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Biomedical subjects

M Zöller

Publications and source records attributed to M Zöller.

At least 109 records · Page 6Linked to original sources
PubMed1991

2,4,6-trinitrophenyl (TNP) responsiveness of anti-TNP (Sp6) transgenic mice.

Transgenic mouse models have demonstrated clonal deletion as well as clonal anergy of monospecific, high-avidity autoreactive B cell. The function and fate of naturally activated B cells, many of them displaying degenerate specificity including autoreactivity, are still a matter of debate. The question was pursued in Sp6-transgenic mice. Sp6, a monoclonal anti-2,4,6-trinitrophenyl (TNP) IgM has been shown to react with a variety of self antigens. Responsiveness of antibody-secreting B cells was followed throughout postnatal development of Sp6-transgenic mice and was related to the availability of antigen- and idiotype-specific help. Thymus as well as spleen cells of transgenic mice contained a significantly higher number of TNP-specific B cell than non-transgenic controls. In contrast to control mice, the number of TNP-specific B cells remained unchanged or decreased in thymus and spleen of transgenic mice after antigenic stimulation with TNP in T-dependent (TD) and T-independent (TI) form. Since the relative frequency of transgenic B cells was in particular diminished after repeated stimulation with TD antigen, it was examined whether limited responsiveness was linked to the available repertoire of helper T cells. Early after birth of transgenic individuals, thymic as well as splenic T cells which proliferated in response to TNP and Sp6 and provided help for B cells were found to be significantly augmented. Their number decreased rapidly during postnatal maturation and Th cells did not expand after antigenic stimulation. There was no indication that in the naive host transgenic B cells would suppress proliferation of TNP- and Sp6-specific T cells, but they did so after antigenic stimulation. Furthermore, and in contrast to B cells of non-transgenic mice, transgenic B cells were unable to present nominal antigen in a stimulatory way. The decrease in the number of B cells after antigenic stimulation indicated that autoreactive transgenic B cells may be subject to (functional) deletion under selected circumstances. In addition, idiotype- and antigen-specific help was impaired in Sp6-transgenic mice and this clearly was due to interactions with B cells expressing the immunoglobulin transgene.

Age Factors↗
PubMed1991

Idiotypic profile of natural autoantibodies in newborn and young adult BALB/c mice.

Idiotypic profiles of autoreactive monoclonal antibodies (MoAb) were evaluated by their reactivity with a panel of alkaline phosphatase (AP)-coupled detector MoAb derived from the same fusions. Attention was given to the question of whether differences exist between MoAb derived from spleen cells (SC) or thymocytes (TC) and whether ID profiles would change during post-natal development. In the newborn, natural autoantibodies and MoAb which did not react with any one of eight autoantigens displayed different ID profiles, autoreactive MoAb being characterized by the expression of a restricted pattern of ID. During post-natal development, changes of ID expression were only observed with autoreactive MoAb. Many ID which were detected on MoAb derived from 6-day-old mice were not detected on SC-derived MoAb from young adults, while a few ID were significantly over-represented. Furthermore, especially with TC-derived MoAb, a clear linkage between certain idiotypes and autoantigen specificities could be demonstrated. Thus, in contrast to non-autoreactive MoAb, natural autoantibodies in the young adult were characterized by expressing only a selected number of ID at high frequency. Furthermore, the B-cell environment apparently played a role, since there were marked differences between ID profiles of TC- versus SC-derived MoAb. The data are interpreted in the sense that expansion and maturation of naturally activated autoreactive B cells are controlled rather than being random processes.

Animals↗
PubMed1991

Autoreactive antibodies in thymus and spleen of neonatal and young adult BALB/c mice: influence of prenatal tolerization.

