Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Functional characteristics of an autoreactive (I-Ek-restricted) T cell line (l/+ T1), previously established from MRL/M(p-)+/+(MRL/+) mice with lpr-GVHD, were analyzed in vivo. Intravenous injection of l/+ T1 cells to non-irradiated H-2k (MRL/+ or AKR) mice (but not H-2d mice) induced enhanced spontaneous proliferation of recipient spleen cells; this was also I-Ek self-restricted. This augmented self-reactivity seemed to be mediated by recipient L3T4+ T cells, since few l/+ T1 cells were detected in the spleen cells of l/+ T1-injected AKR mice by cell surface marker analyses, and the treatment of the spleen cells with anti-Thy-1.1 antibody (Ab) or anti-L3T4 Ab plus complement abolished this enhanced spontaneous proliferation. The production of IgM rheumatoid factor (RF) in AKR mice and IgG RF in MRL/+ mice increased, although no enhancement of anti-ssDNA Ab production was observed. Judging from both spleen B cell proportion and serum Ig levels, autoantibody induction by the injection of l/+ T1 cells was not associated with polyclonal B cell activation. When lethally irradiated B10 congenic mice were used as recipients, B10. BR mice showed elevated levels of IgM anti-ssDNA and IgM RF 1 wk after l/+ T1 cell injection; it is likely that lethal irradiation causes autoantigens, particularly DNA, to be exposed. These findings suggest that the autoreactivity of l/+ T1 cells can be transferred to recipient L3T4+ T cells via T-T interaction or the immunological network, and that increased autoreactivity induces autoantibody production in the presence of autoantigen stimulation. In contrast to the stimulatory effects observed in AKR and MRL/+ mice, MRL/Mp-lpr/lpr(MRL/lpr) mice showed a different response to the injection of l/+ T1 cells; spontaneous proliferation of spleen cells and autoantibody production were not enhanced, and suppression of the mitogen responses was observed. It is discussed that lpr-GVHD may be due to these unusual features of MRL/lpr mice.
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PMID:Auto-MHC class II-reactive T cell line obtained from MRL/+ mice suffering from lpr-GVHD. II. Analyses of functional characteristics of T cell line by in vivo administration. 128 75

Clinical data have suggested that graft-versus-host disease (GVHD) plays a crucial role in the antileukemic effects of bone marrow grafts. We investigated (a) whether bone marrow cells unable to induce GVHD can effect graft-versus-leukemia (GVL) activity and (b) whether such antileukemic capacity depends on the presence of T lymphocytes in the graft. Balb/c mice were inoculated with A20 cells, a B-cell lymphoma/leukemia of Balb/c origin. Four weeks after tumor inoculation the animals were lethally irradiated and received a bone marrow graft. Cells from (Balb/c x C57) F1 or (C3H x Balb/c) F1 hybrids were transplanted into parental-strain Balb/c mice. Since lymphocytes from F1 hybrids are unable to cause graft-versus-host reactivity against a parental-strain animal, we used this experimental setting to explore GVL effects in a GVHD-free system. In vitro incubation with monoclonal anti-Thy-1.2 antibody plus complement was used to eliminate Thy-1+ cells. After syngeneic transplantation, the death rate due to leukemia remained unchanged (91%) compared with that among untreated animals (86%). Following transplantation of F1 marrow cells of either (C57 x Balb/c) F1 or (C3H x Balb/c) F1 origin, death rates of 40% and 50% were observed; these were significantly lower. Depletion of Thy 1+ cells from bone marrow graft caused only a slight increase in the leukemic death rate after transplantation of bone marrow of (C57 x Balb/c) F1 hybrid origin (50%), but a high leukemic death rate was seen after transplantation of (C3H x Balb/c) F1 bone marrow (100%). Additional experiments with fully allogeneic, T-cell-depleted C57 bone marrow transplantation suggest an antileukemic effect that is comparable to that seen after transplantation of unmanipulated F1 bone marrow. Taken together, our results indicate that GVL activity can be dissociated from graft-versus-host reaction.
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PMID:Graft-versus-leukemia activity after bone marrow transplantation does not require graft-versus-host disease. 163 77

