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)

Allogeneic cord blood (CB) transplantation is associated with less severe graft-versus-host disease (GvHD), thought to be due to the immaturity of CB T cells, but how T cells interact with host and donor-derived dendritic cells (DCs) to initiate GvHD has not been elucidated. We therefore investigated the responses of CB and adult blood CD4(+) T cells co-cultured with adult host DCs of different maturities. Primed by adult host DCs, CB and adult blood CD4(+) T cells underwent similar changes in the expression of CD45RA/45RO, CD25, CD40L and CTLA-4. However, CB CD4(+) T cells, when primed by either immature or Bacillus Calmette-Guerin mycobacteria-treated adult host DCs, produced lower interferon-gamma (IFN-gamma) and higher interleukin-10 (IL-10), which is a regulatory T cell-like cytokine profile, as compared with adult blood CD4(+) T cells. In contrast, lipopolysaccharide (LPS)-treated adult host DCs significantly up-regulated IFN-gamma and down-regulated IL-10 production levels from CB CD4(+) T cells to that from adult blood CD4(+) T cells. The sustained low IFN-gamma and high IL-10 production from CB CD4(+) T cells co-cultured with adult blood DCs might account for the less severe GvHD occurrence after CB transplantation, which could be reversed by LPS-treated adult blood DCs.
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PMID:Tolerance associated with cord blood transplantation may depend on the state of host dendritic cells. 1528 45

Following a human leucocyte antigen (HLA)-identical allogeneic stem cell transplantation (allo-SCT), minor histocompatibility antigens (mHags) play an important role in the induction of graft-versus-leukaemia (GvL) and graft-versus-myeloma (GvM). Many mHags show ubiquitous tissue expression and are associated with GvL and graft-versus-host disease. Here we describe a cytotoxic CD4(+) T lymphocyte line and a cytotoxic, CD4(+) T cell clone (CTC), 3AB11, which recognized a tissue-restricted mHag. This CTC was isolated from a multiple myeloma patient with clinical GvM following an HLA-matched allo-SCT. CTC 3AB11 was activated in a HLA-DP*0401 restricted fashion and the antigen was expressed by 27% of HLA-DP*0401 positive Epstein-Barr virus (EBV)-transformed B-cell lines (EBV-B). Tissue distribution analysis of antigen 3AB11 showed it to be expressed by patient-derived EBV-transformed B cell lines (EBVp), the myeloma plasma cell-line UM9 and monocytes. It was weakly expressed by peripheral blood-derived phytohaemagglutinin-induced T-cell blasts and absent on CD40L stimulated peripheral B (CD40L B) cells and stromal cells. The relatively high prevalence of the HLA class II-restricted 3AB11 antigen, together with its apparent haematopoietic-restricted expression, makes it an antigen of interest for cellular immunotherapy.
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PMID:A class II-restricted cytotoxic T-cell clone recognizes a human minor histocompatibility antigen with a restricted tissue distribution. 1560 52

Cotransplantation of donor bone marrow cells (BMCs) in allograft recipients is currently the most promising concept for clinical tolerance induction; however, it still has many difficulties in its successful performance due to the toxicity of the required host conditioning, the risk of engraftment failure, and the problem of graft-versus-host disease (GVHD), as well as the limited accessibility of donor bone marrow cells. Therefore, we performed the studies to determine whether BMCs from multi-donors are simultaneously engrafted and lead to induction of chimerism-based tolerance through the tolerogenic protocol of whom effectiveness we have shown in a previous study. Using a murine model, it was demonstrated that grafted BMCs from BALB/c (H-2(d)) and CBA mice (H-2(k)) establish mixed type and multi-lineage double chimerism and induce immunological donor-specific tolerance to fully MHC-mismatched skin allografts in host C57BL/6 mice (H-2(b)) receiving conditioning with Busulfan and treatment with the two-signal blockade comprised of anti-CD45RB and anti-CD154 monoclonal antibodies.
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PMID:Tolerance induction through simultaneous double bone marrow transplantation with two-signal blockade. 1626 45

