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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)

This study demonstrates that systemic interleukin 2 (IL-2) can decrease the homing of syngeneic immune T cells to the target organ of metastases and accelerate unwanted side effects of allogeneic immune T cells. As a tumor system, we used the well-characterized highly aggressive DBA/2 mouse leukemia ESb and its less aggressive adhesion variant, ESb-MP. Systemic IL-2 treatment was performed with recombinant human interleukin-2 (Proleukin), which was slowly released via an implanted osmotic pump or was modified with polyethylene glycol (PEG-IL-2) to achieve constant plasma levels. Allogeneic B10.D2 antitumor immune spleen cells (ISPL cells) exerted strong graft-versus-leukemia (GvL) reactivity after adoptive transfer into late-stage ESb-MP tumor-bearing DBA/2 mice. Mls(a) superantigen-reactive vbeta6 donor T cells were not eliminated or tolerized by in vivo priming with the tumor cells and were present in active proliferation in liver infiltrates. When exogenous PEG-IL-2 or Proleukin was applied in addition to ISPL cells in such mice, the strong GvL-mediated protective immunity was converted into a fatal graft-versus-host disease. IL-2 treatment alone had no toxic effect and caused a moderate protection effect in the absence of an effect on local tumor growth. Potentiation of GvH reactivity of B10.D2 ISPL by PEG-IL-2 was proven in non-tumor-bearing DBA/2 mice, in which graft-versus-host disease was characterized by: (a) heavy hepatic lymphocytic infiltration, (b) irreversible increase of serum glutamate-oxalacetate-transaminase and glutamate-pyruvate-transaminase levels, (c) weight loss, and (d) death. Antagonistic effects of systemic IL-2 on GvL were observed with syngeneic DBA/2 anti-ESb immune peritoneal effector cells (PECs). There was a detrimental effect of systemic IL-2 on liver target organ infiltration by immune T cells causing, at day 6 after transfer, a drop from 20-30 CD4 or CD8 T cells per liver lobule in the PEC group to <5 in the PEC plus IL-2 group. The results emphasize the importance of a better understanding of IL-2 function in vivo and of its interaction with immune cell function to improve protocols for optimal application in the clinic to achieve maximal GvL effects.
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PMID:Antagonistic effects of systemic interleukin 2 on immune Tcell-mediated graft-versus-leukemia reactivity. 982 26

We screened various mouse strains [C57BL/6, BALB/c, DBA/2, CBA/Ca, (CBAxC57L/6)F1, SJL, C3H] for induction of peripheral immune tolerance. Only CBA/Ca mice treated with anti-CD4 + CD8 monoclonal antibodies and grafted with allogeneic skin showed long-term graft survival (150 to >200 days). Interestingly, T cells from the tolerant CBA/Ca mice rejected bone marrow/spleen cells of the skin graft donor strain and caused lethal graft-versus-host disease when transplanted to the donor strain. Furthermore, peripheral tolerance was easily broken: CBA/Ca mice could be reactivated to reject their tolerated grafts via immunization with (graft donor x recipient strain)F1 bone marrow cells. Thus, in contrast to the generalized nature of central tolerance, our experiments show that peripheral immune tolerance is strain dependent and locally restricted to graft tissue.
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PMID:Analysis of peripheral immune tolerance uncovers a mouse strain-dependent in situ type of graft tolerance. 993 96

Allogeneic bone marrow transplantation (allo-BMT) is associated with both graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effect. In the present study, we examined the contribution of cytotoxic effector mechanisms, which are mediated by tumor necrosis factor-alpha (TNF-alpha), Fas ligand (FasL), or perforin, to GVHD and GVL effect in a murine BMT model. Bone marrow cells plus spleen cells (BMS) from wild-type, FasL-defective, or perforin-deficient donors were transferred into lethally irradiated recipients in the parent (C57BL/6) to F1 (C57BL/6 x DBA/2) BMT model with or without prior inoculation of DBA/2 leukemia L1210 or P815 mast cytoma cells. The effect of anti-TNF-alpha antibody administration was also examined. Whereas the defect or blockade of each cytotoxic pathway could ameliorate lethal acute GVHD, the GVL effect was differentially affected. The wild-type BMS recipients died of acute GVHD within 50 days without residual leukemia cells. The FasL-defective BMS recipients showed 60%< survival over 80 days without acute GVHD or residual leukemia cells. Administration of anti-TNF-alpha antibody resulted in early leukemia relapse and the recipients died within 25 days with massive leukemia infiltration in the liver. The perforin-deficient BMS recipients died within 60 days with residual leukemia cells. These results suggest that blockade of the Fas/FasL pathway could be used for ameliorating GVHD without impairing GVL effect in allo-BMT.
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PMID:Graft-versus-leukemia effect and graft-versus-host disease can be differentiated by cytotoxic mechanisms in a murine model of allogeneic bone marrow transplantation. 1019 54