We investigated the capacity of monoclonal antibody (mAb) treatment to prevent graft-vs.-host disease (GVHD) in lethally irradiated, allogeneically reconstituted mice, employing anti-T cell (subset) mAb and a fully allogeneic strain combination. In this strain combination, purified CD4+ cells were able to induce a lethal GVH reaction, whereas purified CD8+ cells were not. In the same strain combination, a single intraperitoneal injection of IgG2b anti-Thy-1 mAb, one day after reconstitution, caused a dose-dependent improvement of the survival. A single injection of a dose as low as 12.5 micrograms per mouse was already effective. Intravenous and intraperitoneal administration of the mAb appeared equally effective. For effective prevention of GVHD the treatment could be postponed until the 4th day after transplantation, but treatment delayed until day 6 was no longer effective. Treatment with IgG2b mAb specific for either helper or cytotoxic T cells also led to improvement of GVHD and survival, but was less effective than treatment with anti-Thy-1 mAb. Clinically, there was a difference in the effectiveness of anti-CD4 and anti-CD8 treatment, since symptoms of GVHD started earlier in the anti-CD8 treated group and the survival was better in the anti-CD4 treated group. These results press for prospective clinical studies employing anti-T cell mAb treatment early after allogeneic bone marrow transplantation, especially in HLA mismatched cases.
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PMID:Prevention of lethal graft-vs.-host disease by a single low dose injection of anti-T cell monoclonal antibody to the allograft recipients. 167 55

When MRL/Mp(-)+/+(MRL/+) mice are lethally irradiated and then reconstituted with MRL/Mp-lpr/lpr (MRL/lpr) bone marrow and/or spleen cells, these MRL/+ mice develop "lpr-GVHD" which is similar to acute graft-versus-host disease (GVHD). Using a Thy-1 congenic strain of MRL/lpr mice (MRL/lpr-Thy-1.1), we analyzed T cell subpopulations in the thymus and spleen of MRL/+ mice suffering from lpr-GVHD. lpr-GVHD was induced in MRL/+ mice by transplantation of bone marrow cells (BMC) from MRL/lpr-Thy-1.1 mice; severe lymphocyte depletion associated with fibrosis was observed in the spleens after 7 weeks of bone marrow transplantation (BMT). Thymocytes of the host MRL/+ thymus were replaced with donor-derived cells from the early stage of lpr-GVHD, whereas in the spleen, a small number of host T cells (Thy-1.2+) (4-5%) were retained until the late stage of lpr-GVHD. Donor-type (Thy-1.1+) T cell subsets were not different from those of nontreated MRL/+ mice in the thymus, whereas in the spleen. CD8+ T cells (Thy-1.1+) reached a peak at 5 weeks after BMT, and CD4+ T cells (Thy-1.1+), a peak at 6 weeks. The elimination of T cells from MRL/lpr BMC had no evident effect on the prevention of lpr-GVHD. T cell subpopulations showed a similar pattern to GVHD elicited by MHC differences. Analyses of autoreactive T cells expressing V beta 5 or V beta 11 revealed that autoreactive T cells were deleted from the peripheral lymph nodes. Interestingly, the levels of IgG anti-ssDNA antibodies markedly increased, and both IgM and IgG rheumatoid factors slightly increased 5 to 7 weeks after BMT. These findings are discussed in relation to not only GVHD elicited by MHC differences but also autoimmune diseases.
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PMID:Analyses of acute graft-versus-host-like reaction in [MRL/lpr----MRL/+] chimeric mice using MRL/lpr-Thy-1. 1 congenic mice. 167 78

Using a mouse model for MHC-matched unrelated donor transplantation, the relative influences of the CD4 and CD8 T cell subtypes on graft-versus-leukemia (GVL) were examined in a murine erythroleukemia induced in SJL/J mice by the injection of Rauscher virus. Following leukemia induction, the mice were given 9.5 Gy of total body irradiation (TBI) and injected with mixed marrow and spleen cells from normal MHC-matched--but minor histocompatibility mismatched--B10.S donors. Prior to their injection these donor cells were selectively depleted ex vivo for either CD4, CD8 or Thy-1 by exposure to the appropriate monoclonal antibody (MoAb) plus complement. Following transplant the recipients were observed for 20 weeks, along with parallel control groups, for survival, leukemia relapse, graft failure and graft-versus-host disease; 98% of the controls receiving no transplantation therapy died of leukemia. Among the controls that received TBI plus undepleted B10.S cells 30.9% died of leukemia relapse, but another 34.2% survived free of any clinical evidence of their leukemia. Donor cell depletion for Thy-1 increased the relapse to 68.8%, while survival fell to 10.4%. CD8 depletion resulted in a relapse of 55.6%, with a survival of 19.4%. By contrast, CD4 depletion had no effect on relapse, but did significantly increase the incidence of graft failure. At the end of the 20 weeks additional tests were run to determine whether those transplant survivors that had remained leukemia-free were also free of any residual Rauscher virus. Those tests showed that they were not.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The role of CD4 and CD8 T cells in the graft-versus-leukemia response in Rauscher murine leukemia. 168 16

