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Biomedical subjects

E Gleichmann

Publications and source records attributed to E Gleichmann.

At least 91 records · Page 5Linked to original sources
PubMed1984

Allosuppressor and allohelper T cells in acute and chronic graft-vs-host disease. V. F1 mice with secondary chronic GVHD contain F1-reactive allohelper but no allosuppressor T cells.

We studied the alloreactive properties of donor T cells obtained from F1 mice that had recovered from the allosuppression of acute graft-vs.-host disease (GVHD) and showed mild symptoms of chronic GVHD, i.e., so-called secondary chronic GVHD. To this end, we used (B10 x DBA/2)F1 mice that had been injected with 10(8) B10 spleen cells 100-150 d previously. Such GVHD F1 mice were repopulated by lympho-hematopoietic cells of donor (B10) origin, which exhibited split tolerance towards the host: Whereas F1-specific donor T helper (Th) cells as well as T cells proliferating in the mixed lymphocyte reaction were readily demonstrable, F1-specific T suppressor (Ts) and T killer (Tk) cells were not, or were hardly, detectable; responses against third-party alloantigens were normal. Upon adoptive transfer to nonirradiated secondary recipients, the B10 cells obtained from the repopulated GVH F1 mice induced F1-specific enlargement of the draining popliteal lymph node and enhancement of the IgG formation therein. B10 cells of the same kind were unable, however, to induce lethal GVHD upon transfer to 950 rad-irradiated secondary (B10 x DBA/2)F1 recipients. We conclude that alloactivated donor Ts/Tk cells disappear from the host at a relatively early stage of GVHD, i.e., at the end of acute GVHD , presumably because they are short-lived. By contrast, the longevity of alloactivated donor Th cells causes the symptoms of secondary chronic GVHD.

Acute Disease↗
PubMed1984

Allosuppressor- and allohelper-T cells in acute and chronic graft-vs-host disease. IV. Activation of donor allosuppressor cells is confined to acute GVHD.

Groups of nonirradiated BDF1 mice were injected with unseparated spleen cells from B10, B10.D2, or DBA/2 donors. The diverse clinical and pathologic symptoms that developed during the course of the ensuing graft-vs-host reaction (GVHR) were related to the functional subsets of donor-T cells activated in the host. The activation of F1-specific donor T suppressor (TS) cells was confined to those GVH F1 mice that developed acute GVH disease (GVHD) (donor B10 or B10.D2). Moreover, activation in these GVH F1 mice of the Lyt-1-2+ donor TS cells sharply preceded the onset of and coincided with (week 2 to 6) the suppressive pathologic symptoms characteristic of acute GVHD, such as pancytopenia and suppression of splenic IgG production. The activation of these alloreactive TS effector cells was briefly preceded by the activation of F1-specific Lyt-1+-2- donor T helper (TH) cells and stimulation of the host's lymphoid tissue. Thus, in acute GVHD, a sequential alloactivation first of donor TH and then of TS cells was found. Those F1 mice that recovered from acute GVHD and developed stimulatory pathologic symptoms showed a concomitant loss of donor TS cell activity. An initial activation of F1-specific Lyt-1 +2- donor TH cells was also found in that parent----F1 combination (donor DBA/2), which failed to develop acute GVHD. Significantly in that combination, the alloactivation of donor TH cells was not followed by activation of significant numbers of donor TS cells. Instead, the DBA/2-injected BDF1 mice directly developed a persistent increase in splenic Ig formation and lupus-like GVHD.

Acute Disease↗
PubMed1984

Further evidence against random polyclonal antibody formation in mice with lupus-like graft-vs-host disease.

