UMLS:C0018133 - FACTA Search

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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)

Peripheral blood progenitor cells (PBPCs) are increasingly being used to replace bone marrow cells (BMCs) as a source of hematopoietic stem cells also in the field of allogeneic transplantation. Whereas it is well known that PBPC grafts and BM differ significantly in progenitor cell content and lymphocyte dose, the clinical consequences of these differences with respect to engraftment, graft-versus-host disease (GVHD), and the graft-versus-leukemia (GVL) effect are more difficult to assess. We present a murine model that allows us to evaluate engraftment, GVHD, and GVL effect of allogeneic PBPC transplantation (PBPCT). Balb/c mice (H-2d) served as recipients. Donors were major histocompatibility complex-matched DBA/2 mice or syngeneic Balb/c mice, respectively. Experiments with increasing numbers of BMCs or Filgastrim-mobilized PBPCs showed that the number of progenitor cells in the graft was correlated with the probability to engraft, irrespective of the graft type. With identically high cell numbers transferred (1 x 10(9) nucleated cells/kg body weight [BW]), the mortality rates due to GVHD (25%) were about the same after allogeneic BM transplantation (BMT) and allogeneic PBPCT, although PBPC grafts contained four times more CD3+ T cells as compared with BM grafts (6.2 x 10(8) v 1.4 x 10(8)/kg BW). For investigation of GVL activity, Balb/c recipients were injected with syngeneic cells of the B-lymphocytic leukemia cell line A20 2 days before transplantation. After total body irradiation to a dose of 7.5 Gy, 1 x 10(9)/kg BW Balb/c PBPCs, DBA BMCs, or DBA PBPCs were infused. The relapse rates observed were 80% after syngeneic PBPCT (n = 22), 60% after allogeneic BMT (n = 23), and 34% after allogeneic PBPCT (n = 26) (allogeneic BMT v PBPCT, P = .032). We conclude that transplantation of allogeneic PBPCs instead of BM may enhance the GVL effect without an increase of GVHD.
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PMID:Allogeneic peripheral blood progenitor cell transplantation in a murine model: evidence for an improved graft-versus-leukemia effect. 926 90

The DBA/2 and C57BL/6 mouse strains, as well as the BXD RI lines derived from these strains, were used to map the genes controlling experimentally induced systemic lupus erythematosus (SLE). SLE was induced using two immunologic approaches: (1) immunization with the human monoclonal anti-DNA antibody expressing the 16/6Id, to which the DBA/2 strain is susceptible (responder) and the C57BL/6 strain is resistant (nonresponder); and (2) induction of autoimmune GVHD in B6D2F1 hosts by inoculation of parental DBA/2 (induces SLE) or C57BL/6 (does not induce SLE) T cells. By both approaches the BXD RI lines could be divided into distinct DBA/2-like and C57BL/6-like categories. Concordance of SLE induced by both methods was observed for susceptibility and resistance in 13/15 BXD lines (P < 0.005). The results suggest that at least two non-H-2 genes control susceptibility and resistance to experimentally induced SLE, one mapping to chromosome 7 and the other mapping to chromosome 14.
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PMID:Genetic analysis of experimentally induced lupus in mice. 932 66

Significant increases in serum levels of IgE have often been observed in allogeneic bone marrow transplantation patients and have generally been thought to be diagnostic of graft-versus-host disease (GVHD), rather than an agent involved in the pathogenesis of the disease. Experimental murine GVHD models have also indicated associations of hyper-IgE activity, yet the role of IgE in GVHD pathogenesis has never been tested directly. In the current study, we have tried to address this issue by using recently developed peptide analog antagonists for the interaction of IgE with the Fc epsilon RI receptor, which is necessary for triggering mast cells and other cell types when cross-linked by antigens. A synthetic cyclized 13-amino acid peptide was previously designed from the modeled C-C' loop region of the Fc epsilon RI alpha-chain and was found to act as a competitive inhibitor of IgE-Fc epsilon RI alpha binding. The peptide was generated in two forms, a cyclic L-(L-IgEtide) and retro D-amino acid composition (rDIgEtide), the latter to increase resistance to protease degradation for in vivo applications. These two inhibitor peptides were then used to test the hypothesis that IgE could be involved in the pathogenesis of acute GVHD, in the B10.D2-->DBA/2 (900 cGy) strain combination, with GVHD directed to minor histocompatibility antigens. Both peptides demonstrated significant inhibition of the development of lethal GVHD, supporting the involvement of IgE at some level of disease pathogenesis.
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PMID:Peptide analogs that inhibit IgE-Fc epsilon RI alpha interactions ameliorate the development of lethal graft-versus-host disease. 936 Jul 80

