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

The development of methods of avoiding graft-versus-host disease (GVHD) while retaining the alloengraftment-promoting and anti-leukemic effects of allogeneic T cells is a major goal of research in bone marrow transplantation (BMT). We have recently obtained evidence suggesting that natural suppressor (NS) cells derived from T cell-depleted (TCD) syngeneic marrow can protect against GVHD while permitting alloengraftment. We have now attempted to enrich and then propagate NS cells in vitro, with the goal of obtaining an enhanced anti-GVHD effect by adoptive transfer in vivo. Two long-term cell lines were generated culturing BMC depleted of Mac1-positive cells and of Mac1-positive plus Thy1-positive cells in high concentrations of IL-2. Both cell lines showed anti-GVHD effects when administered along with a GVHD-producing inoculum, while permitting complete allogeneic reconstitution. A clone derived from Mac1-depleted BMC protected completely against a more chronic pattern of GVHD. These cell lines demonstrated suppressive activity in vitro, cytolytic activity against a broad range of natural killer (NK)-sensitive and NK-resistant targets, and a novel cell surface phenotype, with characteristics of both alpha beta-TcR-bearing T cells and of NK cells. In some respects, these cells resemble LAK cells and differ from fresh NS cells, and from the cloned NS cells derived from spleens of total lymphoid irradiation (TLI)-treated mice and neonatal mice. To our knowledge, this is the first detailed phenotypic analysis of cell lines with in vivo anti-GVHD activity. If applicability can be demonstrated in large animal models, the ability to use bone marrow as a source of such protective cell lines might also have potential utility in clinical BMT.
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PMID:In vitro and in vivo analysis of bone marrow-derived CD3+, CD4-, CD8-, NK1.1+ cell lines. 214 39

UVB irradiation (700 J/m2) of bone marrow cells (UVB-BMC) before transplantation into lethally gamma-irradiated (10.5 Gy) allogeneic rats prevents graft-versus-host disease (GVHD) and induces a stable complete lymphohematopoietic chimerism. To better understand the underlying mechanism of the development of stable chimerism and induction of tolerance to donor organs in this model, we examined if the addition of T cells or dendritic cells (DC), as antigen presenting cells (APC), would restore the immunogenicity of UVB-BMC in in vitro mixed lymphocyte reaction (MLR) and induce in vivo bone marrow (BM) graft rejection. Whereas gamma-irradiated, unfractionated BMC induce allogeneic T cells to proliferate, UVB irradiation of BMC abolishes the stimulatory capacity of such cells in a primary MLR. Addition of purified T cells, CD4+ T cells, CD8+ T cells or B cells, respectively, failed to restore the capacity of UVB-BMC to stimulate allogeneic T-cell proliferation. In contrast, the addition of only a small number of splenic accessory cells or purified DC, which by themselves were relatively ineffective in stimulating T-cell proliferation, restored the accessory function and the allostimulatory capacity of UVB-BMC. To define the molecular defect induced by UVB irradiation, cytokines were added as costimulatory factors to primary MLRs and the results showed that the addition of interleukin (IL)-2 or IL-6 but not IL-1 or interferon gamma (IFN-gamma) restored the stimulatory capacity of UVB BMC. This finding suggests that UVB may alter the production, and/or utilization of IL-2 and IL-6 either at the membrane or cytoplasmic level. Parallel in vivo studies showed that addition of DC to UVB BM inoculum resulted in failure of BM engraftment, whereas addition of T cells led to development of fatal GVHD, thus suggesting that UVB modulation of accessory cells reduces graft immunogenicity and prevents BMT rejection, while modulation of T cells prevents GVHD. Our data provide evidence that UVB modulation of APC and mature T cells contained within BMC is potentially useful in preventing GVHD without endangering successful engraftment and may serve as a model for induction of adult chimerism and tolerance without the development of GVHD.
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PMID:Prevention of graft-versus-host disease and bone marrow rejection: kinetics of induction of tolerance by UVB modulation of accessory cells and T cells in the bone marrow inoculum. 845 11

Mixed lymphoid chimeras can be established across H-2b-->H-2d by injection of C57BL/6J (B-6) donor bone marrow cells into BALB/c hosts conditioned by sublethal irradiation, 235 cGy x3. These chimeras are specifically tolerant to both donor and host alloantigens. Tolerance cannot be broken even by injection of 4 x 10(8) normal BALB/c spleen cells (SC), suggesting a suppressor mechanism. In contrast to conventional suppression, however, in which suppressors are syngeneic to the cells they suppress, tolerance can be transferred only by cells of the allogeneic donor allotype (1,2). Thy 1+ cell depletion eliminates the capacity of the donor population to transfer tolerance and markedly reduces the capacity of B-6 BMC to induce tolerance (3). In the present studies spleen cells from tolerant chimeras (CSC), when coinjected in a 1:1 ratio, reduced the high GVHD mortality induced in irradiated H-2d/b F1 hybrids by injection of 2 x 10(7) normal BALB/c SC alone (P < .01). When coinjected at a 5:1 ratio CSC eliminated the GVHD mortality and weight loss induced by 5 x 10(6) BALB/c SC (P < .01). Depletion of B-6 cells from CSC removed their capacity to inhibit the GVHD induced by normal BALB/c SC. In contrast to conventional suppression, which requires the continued presence of suppressor cells, the BALB/c cells isolated from CSC, although unable to inhibit the GVHD of normal BALB/c SC, remained nonreactive against the H-2b allotype for a prolonged period following depletion of the B-6 cells. This prolonged response reduction dependent upon some interaction with allogeneic donor cells--which, in turn, are specifically nonreactive to host antigens--is compatible with a veto mechanism.
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PMID:Do donor cells function as veto cells in the induction and maintenance of tolerance across an MHC disparity in mixed lymphoid radiation chimeras? 847 64