The repertoire of autoantibody-producing B cells was evaluated in a collection of spleen- and thymus-derived hybridomas from 6- and 28-day-old BALB/c mice, which were untreated or prenatally tolerized with trinitrobenzenesulphonic acid (TNBS). MoAb were tested for their reactivity with TNP-BSA and the autoantigens thyroglobulin (TG), myoglobin (MG), actin (AC), cytochrome C (CY), collagen (CO), transferrin (TF), single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), and bromelain-treated mouse red blood cells (BrMRBC). More than 10% of spleen cell (SC)-derived MoAb from 6- and 28-day-old control mice did bind to AC, ssDNA, dsDNA, MY, and TG, the frequency of MoAb reacting with MY, TG, and BrMRBC increasing with age. Thymus cell (TC)-derived hybridomas contained autoreactive clones too, but only few of them produced multireactive MoAb. MoAb from prenatally TNBS-treated mice were more frequently autoreactive than MoAb from control mice, especially if derived from TC hybridomas. The most remarkable difference in the reactivity pattern as compared with MoAb from untreated mice consisted of a significant increase in the frequency of TG-, My-, ssDNA- and above all dsDNA-reactive MoAb, all TC-derived multireactive MoAb binding to dsDNA. The differences in autoreactivity between MoAb from prenatally untreated and TNBS-treated mice as well as age- and organ-related variations support the interpretation that part of the repertoire of naturally activated B cells is not random but is influenced by and responding to the available panel of self antigens.

Actins↗
PubMed1991

Intrathymic presentation by dendritic cells and macrophages: their role in selecting T cells with specificity for internal and external nominal antigen.

The present study focused on the question of whether intrathymic dendritic cells and macrophages (DC/M phi) are involved in the processes of T-cell repertoire selection and establishment of tolerance towards nominal antigen. Proliferation of thymocytes (TC) was determined under limiting dilution (LD) conditions after depletion of DC/M phi and after reconstitution of TC, which were depleted of cells expressing major histocompatibility complex (MHC) class II antigens, with thymic DC/M phi. Trinitrophenyl (TNP) [coupled to ovalbumin (OVA)] was used as an internal antigen in prenatally trinitrobenzenesulphonic acid (TNBS)-treated mice and as an external antigen in prenatally untreated mice. Intrathymic DC/M phi were clearly involved in selecting the repertoire of T cells specific for external antigen: they presented the antigen and initiated proliferation of thymic T cells, which were depleted of MHC class II antigen-expressing cells. But they were not the only cells to present nominal antigen in the thymic environment. Intrathymic DC/M phi could also deliver negative signals. This became apparent when evaluating presentation of TNP in prenatally TNBS-treated mice. Thymus-derived DC/M phi from prenatally TNBS-treated mice could not initiate proliferation of TC in response to TNP-OVA. Instead, when prenatally TNBS-treated mice received an antigenic challenge [TNP-sheep red blood cells (SRBC)], thymic DC/M phi inhibited proliferation of cortisone-resistant TC from untreated and prenatally TNBS-treated mice. This can be explained by assuming that in the process of establishing tolerance, intrathymic DC/M phi may exert cytotoxic/cytostatic activity.

Animals↗
PubMed1990

Retardation of metastatic tumor growth after immunization with metastasis-specific monoclonal antibodies.

The influence of 4 murine monoclonal antibodies (MAbs) directed against surface determinants of a metastasizing rat adenocarcinoma (BSp73ASML) on metastatic spread was evaluated and compared to their in vivo binding as well as to the induction of a humoral anti-MAb response, especially with respect to the development of anti-idiotypic (ID) antibodies of the internal image type. In a protocol of explicit immunization, all 4 MAbs transiently inhibited metastatic growth. Survival was prolonged only with one MAb (4.4ASML). With another MAb (1.1ASML), directed against a new variant form of CD44, metastatic growth was accelerated after transient retardation. Retardation of metastatic growth correlated with the humoral anti-MAb response. This accounted for the isotype- as well as for the idiotype-specific response. An exception was noted after immunization with MAb 1.1ASML. Rats with high levels of anti-1.1ASML antibodies, which inhibited binding to the tumor cells (internal image-type antibodies) showed accelerated metastatic spread. Data are interpreted to mean that MAb-induced inhibition of metastatic spread may be based on 2 independent mechanisms: blockade of metastasis-associated epitopes (i.e., with MAb 1.1ASML) and induction of an anti-mouse Ig response. In the latter case it was irrelevant whether the response was isotype- or idiotype-specific.

Adenocarcinoma↗
PubMed1990

Intrathymic T cell repertoire after prenatal trinitrobenzene-sulfonic acid-treatment.