The pathologic symptoms in F1 mice with chronic graft-vs-host disease (GVHD) (GVH F1) strongly resemble those of systemic lupus erythematosus (SLE). Mice with SLE-like GVHD do not produce antibodies to a number of non-self and self antigens. This finding is inconsistent with the widely accepted view that the (auto)-antibody formation in SLE is polyclonal in the sense that B cells are triggered at random, i.e., irrespective of their specificity. In the present study, therefore, we performed a systematic study of the kinetics of total IgM- and IgG-secreting splenic B cells and tested their specificities. The total IgM-secreting B cell population was increased only in the first week after the initiation of SLE-like GVHD; it seemed to reflect a random, but self-limited, polyclonal B cell stimulation. In contrast, the total number of IgG-secreting cells in the GVH F1 mice was increased to a much higher extent than that of the IgM-secreting cells and remained increased. At no time during GVHD was there an increase in the number of plaque-forming cells (PFC) spontaneously secreting IgG antibodies to non-self antigens. The GVH reaction (GVHR) did, however, lead to the appearance of PFC that secreted IgG antibodies to DNA. Similarly, the GVH F1 mice showed high serum titers of antibodies to self antigens characteristic of SLE and to endogenous viruses, but during the entire observation period they failed to develop serum antibodies to non-self antigens and insulin. Hence, the enhanced production of Ig, especially that of IgG, that occurs in SLE-like GVHD is not a random process, because it requires the presence of antigen, or signal 1. The data support our hypothesis that only certain kinds of self antigen, such as DNA and cell membrane epitopes, can cross-link the Ig receptors on the corresponding B cells and thus provide an adequate signal 1. Given the increase in help, or signal 2, in chronic GVHD, only the B cell clones that simultaneously receive an adequate signal 1 seem to be driven into clonal proliferation and IgG secretion.

Animals↗
PubMed1984

Injection of mouse thyroglobulin and/or adult thymectomy do not break tolerance to thyroglobulin during the lupus like graft versus host disease in mice.

In a previous paper (Gleichmann, van Elven & van der Veen, 1982), it had been reported that, in contrast to lupus like autoantibodies such as anti-DNA, autoantibodies to mouse thyroglobulin (MTg) were not detectable in serum of F1 mice suffering from a lupus like graft versus host disease (GVHD) (GVH F1). In the present paper, possible explanations for this restricted autoantibody formation during the potent allogeneic stimulation were investigated. The main question was whether the natural level of circulating MTg was too low to induce the formation of anti-MTg antibodies in GVH F1 mice. Existence, in the F1 mice studied, of B cells capable of producing anti-MTg antibodies was demonstrated by injection of lipopolysaccharide (LPS) and exogeneous MTg. However, MTg injected into various F1 mice at the onset of the GVH reaction (GVHR) failed to overcome the lack of antibody formation to MTg even though the GVHR led to a severe lupus like disease. Furthermore, adult thymectomy (ATx) of either the recipients, the donors, or both also did not break tolerance to MTg during the GVHR, irrespective of administration of exogeneous MTg. Thus, neither intravenous injection of MTg nor ATx, designed to remove T suppressor (TS) cells, is adequate to enable an autoantibody response to MTg during lupus like GVHD. Hence, the non-specific T cell help that causes lupus like GVHD seems to be intrinsically insufficient to trigger the Tg reactive B cells. We suggest that globular proteins, such as Tg, require specific T cell help. In the presence of only non-specific T help, self-antigens such as DNA seem to be more apt than globular proteins to provide an effective signal 1 to the corresponding autoreactive B cells.

Animals↗
PubMed1983

Allosuppressor- and allohelper-T cells in acute and chronic graft-vs.-host (GVH) disease. III. Different Lyt subsets of donor T cells induce different pathological syndromes.

Previous work from this laboratory has led to the hypothesis that the stimulatory pathological symptoms of chronic graft-vs.-host disease (GVHD) are caused by alloreactive donor T helper (TH) cells, whereas the suppressive pathological symptoms of acute GVHD are caused by alloreactive T suppressor (TS) cells of the donor. In the present paper we analyzed the Lyt phenotypes of B10 donor T cells required for the induction of either acute or chronic GVHD in H-2-different (B10 X DBA/2)F1 recipients. First, nonirradiated F1 mice were used as the recipients. We found that unseparated B10 T cells induced only a moderate formation of systemic lupus erythematosus (SLE)-like autoantibodies, but a high percentage of lethal GVHD (LGVHD). In contrast, Lyt-1+2- donor T cells were unable to induce LGVHD in these recipients; these cells were capable, however, of inducing a vigorous formation of SLE-like autoantibodies and the formation of severe immune-complex glomerulonephritis. Lyt-1-2+ T cells were incapable of inducing either acute or chronic GVHD. In another experiment, the sensitivity and accuracy of the GVH system were increased by using irradiated F1 mice as recipients and by comparing donor-cell inocula that contained similar numbers of T lymphocytes. In addition, donor-cell inocula were used that had been tested for their allohelper and allosuppressor effects on F1 B cells in vitro. In the irradiated F1 recipients, too, unseparated donor T cells were superior to T cell subsets in inducing LGVHD; Lyt-1-2+ donor cells were completely and Lyt-1+2- donor cells were almost incapable of doing so. In contrast, Lyt-1+2- T cells, but neither unseparated T cells nor Lyt-1-2+ T cells, were capable of inducing a vigorous formation of SLE-like auto-antibodies. We conclude that the stimulatory pathological symptoms of chronic GVHD are caused by Lyt-1+2- allohelper T cells. In contrast, the development of the suppressive pathological symptoms of acute GVHD appears to involve alloreactive Lyt-1+2+ T suppressor cells.

