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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)

The minor histoincompatible mouse radiation chimera provides a useful model of graft-versus-host disease (GVHD) paralleling conditions in human marrow transplant recipients. While studying the B10.D2/BALB/c model, we noted that a graft-versus-host reaction of particular severity develops in the forestomach near the squamocolumnar junction. Comparison of the dyskeratotic index of this epithelium with that of the skin of the same animal revealed the forestomach to be a more sensitive site for detection of GVHD. In normal mice, both basal forestomach squamous epithelium and cells in the lamina propria expressed class II antigens. During the course of GVHD, class II antigen expression was elevated in the squamous epithelium of the forestomach, the columnar epithelium associated with the stomach, and cells within the associated lamina propria. The demonstration here that the squamocolumnar junction (considered to be a stem cell region for the maintenance of adjacent forestomach squamous epithelium) appears to be a particularly sensitive target tissue in GVHD and earlier identification of other epithelial target tissues of GVHD (hair follicles and rete ridges of epidermis, bile ductules of liver, and crypt cells of the gut) collectively support the hypothesis that GVHD tends to target sites of epithelial proliferation overlying epithelial stem cells.
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PMID:The murine forestomach: a sensitive site for graft-versus-host disease. 207 Jan 31

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

In a multicenter pilot study, 32 patients showing steroid-resistant acute graft-versus-host disease (GVHD) were treated by in vivo administration of anti-interleukin-2 (IL-2) receptor monoclonal antibody (MoAb B-B10). Twenty-three patients received marrow from HLA-matched related donors, four from matched unrelated donors and five from partially matched related donors. The overall grade of GVHD was II in 16 patients, III in two, and IV in five. Five milligrams of B-B10 MoAb was infused in bolus daily for 10 days and then every second day for a further 10 days in an attempt to reduce GVHD recurrence. No clinical side effects were noted during the B-B10 treatment period. A complete response (CR) acute GVHD was achieved in 21 patients (65.6%). Six patients (18.7%) showed partial improvement (PR) and 5 patients (15.6%) no response (NR). A significant factor associated with GVHD response was the delay between the onset of the GVHD and the first day of B-B10 infusion. The earlier B-B10 was introduced, the greater the probability of CR (P = .03). There was no correlation between the serum B-B10 level and GVHD response (P = .69). There was, however, a significant correlation between the clinical response and the B-B10 kinetics as a function of time: serum B-B10 levels attained a plateau level more rapidly in the CR group than in the PR/NR group. Among the 26 complete and partial evaluable responders, GVHD recurred in 10 cases (38.4%). Host anti-B-B10 MoAb immune response occurred in only one (7.1%) of the 14 patients analyzed. Fourteen of the 32 patients (43.7%) are currently alive between 2 and 14 months after GVHD treatment with B-B10 was completed.
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PMID:Treatment of corticosteroid resistant acute graft-versus-host disease by in vivo administration of anti-interleukin-2 receptor monoclonal antibody (B-B10) 226 57

Injection of parental C57BL/10 spleen cells into unirradiated immune-competent (B10 x B10.BR)F1 hosts has been demonstrated to produce a graft-vs.-host-induced immune deficiency in T cell-mediated functions, including mitogen or alloantigen stimulated proliferation or cytotoxic T cell generation. The production of T cell-derived lymphokines affecting hematopoiesis was also altered during GVH. During the first two weeks of GVH, IL-3 and particularly GM-CSF were produced spontaneously; in subsequent weeks, the spontaneous production dropped to normal or subnormal levels. CSF content in concanavalin A-stimulated splenic supernatants was reduced at weeks 1-2, and declined to less than 5% of normal levels by 3-4 weeks of GVH. This decline in CSF content was correlated with a decrease in immune function as assessed by concanavalin A-stimulated IL-2 production and by generation of cytotoxic T lymphocytes. Concurrent with the recovery of immune function during GVH weeks 8-15, mitogen-stimulated production of CSF returned to normal levels. In addition to the decrease in CSF production identified in acute suppressive GVH, CSF content in concanavalin A-stimulated splenic supernatants was also decreased in chronic stimulatory GVH, generated in the strain combination (B6 x B6bm1)F1----(B6bm1 x B6bm12)F1. This decrease in CSF production correlated with a decrease in self-restricted T helper cell function. Finally, a decrease in both immune function and CSF production capacity was observed in the acute GVH following allogeneic (minor histocompatibility loci) bone marrow transplantation into irradiated hosts.
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PMID:Alterations in T cell-derived colony-stimulating factors associated with GVH-induced immune deficiency. 218 11