In our model of murine BMT, the lethal GVHD which develops against DBA/2 host incompatible minor histocompatibility antigens (mHAgs) can be prevented by donor preimmunization before grafting. Recipient mice become long survivors (LS mice) and tolerant to host mHAgs. However, a GVL effect is preserved and mediated by CD8+ CTL able to kill P815 tumor cells in vitro and in vivo. To explain why a GVL exists without GVHD, we compared the CTL activity of LS and B10.D2 donor mice after immunization with DBA/2 spleen cells or with P815 cells. Experimental results indicated that: (1) the level of cytotoxicity for H-2b incompatible cells was similar in LS and B10.D2 mice; (2) CTL recognizing host DBA/2 mHAgs, whose expression is restricted to the spleen or is shared between spleen and P815 cells, were partially unresponsive in LS mice; (3) P815 injection into LS mice predominantly generated CTL specific for antigens restricted to P815 cells, the repertoire of which was not tolerized. Characterization of TCR beta chain showed that the diversity of Vbeta and Jbeta usage by CD8+ T cells activated after P815 injection is considerably restricted in LS mice, compared to B10.D2 donor mice. These results indicated that the GVL effect in LS mice involved mainly T cells specific for tissue-restricted antigens expressed on P815 cells and not on normal DBA/2 spleen cells. In addition, the absence of GVHD may be attributed to the unresponsiveness of CD8+ CTL specific for host mHAgs expressed on DBA/2 spleen cells.
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PMID:CD8+ cytotoxic T cell repertoire implicated in grafts-versus-leukemia effect in a murine bone marrow transplantation model. 1033 53

Despite contemporary typing procedures for bone marrow transplantation (BMT), graft-versus-host disease (GVHD) continues to be a major complication of transplants performed between MHC-matched donors and recipients. Although GVHD can be alleviated by T cell depletion, this procedure increases the risk of graft failure and leukemic relapse and therefore is not a solution to the GVHD problem. The high degree of variation in the intensity of GVHD observed in different patients suggests that multiple non-MHC genetic factors influence GVHD severity. We hypothesize that, in addition to minor histocompatibility antigen disparities, polymorphisms in genes encoding immunologic effector molecules may be important factors influencing GVHD development. This study aims to explore this hypothesis by identifying non-MHC genes that influence the outcome of BMT in a murine model. In this model, B10.D2 donor leukocytes cause acute GVHD in (C57BL/6xDBA/2)F1 (B6D2F1) recipients, whereas DBA/2 donor leukocytes do not. To date, a locus on chromosome 1 has been identified as influencing the severity of GVHD in this model. Our current study shows that a locus on chromosome 2 acts independently of the chromosome 1 locus to also influence GVHD severity in this model. The region of chromosome 2 implicated in our study contains genes encoding beta2-microglobulin, the minor histocompatibility antigen H-3 and the pro-inflammatory cytokine IL-1.
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PMID:A locus on chromosome 2 influences the development of acute graft-versus-host disease in a murine model. 1038 59

Expression of CD134 (OX40) on activated CD4(+) T cells has been observed in acute graft-versus-host disease (GVHD) after human and rat allogeneic bone marrow transplantation (BMT). We investigated the role of interaction between CD134 and CD134 ligand (CD134L) in a murine model of acute GVHD by using a newly established monoclonal antibody (mAb) against murine CD134L. Acute GVHD was induced by transfer of bone marrow cells and spleen cells into lethally irradiated recipients in a parent (C57BL/6) to first filial generation (C57BL/6 crossed with DBA/2) BMT. Administration of anti-CD134L mAb significantly reduced the lethality of acute GVHD and other manifestations of the disease, such as loss of body weight, hunched posture, diarrhea, and patchy alopecia. The survival rate 80 days after BMT in mice treated with the mAb was about 70%, whereas all mice treated with control antibodies died within 43 days. Histologic examinations revealed that inflammatory changes in target organs such as the liver, gut, and skin were also ameliorated in mice treated with the mAb compared with control mice. An in vitro assay of T-cell proliferation showed a marked hyporesponsiveness to host alloantigen in samples from mice treated with anti-CD134L mAb. In addition, low levels of interferon gamma and transiently elevated levels of interleukin 4 and IgE in serum samples were found in mice treated with anti-CD134L mAb. These results suggest that CD134-CD134L interactions have an important role in the pathogenesis of acute GVHD.
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PMID:Blockade of CD134 (OX40)-CD134L interaction ameliorates lethal acute graft-versus-host disease in a murine model of allogeneic bone marrow transplantation. 1073 18