Acute Disease↗
PubMed1983

Allosuppressor and allohelper T cells in acute and chronic graft-vs.-host disease. II. F1 recipients carrying mutations at H-2K and/or I-A.

By induction of a graft-vs.-host reaction (GVHR) in nonirradiated H-2-different F1 mice, one can induce stimulatory pathological symptoms, such as lymphadenopathy and hypergammaglobulinemia, combined with the production of autoantibodies characteristic of systemic lupus erythematosus (SLE). Alternatively, the GVHR can lead to the suppressive pathological symptoms, such as pancytopenia and hypogammaglobulinemia, characteristic of acute GVH disease (GVHD). Whether stimulatory or suppressive symptoms are induced by a GVHR depends, in our view (2-4), on the functional subset of donor T cells activated in the F1 host. The purpose of the present study was to investigate whether class I and/or class II H-2 alloantigens can selectively trigger, out of a pool of unselected donor T cells, those subpopulations of T cells responsible for the stimulatory and suppressive GVH symptoms, respectively. For the induction of the GVHR, 10(8) lymphoid cells from C57BL/6 (B6) donors were injected into three kinds of F1 hybrid mice, which had been bred from H-2 mutant strains on a B6 background. Whereas the I-A-disparate (B6 X bm12)F1 recipients exclusively developed stimulatory GVH symptoms, including SLE-like autoantibodies and immune complex glomerulonephritis, the K locus-disparate (B6 X bm1)F1 recipients showed neither clearly stimulatory nor clearly suppressive GVH symptoms. In marked contrast, the (bm1 X bm12)F1 recipients, which differ from the B6 donor strain by mutations at both K and I-A locus, initially developed stimulatory GVH symptoms, but rapidly thereafter showed the suppressive pathological symptoms of acute GVHD and died. Moreover, spleen cells obtained from (B6 X bm12)F1 mice injected with B6 donor cells helped the primary anti-sheep erythrocyte (SRBC) response of normal (B6 X bm12)F1 spleen cells in vitro, whereas spleen cells (bm1 X bm12)F1 mice injected with B6 donor cells strongly suppressed the primary anti-SRBC response of normal (bm1 X bm12)F1 spleen cells. Spleen cells from the K locus-disparate (B6 X bm1)F1 recipients also suppressed the primary anti-SRBC of normal (B6 X bm1)F1 spleen cells; this suppression, however, was weak when compared with the suppression induced by spleen cells from GVH (bm1 X bm12)F1 mice. Taken together, these findings indicate that a small class II (I-A) antigenic difference suffices to trigger the alloreactive donor T helper cells causing SLE-like GVHD. In contrast, both class I (H-2K) and class II (I-A) differences are required to trigger the subsets of donor T cells responsible for acute GVHD. It appears that alloreactive donor T helper cells induce the alloreactive T suppressor cells, which then act as the suppressor effector cells causing the pancytopenia of acute GVHD. These findings may help to understand the variability of GVH-like diseases caused by a given etiologic agent, their cellular pathogenesis, and association with certain HLA loci.

Acute Disease↗
PubMed1983

Attempts at standardization of lupus-like graft-vs-host disease: inadvertent repopulation by DBA/2 spleen cells of H-2-different nonirradiated F1 mice.