Immunoglobulin production, particularly IgE, is known to be dysregulated in graft-vs-host disease (GVHD). We examined serum levels of the highly T-dependent Ig isotypes, IgE, IgG1, and IgG2a, in two different mouse models of GVHD. GVHD across minor histocompatibility barriers is produced by injection of B10.D2 spleen cells into 600 rad irradiated BALB/c hosts. Both strains are H2d and mls b, but differ at the minor histocompatibility antigens. As GVHD progresses there is a rapid rise in serum IgE (300-fold) and IgG1 (2.5-fold) with a peak at Day 14. Concomitantly, IgG2a falls. Serum immunoglobulin levels return to normal by 11 weeks. The rise in IgE is abolished by increased (900 rad) recipient irradiation, suggesting that host-derived factors are important. GVHD across major histocompatibility barriers is produced by injection of DBA/2 spleen cells into unirradiated or 600 rad irradiated (B6 x DBA/2)F1 hosts. Only in the irradiated recipients is there severe Ig dysregulation. In this situation there is a 100-fold rise in IgE, and 5- to 10-fold rises in IgG1 and IgG2a. While the results in GVHD across minor barriers suggest stimulation of T helper cells secreting IL-4, the increase in IgE, IgG1, and IgG2a levels in GVHD across major barriers suggests activation of IL-4 and IFN-gamma-secreting T cells. These results indicate that different mechanisms may be operating in these two models of GVH. Murine GVHD can serve as a model for studying dysgammaglobulinemias in general and for hyper-IgE formation in particular.
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PMID:Immunoglobulin dysregulation in murine graft-vs-host disease: a hyper-IgE syndrome. 235 59

Two models of murine graft-versus-host disease (GVHD) were studied with respect to autoantibody production and development of systemic lupus erythematosus (SLE) like disease. One model was induced by injection of (B10.A(4R) x B10.A(2R]F1 mice with parental (B10.A(4R] spleen and lymph node cells (groups I GVHD), the other by injection of (DBA/2 x C57/B16)F1 mice with DBA/2 cells (group II GVHD). Group I GVHD mice remained in a seemingly healthy condition and did not show any proteinuria, in spite of high titres of anti-nuclear antibodies including antibodies to dsDNA, anti-Sm and anti-ribosomal P protein antibodies. Measured levels of these autoantibodies as well as their isotypes were comparable with those found in MRL/lpr and NZB/W mice. Group II GVHD mice developed SLE-like disease signs, including severe proteinuria. At 4 months after induction of the GVHD, almost 50% of these mice had died. At the time nephritis was present, group II mice also produced anti-dsDNA and anti-nuclear antibodies of other (unknown) specificities, but no anti-Sm or anti-P. Furthermore, the incidence of these antibodies was lower than observed in group I GVHD, MRL/lpr or NZB/W mice. It is concluded that (high avidity) anti-dsDNA as well as anti-Sm and anti-P may be present in the circulation without giving rise to the development of nephritis.
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PMID:Fine specificities of anti-nuclear antibodies in murine models of graft-versus-host disease. 237 20

Injection of B10.D2 cells into irradiated H-2d compatible (DBA/2xB10.D2)F1 recipients provokes a lethal GVH that can be abrogated by donor preimmunization against host-specific DBA/2 non-H-2 antigens. To study the possible relationship between the observed protection and restoration of immune responsiveness, we compared spleen cellularity, selected T and B cell functions, and NK activity in GVH and protected mice during the 1st month after grafting. Normal and isografted mice served as controls. GVH was found to be characterized by an early stimulation phase associated with splenomegaly and increased percentages (but not numbers) of Lyt-2+ and L3T4+ cells, followed by profound aplasia and abrogation of IL-2 production. Response to a B cell mitogen (LPS) is depressed, and cells from GVH mice exert a strong suppressive effect on the LPS and PHA responsiveness of normal cells. Suppression appears to be mediated by a radioresistant, nylon nonadherent, asialo GM1 negative cell expressing a low level of Thy-1 antigen. In contrast, protection correlates with progressive restoration of spleen cellularity and LPS responsiveness, with decreased but clearly detectable IL-2 production, and transient nonspecific suppressor activity. The immune status of protected mice resembles that of isografted controls. No correlation was found between mortality (or protection) and either PHA responsiveness, which remained depressed in all grafted mice throughout the observation period, or NK activity, which was strongly depressed in both GVH and protected mice. In conclusion, protection correlates with the disappearance of nonspecific suppressor cells and the restoration of cellularity and certain nonspecific immune functions. Donor immunization against host-specific non-H-2 antigens, which protects against mortality, also protects against GVH-associated immune deficiency.
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PMID:Lethal graft-versus-host reaction against non-H-2 antigens. I. Prevention of GVH-associated immunodeficiency by preimmunizing the donor against host-specific non-H-2 antigens. 252 8

