis obliterans and arteriosclerosis obliterans by immunologic means.
Adult↗
The T-cell receptor as analyzed by functional T-cell lines specific to a synthetic polypeptide antigen.
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Animals↗
Fine specificity of antibodies to the synthetic polypeptide poly(L-tyrosine, L-glutamic acid)-poly(DL-alanine)--poly(L-lysine) and its ordered analogs as followed by solid-phase radioimmunoassay.
The fine specificity of antibodies against (T,G)-A--L and its ordered analogs (T-T-G-G)-A--L and (T-G-T-G)-A--L was studied. Fifty percent of the antibodies against (T,G)-A--L are directed toward the T-T-G-G determinants and 19% against T-G-T-G-like determinants. The rest of the antibody response to (T,G)-A--L is directed against determinants which exist in (T,G)-A--L but are not cross-reactive with either T-T-G-G- or T-G-T-G-like determinants. Although (T-T-G-G)-A--L and (T-G-T-G)-A--L differ only in the sequence of tyrosine and glutamic acid in their side chains, no crossreactivity was observed between antibodies toward the two ordered polypeptide antigens.
Animals↗
Genetically regulated human (T,G)-A-L specific helper T cell replacing factors possess HLA-DR and VH determinants.
Human (T,G)-A-L specific T cell helper factors secreted by in vitro activated peripheral blood lymphocytes of normal donors were characterized. Factors were passed through columns of Sepharose coupled either to antibodies against human immunoglobulin or antibodies against the variable region of the heavy (VH) and light (VL) chains of human immunoglobulin. In addition, the same factors were applied to columns of Sepharose coupled to anti-HLA-DR antibodies or to monoclonal antibodies against human Ia or beta 2-microglobulin. The activity of the antigen specific factors was removed by the anti-VH antibodies and not by anti-VL or anti-human immunoglobulin antibodies. The factors passed through Sepharose coupled to anti-DR antibodies could be removed and eluted from columns of anti-DR antibodies relevant to the donors' DR antigens. The same factors were also removed by a monoclonal antibody (anti-Ia) which recognizes a monomorphic determinant on HLA-DR, but not by monoclonal anti-beta 2-microglobulin. The results suggest that the genetically regulated (T,G)-A-L specific helper factors possess HLA-DR as well as VH determinants in their active moiety.
Animals↗
Partial purification and characterization of an antigen-specific helper factor synthesized by a T-cell continuous line.
Antigen-specific factors produced by the T-cell growth factor-dependent T-cell continuous line E-9M(+) were partially purified. Gel analysis of the twice-affinity-purified eluate of a poly(Tyr,Glu)-poly(DLAla)--poly(LLys) [(T,G)-A--L] column revealed the existence of iodinated bands with molecular weights of 17,000 and 15,000, in addition to a diffuse band of high molecular weight. The specific helper activity of the E-9M(+) supernatants was associated with a precipitate from 65-75% ammonium sulfate. Gel electrophoresis of either the eluate of a (T,G)-A--L column or of the 65-75% salt precipitate indicated that in both preparations two fractions contained the biological activity of the factor, one of a high (less than 67,000) molecular weight and the other of a low (15,000-17,000) one. Culture supernatants of the internally [35S]methionine-labeled E-9M(+) line were subjected to a combined purification of sequential ammonium sulfate precipitations, followed by affinity chromatography. Polyacrylamide gel patterns obtained of the eluates of the different salt precipitates demonstrated that the 65-75% ammonium sulfate precipitate contained two 35S-labeled bands with apparent molecular weights in the range of 60,000 and 15,000, similar to the activity patterns obtained by the gel electrophoresis fractionation experiments. Thus, it is suggested that a fraction of low molecular weight preserves the antigen specificity and the helper activity of the factor produced by the T-cell line.
Animals↗
Cross-reactive idiotypic determinants on antibodies and antigen-specific helper T cell continuous lines.
Anti-idiotypic antibodies produced in C57BL/6 mice (H-2b, Igh-1b) against (T,G)-A--L-specific antibodies of C3H.SW mice (H-2b, Igh-1j) were used to probe (T,G)-A--L-specific helper T cell lines and clones for the expression of idiotypic determinants on the cell surface of the monoclonal functional T cells. By using the fluorescence-activated cell sorter (FACS II), anti-idiotypic sera of individual mice that specifically bind C3H.SW anti-(T,G)-A--L antibodies were shown to stain significantly cells of the E-9M(+) continuous T helper line originated from C3H.SW (T,G)-A--L "educated" T cells. The same antisera did not react with a helper T cell line of C3H.SW origin specific to human gamma-globulin. They also did not stain a (T,G)-A--L-specific helper T cell line derived from CWB (H-2b, Igh-1b) mice, which differ from C3H.SW mice only in their heavy chain allotypes. Thus, the expression of the idiotypic determinants on the T cell lines appears to be antigen-specific and linked to the heavy chain allotypic marker as shown for the specific antibodies. Different clones derived from the E-9 M(+) line were tested their reactivity with the individual anti-idiotypic sera. All clones but one (1.11) were stained significantly. The clones were tested for their biologic activity and all of them except clone 1.11 were found to exert helper activity specific to (T,G)-A--L. Thus, individual anti-idiotypic sera against C3H.SW anti-(T,G)-A--L antibodies recognize cross-reactive idiotypic structures on the surface of antigen-specific monoclonal helper T cells.
Animals↗