It is still a matter of debate, whether tolerance toward self-non-MHC antigens is due to intrathymic deletion or to regulatory processes in the periphery. To further pursue this question, responsiveness toward TNP and an anti-TNP monoclonal antibody (Sp6) carrying a recurrent idiotype was evaluated in prenatally trinitrobenzenesulfonic acid (TNBS)-treated mice. In prenatally untreated as well as in TNBS-treated mice, thymocytes proliferating in the absence of nominal antigen were double negative (L3T4-/Lyt2-), but antigen-specific thymocytes were single positive (L3T4+/Lyt2- or L3T4-/Lyt2+). TNBS-treated mice differed from controls inasmuch as in their first week of life T cells proliferating in response to TNP were found in the thymus and detected at increased frequencies in the spleen. The frequency of TNP-specific thymocytes and spleen cells declined rapidly, finally reaching in the spleen a level of 20-30% of controls. Furthermore, after antigenic stimulation, the frequency of thymocytes and spleen cells proliferating in response to TNP was found to be increased in control mice, but TNP-specific T cell were no more recovered in the thymus or the spleen of tolerized mice. The same accounted for thymic and splenic T cells proliferating in response to Sp6. They were expanded in control mice after antigenic stimulation, but were undetectable in TNBS-treated mice. Thus, T cells with specificity for an internal (Sp6) and an external (TNP) antigen, provided the latter was present during ontogeny, were detected in the thymus of control and, transiently, in the thymus of tolerized mice. But, the fate of antigen-specific thymocytes was different in prenatally untreated and TNBS-treated mice. The data are interpreted in the sense that tolerance toward non-MHC antigens may be acquired subsequently to tolerance toward self-MHC antigens and possibly after imprinting of antigen specificity.

Animals↗
PubMed1990

Intrathymic presentation of nominal antigen by B cells.

Prenatal tolerization with TNBS leads to a transient increase in intrathymic TNP-specific B cells during the first postnatal week. To evaluate whether this may influence selection of the T cell repertoire and establishment of tolerance towards the neoself-determinant TNP, the capacity of intrathymic B cells to present TNP as well as an anti-TNP antibody (Sp6), which carries a recurrent idiotype, to thymocytes of prenatally untreated and TNBS-treated litters was explored. Depletion and reconstitution experiments revealed that in the thymus of 10-day-old litters Sp6 as well as TNP was presented exclusively by B cells. After stimulation with TNP-HRBC, B cells could still present the antigen, but depletion of B cells no longer abolished proliferation, i.e. after stimulation intrathymic B cells were no longer the only source for presentation of external antigen. B cells of prenatally tolerized mice differed inasmuch as they initiated proliferation only in response to Sp6, but not in response to the neoself-determinant TNP. Furthermore, after challenge with TNP in an immunogenic form, thymic as well as splenic B cells had lost the capacity to provide positive signals to T cells specific for the neoself determinant as well as to T cells specific for the cognate antibody. It is concluded that B cells are of importance in the intrathymic selection of the T cell repertoire and that they are involved in the process of tolerization towards nominal antigen.

Animals↗
PubMed1990

Alteration of idiotypic connectivity in prenatally tolerized neonatal mice.

Prenatal tolerization with trinitrobenzenesulphonic acid (TNBS) leads to expansion of trinitrophenyl (TNP)-specific B cells, the majority of which become refractory to stimulation during postnatal development. One possible explanation could be that they belong to the repertoire of naturally activated B cells which are limited in expansion after antigenic stimulation due to a high degree of idiotypic connectivity. To evaluate this hypothesis, 59 thymus- and 490 spleen-derived B-cell hybridomas from 6-day-old prenatally untreated and prenatally TNBS-treated mice were tested for reactivity against 33 arbitrarily chosen clones derived from the same fusions, 17 being derived from control and 16 from tolerized litters. Two major points could be deduced: (1) Idiotypic connectivity, including connectivity of TNP- and anti-TNP-reactive monoclonal antibodies (MoAb), was maintained after prenatal tolerization. This accounted for thymus- and spleen-derived MoAb. (2) Only TNP- and anti-TNP-reactive MoAb derived from prenatally untreated and prenatally tolerized mice displayed significantly distinct idiotypic profiles. Differences were pronounced, especially with thymus-derived MoAb. Thus, TNP-specific B cells in prenatally tolerized newborns do not behave like B cells of adult mice stimulated by external antigen, but rather like a part of the naturally activated, idiotypically connected B-cell repertoire of the newborn. This could explain B-cell unresponsiveness at older age as a consequence--at least partly--of their high idiotypic connectivity.

Alkaline Phosphatase↗
PubMed1989

Antigenic differences between metastatic and nonmetastatic BSp73 rat tumor variants characterized by monoclonal antibodies.