CD4 T cells, particularly those of the T-helper 1 (Th1) subset, are important effectors in alloimmune diseases, such as graft-versus-host disease, and in controlling infections with intracellular pathogens. Thus, it is plausible that impaired neonatal CD4 T-cell immunity might contribute to the low incidence of acute graft-versus-host disease after allogeneic transplantation of hematopoietic stem cells using cord blood (CB) compared with adult sources of hematopoietic stem cells. In support of this hypothesis, we found that CB naive CD4 T cells had reduced activation and impaired early Th1 differentiation compared with adult peripheral blood naive CD4 T cells after stimulation by allogeneic dendritic cells derived from adult monocytes. Early Th1 polarization was dependent on interleukin-12 and CD154, and CB CD4 T cell/dendritic cell co-cultures had impaired expression of both proteins. CB naive CD4 T cells had low basal levels of signal transduction and activation of transcription 4 messenger RNA and protein, and, after alloantigen stimulation, reduced interleukin-12-induced signal transduction and activation of transcription 4 tyrosine phosphorylation, compared with adult peripheral blood naive T cells. Lastly, FoxP3 protein expression, a marker for regulatory CD25(high) CD4 T cells, was lower for naive CD4 T cells of CB compared with those of adult peripheral blood, which argued against increased T-regulatory activity as a mechanism for the decreased Th1 differentiation of CB CD4 T cells. Together, these intrinsic limitations in T-cell activation and Th1 differentiation may impair the ability of T cells in CB and the neonate to respond to allogeneic or infectious challenges.
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PMID:Impaired allogeneic activation and T-helper 1 differentiation of human cord blood naive CD4 T cells. 1644 14

During the effector phase of graft-versus-host disease (GvHD) response, donor T cells play an essential role and they are believed to change the expression of activation and co-stimulatory markers associated with functional alloreactivity. We analysed the expression of CD25, CD69, HLA-DR, CD154 and CD134 on CD4+ and CD8+ T cells by flow cytometry during acute GvHD (aGvHD) in 24 patients receiving human leucocyte antigen (HLA)-identical stem cell transplants. Expression of these molecules in nine patients with stages I-IV aGvHD was compared with 15 patients without aGvHD (n = 15). Serial analysis showed that peripheral blood of aGvHD patients presented a significant increase of CD4+ CD25+ cells (P < 0.03), CD4+ CD69+ (P < 0.04) and CD4+ CD134+ cells (P < 0.01). Additionally, there was a significant increase in CD8+ cells expressing CD134 (P = 0.007) and CD154 (P = 0.02). After resolution of aGvHD, the increased expression of these molecules returned to values comparable to patients without aGvHD. Only two of the 15 patients without clinical signs of aGvHD presented activated T cells that could not be attributed to development of aGvHD. In summary, our data show that multiple activation molecules are preferentially up-regulated on CD4+ and CD8+ T cells from patients with aGvHD. These patients had a significant increase in the expression of the co-stimulatory molecules CD134 and CD154.
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PMID:Activation-associated phenotype of CD3 T cells in acute graft-versus-host disease. 1679 71

In HLA-incompatible hematopoietic stem cell transplantation, alloreactive donor T cells recognizing recipient mismatch HLA cause severe graft-versus-host disease (GVHD). Strategies allowing the selective depletion of alloreactive T cells as well as the enhancement of graft-versus-malignancy immunity would be beneficial. We generated donor CD8 T-cell lines in vitro using allogeneic recipient cells mismatched at a single HLA class I allele or haplotype as stimulators. Recipient cells were obtained from acute myeloid leukemias, renal-cell carcinomas, and CD40L-induced B lymphoblasts. Resulting alloreactive T cells were activated by incubating day 21 T-cell cultures with HLA-mismatch transfected K562 cells or recipient-derived fibroblasts. Selective allodepletion (SAD) was subsequently performed by a newly developed immunomagnetic depletion approach targeting the tumor necrosis factor receptor molecule CD137 (4-1BB). Compared with other activation-induced antigens, CD137 showed a superior performance based on a consistently low baseline expression and a rapid up-regulation following alloantigen stimulation. In 15 different SAD experiments, the frequency of alloreactive CD8 T cells was reduced to a median of 9.5% compared with undepleted control populations. The allodepleted T-cell subsets maintained significant antitumor and antiviral CD8 responses. In vitro expansion of tumor-reactive T cells followed by CD137-mediated SAD might enhance the antitumor efficacy of T-cell allografts with lower risk of inducing GVHD.
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PMID:Targeting the activation-induced antigen CD137 can selectively deplete alloreactive T cells from antileukemic and antitumor donor T-cell lines. 1693 26