By induction of a suitable graft-vs-host reaction (GVHR) in nonirradiated, H-2-incompatible F1 mice, one can induce a syndrome strongly resembling systemic lupus erythematosus (SLE). The aim of the present study was to standardize the kind and number of DBA/2 donor cells required for optimal induction of this SLE-like GVH disease (GVHD). Groups of adult (C57BL/10 x DBA/2)F1 (BDF1) mice were injected i.v. with increasing numbers of DBA/2 spleen and lymph-node cells. We found that doses of 100 x 10(6) to 180 x 10(6) spleen and lymph-node cells provided a suitable donor-cell inoculum, whereas doses of donor cells below 100 x 10(6) were suboptimal and doses higher than 180 x 10(6) cells were supraoptimal for the induction of SLE-like GVHD. In a number of those F1 recipients that had received the donor-cell inocula composed of spleen cells, the duration of autoantibody formation was surprisingly brief. This appeared to be due to the fact that these GVH F1 mice were rapidly repopulated by lympho-hemopoietic donor cells. Even after the highest doses of DBA/2 spleen and lymph-node cells administered, this repopulation was not preceded by symptoms of acute GVH disease. Repopulation was avoided and a severe SLE-like disease induced when a mixture deficient in hemopoietic cells, i.e., 280 x 10(6) DBA/2 lymph-node and thymus cells, was used as donor-cell inoculum. Taken together, we reached three conclusions. First, the induction of full-blown SLE-like GVHD depends not only on the injection of a sufficient number of donor T cells but also on the continuous presence of F1 lymphoid cells, which seem to serve as stimulator cells. Second, in addition to the lymphoid hyperplasia and immune-complex glomerulonephritis (ICGN) described previously, the GVHR-induced lesions presenting themselves in the context of SLE-like autoimmunity include a Sjögren-like lymphoid infiltration of the salivary gland, a ubiquitous periarteritis, and a lymphoid infiltration of the bile ducts that is reminiscent of primary biliary cirrhosis. Third, the repopulation by donor cells of nonirradiated, H-2-incompatible hosts need not be accompanied by GVH mortality or symptoms of acute GVHD.

Animals↗
PubMed1982

Allosuppressor and allohelper T cells in acute and chronic graft-vs-host disease. I. Alloreactive suppressor cells rather than killer T cells appear to be the decisive effector cells in lethal graft-vs.-host disease.

Splenic T cells from B10 donors were injected into irradiated (B10 x DBA/2)F1 mice. Either 5 or 6 d later, activated donor T cells were recovered from the spleens of these primary F1 (1 degree F1) recipients and transferred to groups of nonirradiated syngeneic F1 (2 degrees F1) recipients. Whereas day-5-activated parental T cells induced the characteristic symptoms of acute graft-vs.-host disease (GVHD) and eventually lethal GVHD, day-6-activated B10 T cells failed to induce acute GVHD but induced symptoms of chronic GVHD. Interestingly, the inability of day-6-activated T cells to induce lethal GVHD could not be ascribed to a lack in anti-F1 T killer cells. The combined results of functional studies indicated that day-6 cells were enriched for alloreactive helper T cells, whereas day-5 cells were enriched for alloreactive suppressor cells. Hence, our findings indicate that acute GVHD and lethal GVHD are caused by alloreactive donor T suppressor but not T killer cells, and that symptoms of chronic GVHD are caused by alloreactive donor T helper cells.

Acute Disease↗
PubMed1982

Diseases caused by reactions of T lymphocytes towards incompatible structures of the major histocompatibility complex. VI. Autoantibodies characteristic of systemic lupus erythematosus induced by abnormal T-B cell cooperation across I-E.

By induction of a suitable graft-vs-host reaction (GVHR) in H-2-different F1 mice, one can induce the production of autoantibodies characteristic of systemic lupus erythematosus (SLE). The purpose of the present study was to define the intra-H-2 differences in the F1 recipients that are capable of triggering this process. A GVHR was induced in [B10.A(2R) x B10.A(4R)]F1 mice by injecting 10(8) lymphocytes from either parental strain. Whereas the donor B10.A(4R) induced a massive formation of autoantibodies to thymocytes, erythrocytes, nuclear antigens, and double-stranded DNA, the donor B10.A(2R) failed to do so. The intra-H-2 genetics of these two parent leads to F1 combinations are such that the observed autoantibody formation after the injection of B10.A(4R) T cells must have been triggered exclusively by the incompatible I-Ek subregion of the [B10.A(2R) x B10.A(4R)]F1 recipients. Because I-E appears to be the murine analogue of HLA-D/DR, this finding is of interest with respect to the increased frequency of certain HLA-DR alleles in SLE patients, as discussed.