Variants AS and ASML of the BSp73 rat tumor differ markedly with respect to morphology and to the capacity for spontaneous metastasis via the lymphatics. Monoclonal antibodies (MAbs) were raised in order to identify surface molecules associated with both phenotypes. Mice were immunized with either whole cells or isolated membranes and hybridoma supernatants were screened according to the criteria of selective binding to cultured cells of the variant used for immunization. Of two MAbs reacting with the nonmetastasizing AS variant, one showed immunostaining of AS tissue. From 11 MAbs binding to the metastatic ASML variant, 6 showed specific staining of ASML tissue, while the remaining 5 MAbs showed cross-reaction with normal rat tissues. According to Western blot data, the 6 MAbs selectively binding to ASML tissue identified at least 2 different antigens, one of them showing up as a complex of 12 bands.

Animals↗
PubMed1989

Recognition of idiotypic structures in the thymus.

During the passage through the thymus, T cells are selected which recognize self major histocompatibility complex (MHC) antigens with low avidity. Whether the T-cell repertoire for recognition of altered self is also built up intrathymically or in the periphery, and whether it is determined exclusively by external antigens or is shaped by the internal environment is still a matter of debate. This question was addressed by analysing the responsiveness of thymocytes during post-natal development towards a nominal antigen [trinitrophenyl (TNP)] and an anti-TNP monoclonal antibody (Sp6), which carries a recurrent idiotype. During the first weeks of life, in vitro cultures of thymocytes proliferated strongly in the absence of nominal antigen. Proliferation rates were not increased by the addition of nominal antigen [TNP-ovalbumin (OA)], but a significant increase was noted in the presence of Sp6, thymocytes recognizing the processed immunoglobulin. After in vivo stimulation with TNP conjugates, 'antigen-specific' clones could also be detected in the thymus, the frequency of clones proliferating in response to Sp6 being further augmented. With increasing age, the proliferative capacity of thymocytes from unstimulated and antigenically stimulated mice decreased significantly. Responsiveness of spleen cells (SC) differed in some respects. The response towards Sp6 decreased with age, while antigen-specific clones were detected at increasing frequencies during post-natal development. Furthermore, after antigenic stimulation, the frequency solely of antigen-specific, but not of Sp6-specific clones was increased. Thus, it appears that the T-cell repertoire is shaped already during the intrathymic passage, being influenced primarily by the B-cell repertoire and modulated further by external antigen.

Animals↗
PubMed1989

Comparison between thymus- and spleen-derived B-cell hybridomas.

When fusing thymocytes and spleen cells (SC) of 7- and 28-day-old BALB/c mice with Sp2/0, comparable numbers of clones were obtained. Immunoglobulin secretion was observed in 53-79% of splenic, but only 10-18% of thymic hybridomas. This was irrespective of tolerization through prenatal treatment with trinitrobenzenesulphonic acid (TNBS). Differences between control and tolerant mice were observed with respect to the frequency of anti-trinitrophenol (TNP)-producing hybridomas: in 7-day-old tolerant litters their frequency was increased in thymus and spleen as compared with controls, but it was decreased in 28-day-old tolerant mice. It is concluded that the majority of thymic B cells are in an activated, but non-producing state and that the repertoire of thymic B cells is influenced by prenatal contact with nominal antigen.

Animals↗
PubMed1989

Depression of nonadaptive immunity after surgical stress: influence on metastatic spread.

The question of increased tumor cell dissemination after surgical stress was addressed in the model system of the spontaneously metastasizing rat adenocarcinoma BSp73ASML, wherein amputation of the hind leg 7 days after intrafootpad implantation of tumor cells cured the animals, while surgical stress by laparotomy 2 days prior to amputation resulted in lung metastases in 80% of rats. A detailed in vitro analysis of natural killer (NK) and macrophage (Mo) activity in different lymphatic compartments revealed the following impacts of surgery: splenic NK cells displayed unaltered activity. Yet, there was a considerable decrease in the number of lymphoid cells during the first 4 days after surgery, being followed by an overshooting repopulation. In the peripheral blood, activity levels of NK cells dropped significantly during the first 24 h after surgery; later on, NK cells appeared activated with an over 2-fold increase in lytic units (LU), 4 days after surgery, NK activity had returned towards normal levels. Most dramatic changes were observed in the peritoneal cavity, being directly involved in the surgical intervention. Six hours after surgery the peritoneal cavity was nearly depleted of NK cells and Mo, the few remaining cells being highly activated. Within 2 days the peritoneal cavity was repopulated with a 3-4 fold excess of lymphoid cells and Mo, but the repopulating cells were extremely low in lytic activity. It is concluded that depression of nonadaptive immunity after surgical stress is mainly due to traffic and repopulation with immature cells, i.e. there was no indication of suppressor cell activity. This was confirmed by a combined treatment consisting in a systemic application of Corynebacterium parvum 2 days before surgery and a local application of C. parvum after surgery, which counter-balanced the stress-induced depression of NK and Mo activity. Accelerated and increased metastatic spread could be prevented concomitantly.