The relationship between acute and chronic graft-versus-host disease (GVHD) is not well understood. A murine model of acute and chronic GVHD is the B6D2F1 parent-->F1 model in which transfer of C57BL/6 parental strain lymphoid cells to B6D2F1 recipients results in development of Th1-mediated acute GVHD, whereas transfer of DBA/2 parental strain lymphoid cells to B6D2F1 recipients results in development of Th2-mediated chronic GVHD. Numerous studies have investigated the reason for the differential development of acute versus chronic GVHD in this model but have as yet failed to identify the factor that determines which type of T helper cell will predominate and thereby which type of GVHD will develop. In this report, we demonstrate, using congenic strains of mice, that a locus in the vicinity of the Mtv7 locus on Chromosome 1 of the mouse significantly influences development of acute versus chronic GVHD in the B6D2F1 model.
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PMID:A locus closely linked to Mtv7 on mouse chromosome 1 influences development of acute versus chronic graft-versus-host disease in a murine model. 1079 27

The development of chronic graft-versus-host disease (GVHD), which is induced by the transfer of DBA/2 spleen cells into (C57BL/6 x DBA/2)F1 (BDF1) mice, is closely related to diminished donor anti-host CTL activity and host B cell hyperactivation. Therefore, an approach which activates donor CD8+ T cells or suppresses donor CD4+ T cell-host B cell interaction may have clinical utility in the treatment of chronic GVHD. We have previously demonstrated that IL-18 induces the development of naive CD8+ T cells into type I effector cells in DBA/2 anti-BDF1 MLC. In this paper we examined the effect of IL-18 administration on the development of chronic GVHD in mice. The treatment was started before or after the onset of clinical evidence of the disease. Regardless of the treatment schedule, IL-18 significantly decreased immunological parameters indicative of chronic GVHD, such as elevated serum IgG antinuclear Abs, IgG1, and IgE levels, and host B cell numbers and their activation. Importantly, IL-18-treated mice did not show the same acute GVHD-like symptoms reported for IL-12 treatment, because there was no weight loss, death, or severe immunodeficiency as indicated by a decrease in IL-2 and IFN-gamma production by Con A-stimulated spleen cells. In contrast, IL-18 treatment partially but significantly restored the production of these cytokines. Data further suggested that these IL-18-mediated therapeutic effects may be due to the induction of donor CD8+ CTL, the decrease in donor CD4+ T cell numbers, and a down-regulation of host B cell MHC class II expression. Thus, our results suggest that IL-18 has beneficial effects in the prevention and treatment of chronic GVHD.
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PMID:IL-18 prevents the development of chronic graft-versus-host disease in mice. 1082 Feb 92