Irradiated C57BL/6(B6) mice, when they were injected with spleen cells of C57BL/6J-lpr/lpr(B6-lpr) mice, developed splenomegaly at 2 weeks post-transfer, but afterward displaced by GVH-like disease. At 2 weeks the enlarged spleen in the chimeric mice, designated as [B6-lpr----B6] chimera, contained about 70% of the total cell population as CD8-positive T cells. Spleen cells from [B6-lpr----B6] chimeras were unresponsive to Con A and LPS stimulation and suppressed the mitogenic response of B6, B6-lpr, and C3H spleen cells to Con A. However, they had no cytotoxic activity towards Con A blasts of B6 and B6-lpr spleen cells. The suppressor activity found in the [B6-lpr----B6] spleen cells was removed by pretreatment of them with anti-Thy-1.2 or anti-CD8(Lyt2.2) plus complement. The present experiment showed that enormous proliferation of CD8-positive suppressor T cells was induced in the [B6-lpr----B6] chimeras. These cells were probably responsible for the GVH-like lymphoid atrophy observed in these [B6-lpr----B6] chimeras.
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PMID:Analysis of the mechanism of graft-versus-host-like disease in B6 mice with transferred B6-lpr spleen cells. 171 58

Graft-versus-host disease (GVHD) is known to cause profound dysregulation of the immune system, although its effector mechanisms are poorly understood. We now describe an effector lymphocyte of unusual phenotype in the skin of mice with GVHD. This cell is of donor origin and expresses several T-cell surface proteins including Thy-1, CD2, and CD4 but does not express CD8, CD3, NK1.1, or macrophage antigens. Mononuclear cells of this phenotype are the predominant lymphocyte in the epidermis of mice with GVHD 3 weeks after transplant but are not detected in transplanted mice without GVHD. Isolation and transfer of these lymphocytes into secondary recipients causes epidermal damage characteristic of GVHD. These data demonstrate that CD4+ CD8- CD3- lymphocytes are an important effector population that can be amplified outside the thymus and that can mediate target organ damage of GVHD.
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PMID:Lymphocytes with a CD4+ CD8- CD3- phenotype are effectors of experimental cutaneous graft-versus-host disease. 183 92

Considerable variations in the suppression of graft-versus-host disease with monoclonal anti-Thy-1 antibodies were found to relate to substantial differences noted in the expression of mouse Thy-1 marker on lymph node and spleen cells of Thy-1.1 (AKR/J, C57BL/6.Thy-1.1) and Thy 1.2 (AKR/Cu, C57BL/6) mice. Thy-1.1 mice showed a population of 22% (AKR/J) or 13% (C57BL/6-Thy-1.1) of Thy-1 negative cells among peripheral T cells carrying Ly-1 marker. This was in sharp contrast with Thy-1.2 mice, where as expected practically all peripheral T cells expressed both Thy-1 and Ly-1. Double-marker analysis on FACScan revealed that the Thy-1-/Ly-1+ cell population identified in Thy-1.1 but not in Thy-1.2 mice doubtless represents T cells because they express CD3 and either the L3T4 (CD4) or Lyt2 (CD8) phenotype. Using quantitative fluorescence-measurement techniques, it was found in addition that the Thy-1 antigen-binding sites on Thy-1+ cells from Thy-1.1 mice are considerably fewer than those present in Thy-1.2 mice. In fact, the Thy-1 antigen-binding sites approximate the level of Ly-1 density. Consequences of the reduced expression of Thy-1 became apparent in vivo: (1) lymphnode and splenic T cell areas in Thy-1.1 mice were clearly less depleted when Thy-1.1 and Thy-1.2 mice had been injected with rat IgG2b anti-Thy-1 mAb; and (2) GvHD was prevented completely in fully mismatched mice by anti-Thy-1 mAb if the donor mice expressed Thy-1.2 but was barely delayed if the donors expressed Thy-1.1. Thus the present study provides a transplantation model for comparing differences in T antigen density and their consequences for antibody-induced immunosuppression.
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PMID:Antilymphocytic antibodies and bone marrow transplantation. XI. Evidence that reduced Thy-1 expression in Thy-1.1 mice prevents suppression of graft-versus-host disease with anti-Thy-1 monoclonal antibodies. 197 Feb