Animals↗
PubMed1988

Interferon-gamma treatment of B16 melanoma cells: opposing effects for non-adaptive and adaptive immune defense and its reflection by metastatic spread.

The impact of interferon-gamma (IFN) treatment of tumor cells on non-adaptive and adaptive immune defense and its reflection by metastatic spread were evaluated using a weakly metastasizing variant of B16 melanoma (B16-FI). Treatment of B16-FI with IFN resulted in a decrease in binding structures for NK cells and concomitantly in augmented metastasizing capacity. In line with this, activation of NK cells and Mo, which led to reduction of metastatic nodes, was less efficient with IFN-treated B16-FI, while after elimination of non-adaptive immune defense, the number of metastases increased significantly, but irrespective of IFN treatment. On the other hand, IFN-treated B16-FI cells become more prone to killing by cytotoxic T-cells (CTL). This was due to increased lysability by CTL and to increased immunogenicity; i.e., a higher frequency of B16-specific CTL was observed after immunization with IFN-treated than with untreated B16-FI. The reverse phenomenon was observed with anomalous and/or lymphokine-activated killer cells (AK/LAK). The common cause of increased antigenicity and immunogenicity may reside in increased expression of class-I and de novo expression of class-II MHC antigens after IFN treatment. Increased antigenicity and immunogenicity of IFN-treated B16-FI was reflected by significant reduction of metastatic nodes, prolonged survival and increased TD100 in animals immunized with IFN-treated vs. untreated melanoma cells. Comparison of the divergent effects of IFN treatment on B16-FI melanoma cells showed that the benefit of increased antigenicity/immunogenicity clearly outweighed the disadvantage of reduced susceptibility to non-adaptive immune defense.

Animals↗
PubMed1988

Postnatal B cell development: influence of trinitrobenzenesulfonic acid treatment during pregnancy.

Prenatal treatment with a reactive hapten may be well suited for analyzing the establishment of self tolerance because the hapten binds ubiquitously to proteins and cells and persists for a long period in the developing organism. Based on this consideration, pregnant BALB/c mice were treated with 2,4,6-trinitrobenzenesulfonic acid (TNBS), searching for differences in 2,4,6-trinitrophenyl (TNP) responsiveness in their offspring as compared to litters of untreated mice. The frequency of TNP-specific T-independent B cells of litters from TNBS-treated mothers was very low at birth and remained below 10% of controls until the age of 42 days. On the contrary, in 8-day-old prenatally TNBS-treated litters, the frequency of TNP-specific T-dependent B cells was higher than in controls. Expansion of TNP-specific B cells after antigenic stimulation of control mice started at the age of 3-4 weeks and expansion rates increased with age, while in prenatally TNBS-treated mice, significant expansion rates were seen at the age of 2 weeks only. Yet, after restimulation with TNP-lipopolysaccharide or with a TNP-anti-TNP conjugate, but not after restimulation with TNP-ovalbumin, similar numbers of plaque-forming cells (PFC) were observed with spleen cells of prenatally untreated and TNBS-treated mice, the latter revealing an exceptional predominance of IgG PFC. Thus, TNP-specific B cells were not deleted, but prenatal TNBS treatment resulted in an altered composition of TNP-specific B cell subpopulations, their regulation differing qualitatively from the one observed in prenatally untreated mice.

Age Factors↗
PubMed1988

Tolerization during pregnancy: impact on the development of antigen-specific help and suppression.