With donor and recipient matched at the major histocompatibility complex (MHC) locus, peripheral lymphoid tissue transplantation can be carried out without producing a graft-versus-host reaction or graft-versus-host disease (GVHD), thus correcting profound T cell immunodeficiencies of neonatally thymectomized mice. This analysis set the stage for clinical application of bone marrow transplantation (BMT) to provide for the first time cure of a human disease. With successful BMT, we cured immunologic deficiencies of a patient with XL severe combined immunodeficiency; thereafter we were the first to employ BMT to cure aplastic anemia. BMT regularly corrects immune and hematologic deficiencies caused by fatal irradiation without producing GVHD if the bone marrow (BM) used for the transplants has been purged of postthymic T cells. Over two decades in conjunction with Ikehara et al., we have shown that lethal total body irradiation (TBI) plus allogeneic BMT prevents or cures many organ-specific and systemic experimental autoimmune diseases. Animal models successfully treated by BMT include type I diabetes in nonobese diabetes (NOD) mice, type II diabetes in insulin-insensitive, glucose intolerant, diabetes mellitus (KK/Ay) mice, and autoimmune lupus erythematosus (LE) and glomerulonephritis in New Zealand Black x New Zealand White first generation hybrid (NZB x NZW)F1 females. El-Badri extended Ildstad's original research showing a high frequency of survival with a normal functioning immune system after stable mixed chimerism is produced by mixed BMT in C57BL/6 (normal long-lived black strain) mice transplanted with T cell-depleted marrow (TCDM) from BALB/c ("normal" long-lived strain) allogeneic donors and C57BL/6 syngeneic donors. We showed that osteoblasts act as facilitator cells for allogeneic BMT and promote engraftment of allogeneic hematopoietic stem cells. Wang et al. then showed that the autoimmunities and fulminating renal disease of BXSB (C57BL x SB cross and selective lupus-like systemic autoimmunity) male mice was prevented and could be cured by transplantation using TCDM from both BALB/c (resistant) and BXSB (susceptible) strains given to BXSB recipients after lethal TBI. This treatment produced mixed BMT and a stable mixed chimerism, increased longevity, corrected all manifestations of autoimmunity, and cured fulminant glomerulonephritis in these recipients. These studies generated a new perspective on the potential usefulness of BM and stem cell transplants to cure major diseases that can possibly be treated by BMT. Mixed BMT from TCD BALB/c and BXSB mice cured autoimmunities and fulminant glomerulonephritis in BXSB mice. LE disease plus coronary vascular disease that occurs in (NZW x BXSB)F1 mice, along with idiopathic thrombocytopenic purpura, is also cured in lethally irradiated (NZW x BXSB)F1 mice by BMT from C57BL/6 donors. Furthermore, hemolytic anemia, autoimmune phenomena, and hyalinizing glomerular renal disease of New Zealand Black (NZB) mice were prevented or cured by stem cell transplants using purified stem cells from MHC-matched DBA/2 donors or NZB donors. Consequently, we reasoned that autoimmunities reside in stem cells. More recently, we found that transplants of both BM cells and bones can completely and permanently prevent otherwise highly resistant autoimmune diseases of MRL/lpr lpr mice and an autoimmune polyarthritis of NZB/Kn mice. Ildstad concluded that lethal preparative measures would not be acceptable for preparations to treat autoimmune diseases, so we now employ a gentle method for producing stable mixed chimerism described by Sharabi and Sachs to achieve mixed marrow transplantation and mixed hematopoietic chimerism. Other diseases we are approaching using this gentle manipulation include two forms of diabetes: insulin-dependent diabetes mellitus (IDDM) type I in NOD mice and non-insulin-dependent diabetes mellitus (NIDDM) type II in KK/Ay mice, atherosclerosis of apolipoprotein-E + kno
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PMID:Progress toward production of immunologic tolerance with no or minimal toxic immunosuppression for prevention of immunodeficiency and autoimmune diseases. 1083 46

Administration of a tumor necrosis factor (TNF) inhibitor-encoding adenoviral vector decreases the severity of colonic inflammation in a DBA/2-->B6D2F1 murine model of colonic graft-versus-host disease (GVHD). The present studies evaluated the effect of TNF blockade on the splenic and colonic T-cell responses. cDNA encoding an artificial fusion protein consisting of the extracellular domain of the human 55-kDa receptor for TNF fused to a mouse IgG heavy chain was subcloned into an E1a-deficient adenoviral vector. Following transfer of DBA/2 T cells and bone marrow cells into irradiated B6D2F1 mice, the mice then received either the control adenovirus or the TNF inhibitor-encoding adenovirus. Splenic and colonic lymphocytes were isolated, stained with anti-H-2b, anti-H-2d, anti-CD3, anti-CD4, anti-CD8, and anti-CD45RB antibodies, and analyzed by flow cytometry. Splenic and colonic lymphocyte cytokine profiles also were assessed. More colonic T cells of donor origin were isolated from the control adenovirus recipients than from recipients of the TNF inhibitor encoding adenovirus (P = .027). Fewer CD4+ and CD8+ T cells were observed in colon but not in the spleen in the TNF inhibitor recipients. Fewer CD45RBlow (memory) T cells were observed in the CD4+ colonic lymphocytes isolated from the TNF inhibitor recipients than from controls. Importantly, lower levels of interleukin-2(IL-2) and interferon-gamma (INF-gamma) but not of IL-4 were observed in the lamina propria lymphocyte RNA isolated from the TNF inhibitor recipients. Infiltration and expansion of donor T cells and T-cell activation in the colon appear to be regulated by TNF during murine DBA/2 --> B6D2F1 gut GVHD.
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PMID:T-cell activation and differentiation are regulated by TNF during murine DBA/2-->B6D2F1 intestinal graft-versus-host disease. 1105 Dec 80


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