The use of allogeneic bone marrow transplantation as a means of inducing donor-specific tolerance across MHC barriers could provide an immunologically specific conditioning regimen for organ transplantation. However, a major limitation to this approach is the toxicity of whole body irradiation as currently used to abrogate host resistance and permit marrow engraftment. The present study describes methodology for abrogating host resistance and permitting marrow engraftment without lethal irradiation. Our preparative protocol involves administration of anti-CD4 and anti-CD8 mAbs in vivo, 300-rad WBI, 700-rad thymic irradiation, and unmanipulated fully MHC-disparate bone marrow. B10 mice prepared by this regimen developed stable mixed lymphohematopoetic chimerism without any clinical evidence of graft-vs.-host disease. Engraftment was accompanied by induction of specific tolerance to donor skin grafts (B10.D2), while third-party skin grafts (B10.BR) were promptly rejected. Mice treated with the complete regimen without bone marrow transplantation appeared healthy and enjoyed long-term survival. This study therefore demonstrates that stable mixed chimerism with donor-specific tolerance can be induced across an MHC barrier after a nonlethal preparative regimen, without clinical GVHD and without the risk of aplasia.
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PMID:Mixed chimerism and permanent specific transplantation tolerance induced by a nonlethal preparative regimen. 256 84

Previous studies have demonstrated that T cell-depleted (TCD) syngeneic marrow protects against graft-versus-host disease (GVHD) when given along with an allogeneic lymphocyte plus bone marrow (BM) inoculum to lethally irradiated mice. In spite of this anti-GVHD effect, TCD syngeneic marrow is ultimately eliminated by non-TCD allogeneic marrow, permitting complete allogeneic reconstitution. These observations suggested that allogeneic BM might also eliminate host-type leukemic cells in a model in which TCD syngeneic marrow is co-administered to provide protection from GVHD. In the present studies, we describe the establishment of a new model using the EL4 leukemia/lymphoma. Lethally irradiated B10 (H-2b) mice were given a lethal dose of EL4 cells (H-2b) along with syngeneic marrow or a mixture of TCD syngeneic plus non-TCD allogeneic (B10.D2, H-2d) marrow. Non-TCD allogeneic marrow, in contrast to TCD or unmanipulated syngeneic marrow, delayed or prevented mortality from the otherwise lethal EL4 inoculum, without producing clinically apparent GVHD. The anti-leukemic effect of allogeneic marrow alone was not attenuated by the co-administration of TCD syngeneic marrow, and such animals repopulated as completely allogeneic chimeras. Similar anti-leukemic effects of mixed marrow inocula in a haploidentical strain combination, and an anti-leukemic effect against established tumor were also demonstrated. This model may have the potential to increase the safety of clinical bone marrow transplantation across greater HLA disparities, while permitting utilization of the anti-leukemic and alloengraftment-promoting effects of T cells in allogeneic marrow inocula.
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PMID:Graft-versus-leukemia effect using mixed allogeneic bone marrow transplantation. 279 Mar 25

An in vitro assay was used to determine whether mouse complement (C') was able to lyse T cells coated with a monoclonal IgM anti-Thy-1 antibody. Using lymph node cells (LNC) as targets, it was found that antibody-coated mature T cells were efficiently lysed by serum from C57BL/6, but inefficiently lysed by serum from BALB/c mice. Serum from both strains lysed antibody-coated thymocytes, demonstrating that BALB/c serum is not deficient in one of the C' components. The lytic activity of BALB/c serum could be improved by increasing the concentration of monoclonal anti-Thy-1 used to coat the target LNC. In contrast, serum from C5-deficient A/HeJ mice was unable to lyse either of the antibody-coated target cells in vitro. These in vitro results were confirmed in vivo using a model of lethal graft-versus-host disease (GVHD) induced to minor histocompatibility antigens. In this model, GVHD occurs when lethally irradiated mice are transplanted with bone marrow plus spleen cells from H-2-identical donor mice. GVHD is prevented when T cells are removed from the cells by in vitro treatment with anti-Thy-1 antibody plus rabbit C'. As predicted by the in vitro data, C57BL/6 mice were protected from GVHD when transplanted with LP cells treated with a 1:100 dilution of anti-Thy-1 antibody, but without complement, but BALB/c recipients of antibody-coated B10.D2/nSN cells were not. When the concentration of anti-Thy-1 used to coat the donor cells was increased to 1:50, 8 of 9 recipients were protected from GVHD. In contrast, none of the C5-deficient DBA/2 recipients of anti-Thy-1 (1:50 dilution) treated B10.D2 cells were protected from GVHD. Complement-mediated lysis appears to be the primary mechanism by which T cells coated with a monoclonal IgM anti-Thy-1 antibody are functionally inactivated in vivo.
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PMID:Prevention of graft-versus-host disease using antibody to Thy 1. A role for complement in vivo. 286 76


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