Animals↗
PubMed1981

Capacity of genetically different T lymphocytes to induce lethal graft-versus-host disease correlates with their capacity to generate suppression but not with their capacity to generate anti-F1 killer cells. A non-H-2 locus determines the inability to induce lethal graft-versus-host disease.

When comparing, in a murine model, the kind of graft-versus-host (GVH) disease (GVHD) induced by the donor strain DBA/2 on the one hand and several H-2-congenic resistant B10 donor strains on the other, we found that strain DBA/2 was a universal nonkilling GVH donor for H-2-incompatible nonirradiated F1 hybrid recipients. In this respect, DBA/2 T cells differed from those of the H-2-identical donor strain B10.D2 as well as those of other b10 donor strains. The inability of strain DBA/2 to kill by GVH reaction was not limited to certain H-2 incompatibilities in the F1 recipients, but was nonspecific. The inability to kill is determined by a dominant locus not linked to H-2. DBA/2 T cells were also incapable of inducing the severe suppression of hematocrit values, bone marrow erythropoiesis, thymic cell proliferation, and splenic IgG production in the F1 recipients that was observed after the injection of T cell from the B10 strains. However, DBA/2 T cells, in contrast with those of the B10 donor strains, were vigorous stimulators of IgG production in H-2-incompatible F1 hybrid recipients. Surprisingly, strain DBA/2 as well as the B10 donor strains had good capacity to generate anti-F1 TK cells. Taken together, these findings raise the possibility that lethal GVHD disease is not caused, or not caused exclusively, by donor killer T cells, but by those donor T cells that directly or indirectly induce a suppression of cell proliferation in certain vital organs of the recipient.

Animals↗
PubMed1981

Diseases caused by reactions of T lymphocytes to incompatible structures of the major histocompatibility complex. V. High titers of IgG autoantibodies to double-stranded DNA.

IgG autoantibodies to double-stranded DNA (dsDNA), reaching a maximal serum titer of 1 in 2560, were spontaneously produced by (C57BL/10 x DBA/2)F1 mice injected with T lymphocytes from strain DBA/2. Anti-dsDNA antibodies were detected by the indirect immunofluorescence technique applying the kinetoplast dsDNA of Crithidea luciliae as antigenic substrate. The anti-dsDNA antibodies belonged to the IgG1, IgG2, IgM, and IgA (sub)classes. That of least some of them were produced by B cells of the F1 recipients was shown by the presence of F1-derived Ig-1b allotypic markers on such antibodies. In the F1 recipients, an incompatibility at H-2 was required for the formation of anti-dsDNA. These findings are consistent with the concept that the mechanism underlying the formation of SLE-like autoantibodies in this model is an abnormal cooperation between alloreactive donor T cells, presumably helper T (TH) cells, and H-2-incompatible F1 B cells. It is known from the literature that abnormal T-B cell cooperation is a unique tool for inducing vigorous primary antibody responses to antigens that carry repeating antigenic determinants on a rigid backbone and are poor immunogens or tolerogens in the absence of abnormal T-B cell cooperation. We suggest that the self-antigen dsDNA falls into the same category of structurally and immunologically peculiar antigens.

Animals↗
PubMed1981

Diseases caused by reactions of T lymphocytes to incompatible structures of the major histocompatibility complex. IV. Autoantibodies to nuclear antigens.

We studied the requirements for induction of ANA formation in non-irradiated F1 hybrid mice undergoing a chronic graft-versus-host reaction (GVHR) after the injection of parental-strain lymphocytes. T lymphocytes in the donor cell inoculum were both needed and sufficient for the induction of ANA formation. For optimal ANA formation, the F1 recipient mice had to differ at H-2 from the parental donor strain. ANA belonged to the IgG1, IgG2, IgM and IgA (sub)classes of immunoglobulin. IgG ANA occurred in maximal serum titres of 1 in 5,120. ANA were not donor anti-host alloantibodies. At least some ANA were true autoantibodies, i.e. of F1 origin, because they carried the Ig allotypic markers characteristic of the F1 hybrid recipients. These findings are consistent with the concept that the pathogenic mechanism underlying autoantibody formation during the GVHR is an abnormal T-B-cell co-operation. In this process, donor T cells react against foreign histocompatibility antigens of the F1 recipient and generate non-specific help for B cells, including the autoreactive B cells.

Animals↗