Recently it was shown that delayed graft-versus-host disease (GVHD) in mice can be completely prevented by repeated injections of interferon-gamma (IFN-gamma). The characteristics of this sustained IFN-gamma-induced chimerism were studied in more detail. First, the potency of IFN-gamma as a modulator of GVHD was tested in a fully H-2 mismatched murine bone marrow transplantation (BMT) model. Donor bone marrow cells (BMC; C57BL/Rij; H-2b) were mixed with increasing numbers of donor spleen cells (SC) and transplanted into lethally irradiated recipients (C3H/Law; H-2k). Secondly, BMC and SC of the IFN-gamma-induced chimeras (C3H/Law; H-2b) were tested on their immunological competence and GVHD inducing capacity. Repeated injections of the host with IFN-gamma were able to prevent GVHD even when up to 10(5) SC were added to the graft; adding higher numbers of SC resulted in a rapid increase in the frequency of lethal GVHD. Donor-derived lymphocytes (H-2b) obtained from chimeric animals were immunocompetent as concluded from Con A stimulation in vitro. Chimeric-derived BMC (H-2b) were mixed with up to 10(7) chimeric SC (H-2b) and transplanted into a new group of lethally irradiated C3H/Law (H-2k) recipients. All transplanted animals survived the latter treatment without any macroscopic signs of histological lesions typical of GVHD. We conclude that IFN-gamma treatment allows the development of mature donor-derived immunocompetent T cells, which are allo-tolerant for the recipient.
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PMID:Interferon-gamma-mediated prevention of graft-versus-host disease: development of immune competent and allo-tolerant T cells in chimeric mice. 908 39

This study was aimed to eveluate the role of CCR5 on donor cells in recipient models received intensive conditioning, so as provide the scientific evidence for clinical application of allo-HSCT. Lethally irradiated BALB/c mice received allogeneic bone marrow transplants from C57BL/6 mice. Mice divided into 4 groups according to receiving variant donor cells: B6 CCR5 KO group, receiving C57BL/6 CCR5(-/-) mice bone marrow cells and splenocytes; B6 WT BMC group, receiving C57BL/6 mice bone marrow cells and splenocytes; B6 CCR5 KO BMC group, receiving C57BL/6 CCR5(-/-) bone marrow cells alone; B6 WT BMC group, receiving C57BL/6 mice bone marrow cells alone. The result showed that compared to B6 WT BMC group, B6 CCR5 KO group succumbed to acute GVHD at an accelerated rate. Donor CD8(+) T cells expanded to a significantly greater extent in recipients of CCR5 KO, compared with B6 WT control cells. T cells recovered from recipients of CCR5 KO cells produced more IFN-gamma and TNF-alpha and proliferated to a T-cell at a significantly higher level than T cells from recipients of WT cells, indicating that CCR5 plays a role in downregualting donor alloreative CD8(+) T-cells expansion. Histological assessment of the mice indicated pathological lesions in the kidneys and a greater degree of liver pathological changes in mice that received CCR5 KO donor grafts. It is concluded that the knock-out of CCR5 on donor cells results in increase of GVHD and donor CD8(+) T cell expansion, as well as hepatic and renal lesions in allo-HSCT, which indicates that CCR5 is very important in allo-BMT.
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PMID:[Relationship between CCR5 and acute graft-versus-host disease in murine bone marrow transplantation]. 1709 92

We evaluated mixed chimerism with costimulatory blockade for the achievement murine allogeneic small bowel transplantation (SBTx) tolerance. B6 mice received various combinations of anti-CD8 (day -2) and anti-CD154 mAbs with or without 3Gy total body irradiation (TBI) (day -1), and 20 x 10(6) fully MHC-mismatched B10.A bone marrow cells (BMC, day -1). Heterotopic SBTx was performed on day 0. Chimerism in peripheral blood was followed by flow cytometric (FCM) analysis and the frequency of TCR Vbeta usage was determined by FCM to assess deletion of donor-reactive T cells. All animals without any treatment (n=6) showed acute rejection within 18 days after transplantation. Mice treated with anti-CD8 and anti-CD154 mAbs alone rejected their grafts within 100 days after transplantation (n=10). Mice treated with anti-CD8 and anti-CD154 mAbs, TBI, and BMT achieved long-term multilineage mixed chimerism and accepted small bowel allografts permanently (>350 days) without any evidence of graft-versus-host disease(n=11). There was specific deletion of donor-reactive cells and skin was accepted as allografts from B10.A donors, but 3rd party B10.BR skin was rejected. Donor-specific tolerance was achieved by inducing mixed chimerism with costimulatory blockade in murine SBTx recipients. This approach which provides a reliable method to induce SBTx tolerance, has potential clinical applications.
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PMID:Small bowel transplantation tolerance achieved by costimulatory blockade leading to mixed chimerism. 1748 79