Analysis of splenic B cells in the offspring of BALB/c mice which were treated with 2,4,6-trinitrobenzenesulfonic acid (TNBS) throughout the gestational period revealed that reduced responsiveness was predominantly reflecting changes in regulatory cells. Since development of T cells takes place in the thymus, postnatal maturation of helper (Th) and suppressor (Ts) T cells was evaluated in the thymus as well as in the spleen. To elaborate the impact of prenatal TNBS-treatment on the trinitrophenyl (TNP) repertoire, TNP-sheep red blood cell- and fluorescein isothiocyanate-specific regulatory elements were determined in parallel. It was found that the thymus contained activated helper and suppressor cells during the first 2 weeks of postnatal life, the majority of which appeared to be self-specific. Self reactivity in thymus and periphery disappeared within 3 weeks. Prenatally TNBS-treated mice differed inasmuch as they apparently recognized TNP-self as a self component, TNP-self reactivity being down-regulated similar to self reactivity in prenatally untreated mice. This explains why prenatally TNBS-treated mice responded poorly to stimulation with conventional T-dependent TNP-carrier conjugates. Yet, they responded transiently to TNP-anti-TNP conjugates. It could be shown that this was due to down-regulation of putatively idiotype-specific Ts, which were highly increased in prenatally TNBS-treated mice. Data are interpreted in the sense that the establishment of self tolerance is preceded by activation of self-reactive Th, which become partially eliminated. Remaining autoreactivity is controlled by the establishment on an equilibrium between idiotypic and anti-idiotypic elements.

Animals↗
PubMed1988

Self versus non-self carrier in primary and secondary anti-TNP B cell response: I. Specificity of help.

Humoral anti-hapten responses are supposed to require carrier-specific help. Yet, "TNP-specific" help can be activated with TNP coupled to syngeneic lymphocytes. To further clarify the role of hapten-specific vs. carrier-specific helper T cells (TH) in the humoral anti-TNP response, BALB/c mice were immunized with TNP coupled to cellular or soluble self or non-self carriers, and we analyzed primary and secondary B cell responses as well as the apparent specificity of help. TNP bound to syngeneic red blood cells (sRBC), syngeneic albumin (sA) and syngeneic polyclonal or monoclonal immunoglobulin (sIg/smIg) and TNP coupled to non-self carriers initiated equivalent primary anti-TNP responses. On the other hand, a secondary anti-TNP response was only obtained with heterologous carriers or with smIg. Even with heterologous carriers or with smIg, the magnitude of the secondary anti-TNP response exceeded only slightly the amplitudes of a primary anti-TNP response. Furthermore, if animals were challenged shortly after priming, they appeared un/-hyporesponsive. In vitro analysis revealed that in the primary as well as in the secondary anti-hapten response, TNP-specific TH were involved, i.e., the primary response to sIg, sA and sRBC was exclusively due to TNP-specific help, the response after priming with TNP-smIg or TNP-heterologous carrier was due to the additive effects of carrier- and TNP-specific help. Since "carrier-specific" help with smIg was independent of the antibody specificity as well as of the Ig class, we suppose that smIg activated idiotype-specific TH, which functioned like "carrier" TH. Two mechanisms were responsible for the low magnitude of the secondary anti-hapten response: competition for carrier-specific help (using heterologous carriers), and antibody (AB)-dependent suppression.

Animals↗
PubMed1988

Induction of tolerance towards TNP entails down-regulation of an autoimmune attack.

In order to follow the process of induction and maintainance of tolerance, BALB/c mice were tolerized by free hapten, and effector and regulatory cell interactions were analysed by limiting-dilution (LD) cultures. Injection of trinitrobenzenesulphonic acid (TNBS) resulted, predominantly, in the activation and expansion of self-reactive cytotoxic T cells (CTL), which were observed transiently at frequencies comparable to allo-specific CTL. In addition, self-reactive helper T cells (Th) were activated and expanded in tolerized mice. TNP-specific reactivity was difficult to evaluate, since cytotoxic activity against haptenized self followed the pattern of self-reactivity throughout the test period. But in LD cultures determining proliferation, two populations of Th responding to TNP-self were observed, while only one Th population could be detected in response to self. Expansion/activation of Th and CTL precursors (CTLp) was followed by activation of suppressor T cells (Ts). The suppressor population could be divided into two subpopulations, one interfering with Th, the second interacting directly with CTL (veto cells). The results indicate that during the induction of tolerance, animals pass through an autoimmune attack, with expansion and activation of self-reactive clones (CTL, Th). The final status of non-responsiveness towards TNP is not due to the deletion of effector or regulatory cells, but results from the establishment of a steady state of dominance of self-reactive and TNP-self-reactive suppression.

Animals↗