Mice with chronic graft-versus-host disease (GvHD), induced by injection of DBA/2 lymphocytes into (C57BL10*DBA/2)F1 hybrids, develop a lupus-like syndrome with immune complex glomerulonephritis. Circulating autoantibodies are reactive with various self-antigens, including DNA, renal tubular epithelium (RTE), and laminin-1. To elucidate the reactivity of autoantibodies with renal antigens in experimental lupus nephritis further, the reactivity of the autoantibodies was studied in more detail by generating hybridomas from GvHD spleen cells. Hybridomas were selected for reactivity with RTE and laminin-1 coated on nitrocellulose sheets. Four stable clones were obtained (GV1-GV4). Monoclonal antibody (mAb) GV1 showed no reactivity on kidney sections, while GV2 stained the brush border of proximal tubular epithelial cells. Both GV1 and GV2 reacted only with RTE in ELISA. GV3 showed a nuclear staining pattern, while GV4 stained matrix structures on F1 kidney sections. GV3 and GV4 both reacted with RTE, laminin-1, ssDNA, and dsDNA in ELISA. Growth of hybridomas in mice, but not passive transfer of the mAbs, led to glomerular Ig binding for mAbs GV3 and GV4 without development of proteinuria. Our results show that in addition to anti-nuclear autoantibodies cross-reactive with renal antigens, autoantibodies reactive with renal antigens and not with DNA are generated during chronic GvHD. Based on these results, combined with those of earlier experiments, we conclude that a combination of autoantibodies against multiple epitopes is necessary for the induction of glomerular damage in this model for lupus nephritis.
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PMID:Characterization of reactivity of monoclonal autoantibodies with renal antigens in experimental lupus nephritis. 939 43

Using a murine transplantation model, we simulated a clinical situation in which major histocompatibility complex (MHC)-identical allogeneic peripheral blood progenitor cells (PBPCs) are transplanted for the treatment of a malignant disease that is resistant to resting natural killer (NK) cells but sensitive to cytokine-activated NK cells and T cell-mediated antitumor activity. We determined the influence of selective T cell depletion of allogeneic PBPC grafts on graft-vs.-leukemia (GVL) activity and investigated the effectiveness of ex vivo treatment with NK cell-activating cytokines to compensate for the putative loss of T cell-derived factors stimulating natural cytotoxicity. After pretreatment of Balb/c (H-2d) recipients with 7.5 Gy of total body irradiation, 2x10(7) rhG-CSF-mobilized PBPCs of splenectomized syngeneic or MHC-identical DBA (H-2d) mice were transferred. Selective T cell depletion (TCD) was performed by immunomagnetic purging with a mononoclonal antibody directed against CD3. In some experimental groups, T cell-depleted PBPCs were incubated with 200 U/mL interleukin (IL)-2 and 100 U/mL IL-12 for 24 hours. To investigate antileukemic activity in vivo, recipient mice were inoculated with 1x10(5) A20 cells (a B-lymphoblastic leukemia of Balb/c origin) 2 days before PBPC transplantation (PBPCT). After transplantation of unmanipulated allogeneic cells, 25% of the animals died with signs of graft-vs.-host disease (GVHD) but 71% were free from relapse 100 days after PBPCT. After TCD of allogeneic grafts with anti-CD3, the incidence of GVH-related mortality was below 5% but the leukemia-free survival rate was significantly (p < 0.05) decreased to 25% and thus was similar to that observed after syngeneic PBPCT (17%). When CD3-depleted grafts were incubated with IL-2 and IL-12, 45% of the animals remained free from leukemia; however, the difference was not statistically significant. Our results suggest that ex vivo activation of residual NK cells with IL-2 and IL-12 does not fully compensate for the abrogation of GVL activity after depletion of CD3+ T cells from MHC-matched PBPCT.
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PMID:Abrogation of graft-vs.-leukemia activity after depletion of CD3+ T cells in a murine model of MHC-matched peripheral blood progenitor cell transplantation (PBPCT). 947 98