Remarkable differences in the suppression of graft-versus-host disease (GVHD) have been found for anti-Thy-1 antibodies to relate to (1) antigen density and antibody coating on the target cells, (2) antibody isotype, and (3) uptake of complement subcomponent C1q. Regarding (2) and (3) we now demonstrate that depletion of the third complement component C3 by cobra venom factor (CVF) differentiates two T-cell elimination pathways in mice: four rat IgG2c anti-Thy-1 monoclonal antibodies (MoAbs) with low uptake of mouse C1q lost most of their T-cell-depleting and consequently GVHD-preventing effect in C3-depleted H2 IA incompatible semiallogeneic (C57BL/6xCBA)F1 mice. In contrast, eight rat IgG2b, mouse IgG2a, and 2b anti-Thy-1 MoAbs with high affinity for C1q still remained strongly T-cell-depleting and prevented GVHD even in fully mismatched CBA mice depleted of C3. In conjunction with our observation that anti-Thy-1 MoAbs also suppress GVHD in C5-deficient AKR mice, we conclude that complete complement activation until T-cell lysis is not required for our antibodies to be effective in vivo. Activation, but only until deposition of C3b on target-cells for opsonisation via C3b receptors, is necessary with the less immunosuppressive anti-Thy-1 IgG2c isotype with low affinity for C1q. Mouse C1q uptake and C3/C4 deposition on target cells were measured with labeled antibodies and localized in T-cell areas. Interestingly, not even activation until C3b is necessary with the most immunosuppressive C1q-high-affine isotypes. As far as the latter is concerned, we discuss whether elimination of antibody-coated cells via Fc receptors is enhanced by binding to C1q-receptors and/or by intercalating C1q expressed on macrophages.
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PMID:Antilymphocytic antibodies and marrow transplantation. XIV. Antibody-induced suppression of graft-versus-host disease in C3-decomplemented mice differentiates two T-cell-depletion pathways. 202 84

When MRL/Mp-(+)/+ (MRL/+) mice are lethally irradiated and then reconstituted with bone marrow or spleen cells from MRL/Mp-lpr/lpr (MRL/lpr) mice, they develop a graft-versus-host disease (GVHD)-like syndrome, colloquially known as "lpr-GVHD". To analyze the roles of the MRL/lpr T cells in the development of "lpr-GVHD" and autoimmune diseases, several T cell lines were established from the spleen cells of MRL/+ mice suffering from "lpr-GVHD". The surface phenotypes, specificities, and functions of a representative clone (l/+T1) of the cloned T cell lines were characterized. The l/+T1 cells showed Thy-1.2+, L3T4+ and T3+, but Lyt-2- and B220- phenotypes. Proliferative response was observed by co-culturing the cells with spleen cells from MRL/+, MRL/lpr, AKR/J, and C3H/HeN mice, but not from BALB/c or C57BL/6 mice. Furthermore, the l/+ T1 cells responded to spleen cells of B10.BR and B10.A but not B10.D2 mice. The proliferative response of l/+ T1 cells to MRL/+ spleen cells was inhibited by anti-I-Ek (but not anti-I-Ak or anti-Kk) antibodies, suggesting that the specificity of l/+T1 cell culture enhanced the proliferative response only in the presence of appropriate stimulators. Treatment of stimulator cells with J11d.2 + C (but not anti-Thy-1.2 + C or 33D1 + C) abolished the stimulatory effect, indicating that B cells are effective stimulator cells for auto-MHC class II-reactive l/+T1 cells. When MRL/+ splenic B cells were co-cultured with l/+T1 cells, both B cell proliferation and IgM production were observed. In addition, IgM-class rheumatoid factor and anti-ssDNA antibody activities were found in the supernatants of MRL/+ splenic B cells co-cultured with l/+T1 cells. These results are discussed in relation to "lpr-GVHD" and autoimmunity in MRL/lpr mice.
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PMID:Auto-MHC class II-reactive T cell line obtained from MRL/+mice suffering from "lpr-GVHD". I. Characterization of surface phenotypes, specificities and functions in vitro. 209 6


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