Human stem cells are in evaluation in clinical stem cell trials, primarily as autologous bone marrow studies, autologous and allogenic mesenchymal stem cell trials, and some allogenic neural stem cell transplantation projects. Safety and efficacy are being addressed for a number of disease state applications. There is considerable data supporting safety of bone marrow and mesenchymal stem cell transplants but the efficacy data are variable and of mixed benefit. Mechanisms of action of many of these cells are unknown and this raises the concern of unpredictable results in the future. Nevertheless there is considerable optimism that immune suppression and anti-inflammatory properties of mesenchymal stem cells will be of benefit for many conditions such as graft versus host disease, solid organ transplants and pulmonary fibrosis. Where bone marrow and mesenchymal stem cells are being studied for heart disease, stroke and other neurodegenerative disorders, again progress is mixed and mostly without significant benefit. However, correction of multiple sclerosis, at least in the short term is encouraging. Clinical trials on the use of embryonic stem cell derivatives for spinal injury and macular degeneration are beginning and a raft of other clinical trials can be expected soon, for example, the use of neural stem cells for killing inoperable glioma and embryonic stem cells for regenerating beta islet cells for diabetes. The change in attitude to embryonic stem cell research with the incoming Obama administration heralds a new co-operative environment for study and evaluation of stem cell therapies. The Californian stem cell initiative (California Institute for Regenerative Medicine) has engendered global collaboration for this new medicine that will now also be supported by the US Federal Government. The active participation of governments, academia, biotechnology, pharmaceutical companies, and private investment is a powerful consortium for advances in health.
BMC Med 2009 Jun 11
PMID:New perspectives in human stem cell therapeutic research. 1951 78

The aim of the study was to follow the development of microchimerism after allogeneic vascularized bone marrow transplantation (VBMT) versus conventional bone marrow transplantation (BMT). In one group, a VBMT model consisted of donor Brown Norway rat hind limb heterotopic transplanted on recipient Lewis rats. An intravenous infusion of donor bone marrow cells in suspension equivalent to that grafted in the vascularized femur limb was administered intravenously to recipient rats in the second group. Cellular microchimerism was investigated in recipients of VBMT versus BMT. Donor-derived cells could be detected in VBMT recipients at 30 and 60 days but not in recipients of intravenous suspension of BMC. VBMT provides a theoretical alternative to conventional cellular bone marrow transplantation by addressing crucial clinical problems such as failure of engraftment or graft-versus-host disease.
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PMID:Vascularized bone marrow transplantation model in rats as an alternative to conventional cellular bone marrow transplantation: preliminary results. 2209 39

Graft-versus-host disease is one of the major transplant-related complications in allogeneic hematopoietic stem cell transplantation. Continued efforts have been made to prevent the occurrence of severe graft-versus-host disease by eliminating or suppressing donor-derived effector T cells. Conventional immunosuppression does not adequately prevent graft-versus-host disease, especially in mismatched transplants. Unfortunately, elimination of donor-derived T cells impairs stem cell engraftment, and delays immunologic reconstitution, rendering the recipient susceptible to post-transplant infections and disease relapse, with potentially lethal consequences. In this review, we discuss the role of dynamic immune regulation in controlling graft-versus-host disease, and how cell-based therapies are being developed using regulatory T cells and other tolerogenic cells for the prevention and treatment of graft-versus-host disease. In addition, advances in the design of cytoreductive conditioning regimens to selectively target graft-versus-host disease-inducing donor-derived T cells that have improved the safety of allogeneic stem cell transplantation are reviewed. Finally, we discuss advances in our understanding of the tolerogenic facilitating cell population, a phenotypically and functionally distinct population of bone marrow-derived cells which promote hematopoietic stem cell engraftment while reducing the risk of graft-versus-host disease.
BMC Med 2012 May 15
PMID:Novel regulatory therapies for prevention of Graft-versus-host disease. 2258 83

Mesenchymal stromal cells (MSCs) are multipotent progenitor cells known to modulate the immune system and to promote hematopoiesis. These dual effects make MSCs attractive for use as cellular therapy in hematopoietic cell transplantation (HCT). MSCs can be used peri-HCT or pre-engraftment to modulate immune reconstitution, promoting hematopoietic stem cell (HSC) engraftment and/or preventing graft-versus-host disease (GVHD). Pre-clinical studies have demonstrated that MSCs can potentiate HSC engraftment and prevent GVHD in a variety of animal models. Clinical trials have been small and largely non-randomized but have established safety and early evidence of efficacy, supporting the need for larger randomized trials.
BMC Immunol 2015 Dec 16
PMID:Mesenchymal stromal cells to modulate immune reconstitution early post-hematopoietic cell transplantation. 2667 7


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