The effects of chloroform extract of Tripterygium Wilfordii Hook f (TWH extract) on chronic graft-versus-host disease (GVHD) were examined in a murine experimental model. Chronic GVHD was induced by intravenous transfer of parental DBA/2 spleen cells into unirradiated (C57BL/6 x DBA/2)F1 recipient mice. The effects of TWH extract on GVHD were assessed by measuring both the degree of splenomegaly and the total serum IgE levels 3 weeks after the cell transfer. Subcutaneous administration of TWH extract once a day for 3 weeks suppressed chronic GVHD in a dose-dependent manner. Significant suppression of splenomegaly was first noted in mice treated with 7.5 micrograms/kg of the agent. The maximum inhibition was observed when mice were treated with more than 10.0 micrograms/kg (but not 5.0 micrograms/kg) caused complete suppression of serum IgE hyperproduction. The ability of donor T cells purified from recipient spleen cells to produce interleukin 4 in response to stimulation with anti-CD3 monoclonal antibody was significantly abrogated when recipient mice were treated with 10.0 micrograms/kg of the agent. These results strongly suggest that TWH extract will be an addition to the cohort of immunosuppressive therapies used in solid organ and bone marrow transplantation.
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PMID:Inhibition of murine chronic graft-versus-host disease by the chloroform extract of Tripterygium wilfordii Hook f. 950 54

T cell repertoire alterations occurring after allogeneic BMT and related emergence of aGVHD has not been directly demonstrated. CD4, CD8 and Vbeta usage of T cells infiltrating spleen, lymph nodes and liver was compared in lethally irradiated F1(DBA/2 x B10.D2) recipients which develop (GVHD mice) or not (long survivor:LS mice) aGVHD across minor histocompatibility antigens (mHAgs) and Mtv-6 and Mtv-7 encoded super-antigens (SAgs) barriers according to experimental conditions. The early expansion in GVHD mice of CD4Vbeta6+ and of CD4Vbeta3+ T cell subsets specific for Mtv-7 and Mtv-6 SAgs, respectively, is abolished in LS protected mice. By contrast, CD8+ T cells infiltrate lymph nodes, the liver but not the spleen of LS as in GVHD mice. Vbeta subset overexpression is frequent in all T cell phenotypes in GVHD but only among CD8+ T cells in LS mice. Predominant Vbeta pattern subpopulation is unique to each mouse. Overexpressed Vbeta subpopulation sequencing clearly indicates that expansion results from a very limited number of clones. Association of a given Vbeta segment with different Jbeta for each mouse suggests that the response is directed towards many different antigens. The data emphasize that Mtv-SAg and mHAgs CD4+ T cells are of crucial importance during GVHD and that there is no relationship between CD8+ T cell repertoires and pathological status.
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PMID:Relative importance of CD4+ and CD8+ T cell repertoires in the development of acute graft-versus-host disease in a murine model of bone marrow transplantation. 954 62

Mice with chronic graft-versus-host disease (GvHD) induced by injection of DBA/2 lymphocytes into (DBA/2 x C57BL/10) F1 hybrids (DBA/2 GvHD) develop a lupus-like glomerulonephritis with global glomerulosclerosis 12 weeks after induction of the disease. In two other strain combinations with similar H-2 incompatibilities [BALB/c into BALB/c x BL10 (BALB/c GvHD) and BALB.D2 into BALB.D2 x BL10 (BALB.D2 GvHD)], GvHD induction leads to lupus nephritis without global glomerulosclerosis. This study investigated the identity of kidney-infiltrating leukocytes and their involvement in the development of glomerulosclerosis in these three strain combinations. In mice with DBA/2 GvHD, a significant increase in glomerular CD11a-positive cells was found 4 weeks after disease induction. Mice with BALB/c or BALB.D2 GvHD did not show an increase in glomerular CD11a-positive cells at any time point. In the interstitium, CD11a-positive cells were observed 4 weeks after disease induction only in mice with DBA/2 GvHD. In mice with BALB.D2 GvHD, no increase was found in interstitial CD11a-positive cells. In mice with BALB/c GvHD, interstitial CD11a-positive cells were found from week 4 onward. Further immunohistochemical analysis of the glomerular CD11a-positive cells in mice with DBA/2 GvHD showed that these cells were neither polymorphonuclear leukocytes (PMN), nor CD3-positive (T cells), B220-positive (B cells), or F4/80-positive (macrophages). They were all CD45-positive (leukocytes) and MHC class II-positive. In conclusion, we have shown in this model of chronic lupus nephritis that glomerular influx of as yet unidentified CD11a-positive leukocytes is associated with the development of glomerulosclerosis.
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PMID:Association between leukocyte infiltration and development of glomerulosclerosis in experimental lupus nephritis. 960 15