"Mini" allogeneic bone marrow transplants using non-myeloablative conditioning have reduced early treatment-related mortalities, but graft-versus-host disease (GVHD) and graft rejection remain clinical problems. Our preliminary studies indicated that low-dose busulfan conditioning and costimulatory blockade using anti-CD154 monoclonal antibody (mAb) in combination with a pretransplantation "tolerating" dose of bone marrow (BM) cells were sufficient to establish stable mixed-chimerism without GVHD when transplanting moderate doses of T cell depleted (TCD)-BM from major histocompatibility complex (MHC) fully-mismatched donors (Adams AB, Durham MM, Kean L, et al. J Immunol. 2001;167:1103-1111). In this study, donor splenocytes were administered before transplantation as a tolerating cell infusion with a conditioning regimen consisting of low-dose busulfan and anti-CD154 mAb. We compared the ability of viable and apoptotic donor cells of different ex vivo treatments and purified different donor cell populations (CD3(+), CD3(-), CD11b(+), and CD11b(-) splenocytes) to induce tolerance and enhance donor chimerism in a MHC mismatched model of murine bone marrow transplantation. We found that mixed chimerism without GVHD was enhanced by pretransplantation administration of viable allogeneic splenocytes and diminished in mice with prior exposure to apoptotic/necrotic donor splenocytes. CD11b(+)-enriched splenocytes more potently enhanced donor chimerism compared to unfractionated splenocytes or other splenocyte subsets. Mixed lymphocyte cultures demonstrated that apoptotic stimulators overcame the immune-tolerating activity of anti-CD154 mAb and led to increased interferon gamma and tumor necrosis factor alpha synthesis, increased proliferation of responder T cells, and decreased production of interleukin-10. In conclusion, viable donor splenocytes administered before transplantation in combination with costimulatory blockade induced tolerance and enhanced donor chimerism, whereas pretransplantation administration of apoptotic/necrotic donor cells led to host T cell activation and decreased overall donor engraftment.
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PMID:Apoptotic donor leukocytes limit mixed-chimerism induced by CD40-CD154 blockade in allogeneic bone marrow transplantation. 1716 5

To facilitate the establishment of mixed chimerism with limited dose of bone marrow (BM) cells, and to achieve tolerance in skin graft model, combined blocking of costimulatory pathway and IL-2 pathway was used in minimally myeloablative model using busulfan. BM cells (2.5x10(7)) of BALB/c were injected into C57BL/6 mice at day 0 with full thickness skin graft after single dose injection of busulfan (25 mg/kg) on day-1. Recipients were grouped and injected the anti-CD154, CTLA4-Ig, anti-IL-2R at days 0, 2, 4, and 6 according to protocol. Mixed macrochimerism were induced in groups treated with anti-CD154+anti-CTLA4-Ig, anti-CD154+anti-IL-2R, and anti-CD154+anti-CTLA4 Ig+anti-IL-2R. Three groups having chimerism enjoyed prolonged graft survival more than 6 months. Superantigen deletion study revealed deletion of alloreactive T cells in combined blockade treated groups. In graft versus host disease model using CFSE staining, CD4+ T cell and CD8+ T cell proliferation were reduced in groups treated with CTLA4-Ig or anti-IL-2R or both in combination with anti-CD154. However, anti-IL-2R was not so strong as CTLA4-Ig in terms of inhibition of T cell proliferation. In conclusion, IL-2 pathway blocking combined with anti-CD154 can establish macrochimerism with limited dose of BM transplantation and induce specific tolerance to allograft.
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PMID:IL-2 pathway blocking in combination with anti-CD154 synergistically establishes mixed macrochimerism with limited dose of bone marrow cells and prolongs skin graft survival in mice. 1717 77

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

Treatment regimens consisting of CTLA-4 Ig/anti-CD154 or agonistic anti-CD28/rapamycin have both been shown to prevent GVHD in fully allogeneic murine model systems. Using a transgenic approach to track the fate of host-reactive T cells in a minor antigen disparity model of GVHD, we found that while treatment with CTLA-4 Ig/anti-CD154 retained efficacy, the costimulation agonist anti-CD28 combined with rapamycin failed to prevent GVHD. Analysis of the host-reactive CD4(+) and CD8(+) T-cell responses revealed that in contrast to CTLA-4Ig/anti-CD154-treated recipients, host-reactive T cells in recipients treated with agonistic anti-CD28/rapamycin displayed enhanced and accelerated T-cell proliferation and failed to undergo activation-induced cell death. An increase in systemic levels of inflammatory cytokines was observed in the anti-CD28/rapamycin-treated recipients of the minor but not major antigen disparity bone marrow transplants. Our results demonstrate the intricacies of costimulatory receptor signaling pathways, and reveal how agonism of the CD28 pathway can have opposing outcomes depending on the degree of antigenic disparity.
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PMID:Antigenic disparity impacts outcome of agonism but not blockade of costimulatory pathways in experimental transplant models. 1751 77


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