The influence of graft-versus-host (GVH) reaction on the host hematopoietic cells clinically manifests itself both as adverse reactions in transfusion-associated GVH disease (GVHD) and as a therapeutic graft-versus-leukemia (GVL) effect in either donor lymphocytes transfusion (DLT) or allogeneic bone marrow (BM) transplantation. We examined the effect of GVH reaction on the host hematopoiesis in the murine parent-into-F1 (P1 --> F1) model of GVHD. The systemic transfer of 5 x 10(7) of C57BL/6 (B6) splenocytes into (B6xDBA/2)F1 mice (BDF1), which results in acute GVHD, reduced the peripheral blood cell counts, the number of BM cells, and colony-forming unit-granulocyte macrophage (CFU-GM), whereas the injection of 10(8) of DBA/2 cells into BDF1, which results in chronic GVHD, did not affect hematopoiesis 2 weeks after the transfer. To clarify the mechanism of such myelosuppression, we examined the Fas expression in both hematopoietic progenitor cells as well as whole BM cells. The Fas expressions in each fraction significantly increased in BDF1 mice 2 weeks after the induction of acute GVHD, whereas no such effects were observed in the BDF1 mice with chronic GVHD. Furthermore, when such BM cells were incubated with anti-Fas antibody (Jo2), which induces apoptosis through Fas, the fraction of apoptotic cells increased and the number of CFU-GM decreased significantly. The in vivo administration of neutralizing anti-FasL antibody into BDF1 mice receiving with B6 spleen cells thus protected the host mice from BM failure. These results indicate that the functional expression of Fas on hematopoietic cells plays an essential role in the myelosuppressive effect of GVHD.
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PMID:Involvement of Fas-mediated apoptosis in the hematopoietic progenitor cells of graft-versus-host reaction-associated myelosuppression. 963 5

In a newly developed murine model of allogeneic peripheral progenitor transplantation (PBPCT) we investigated the immunotherapeutic potential of allogeneic peripheral stem cells. The following topics were addressed by our experiments: (1) comparison of the graft-versus-leukemia effect exerted by allogeneic PBPCT compared to allogeneic BMT; (2) the influence of T-lymphocytes on GVL activity; (3) the possibility to enhance the GVL activity of allogeneic PBPCT grafts by ex vivo cytokine incubation. Balb/c mice received cells of the syngeneic B-lymphatic leukemia A20 2 days prior to TBI (7.5 Gy) and the respective graft. The recipients received allogeneic bone marrow grafts or allogeneic peripheral progenitor cells obtained after mobilization of the donors (DBA/2) with either G-CSF in a dose of 250 microg/kg/day for 5 days. In some experiments T lymphocytes were removed by immunomagnetic depletion with CD3-coated beads. An additional group received T cell-depleted and IL-2/IL12-activated PBPCT grafts. The antileukemic activity of an allogeneic PBPCT graft was significantly greater than the antileukemic activity of an allogeneic BMT graft of the same size. Relapse rates were 80% in syngeneic PBPCT, 60% after allogeneic BMT and 34% after allogeneic PBPCT. This rise in antileukemic activity is not accompanied by a rise in GVHD mortality. Depletion of T lymphocytes by CD3-coated beads resulted in a nearly complete loss of the GVL activity with a relapse rate of 75%. Incubation of the T-depleted graft with IL-2 and IL-12 to enhance NK-based GVL activity has only limited success after MHC-matched transplantation with a relapse rate of 55%. Allogeneic PBPC exert a pronounced antileukemic effect. After MHC-matched PBPCT, this GVL effect resides mostly on the T cells of the graft. Ex vivo activation of T cell-depleted grafts by IL-2 and IL-12 is accompanied by an only limited reduction of relapse rate. PBPC are a valuable modality for primary transplantation in situations with high risk of relapse and for the treatment of relapse after BMT.
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PMID:Immunotherapeutic aspects of allogeneic peripheral progenitor cells. 971 83

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