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)

The occurrence of post-transplant lymphoproliferative disorder (PTLD) in relation to immunosuppressive treatment was determined in 257 patients treated with non-T-cell-depleted allogeneic stem cell transplantation from an HLA-matched sibling (173 patients) or unrelated donor (84 patients). The conditioning consisted of total body irradiation and cyclophosphamide (myeloablative conditioning, 250 patients), or fludarabine combined with cyclophosphamide or a single 2 Gy dose of TBI (nonmyeloablative conditioning, seven patients). In transplantations from an unrelated donor, the patients also received antithymocyte globulin (ATG). The prophylaxis against graft-versus-host disease (GVHD) consisted of cyclosporine A, methotrexate, and methylprednisolone. The autopsy reports of deceased patients were systematically reviewed, and the autopsy materials of cases suggestive of PTLD were re-examined histologically for Epstein-Barr virus (EBV). Nineteen patients with EBV-positive PTLD were identified, of whom six had been transplanted from a sibling donor and 13 from an unrelated donor. All the patients who developed PTLD had been given ATG either for the treatment of steroid-resistant acute GVHD (all PTLD patients with a sibling donor and one with an unrelated donor), or as part of the conditioning (all patients with an unrelated donor). In conclusion, in transplantations from an HLA-identical donor with a non-T-cell-depleted graft, the risk of PTLD correlated strongly with the intensity of the immunosuppressive treatment.
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PMID:High incidence of PTLD after non-T-cell-depleted allogeneic haematopoietic stem cell transplantation as a consequence of intensive immunosuppressive treatment. 1281 84

Graft-versus-host disease (GVHD) represents one of the major complications of allogeneic hematopoietic stem cell transplantation. Techniques to prevent GVHD have included ex vivo T-cell depletion of the graft or prolonged in vivo immunosuppression. Both reduce the frequency and severity of GVHD but also reduce T-cell-mediated graft-versus-malignancy effect, and increase the risk of infection. A major goal in transplantation is to prevent alloreactivity while preserving activity against tumors and infectious agents. We have used activation of the Notch pathway to try to generate T cells able to specifically regulate alloantigen responses. We used allogeneic Epstein-Barr virus lymphoblastoid B cells (EBV-LCLs) as stimulator cells. Such LCLs are excellent (allo) antigen-presenting cells and can be obtained in large numbers even from donors who have received extensive chemo/radiotherapy. We overexpressed a Notch ligand, Jagged-1, in these cells by adenoviral vector transduction. Stimulation of CD45RA+ naive T cells by Jagged-1 EBV-LCL reduces production of interferon-gamma, interleukin-2, and interleukin-5, but up-regulates transforming growth factor-beta 1 synthesis, consistent with induction of a regulatory T-cell phenotype. Transfer of these T cells to fresh lymphocyte cultures inhibits proliferative and cytotoxic immune responses to the priming alloantigens while sparing responses to third-party stimulator cells. Notch activation in the presence of alloantigen-presenting cells may therefore be a means of inducing specific regulatory T cells while preserving other T-cell functionality.
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PMID:Overexpression of the Notch ligand, Jagged-1, induces alloantigen-specific human regulatory T cells. 1284 95

Many patients suffer febrile diseases soon after allogeneic stem cell transplantation (SCT). Some of the symptoms of viral infections and acute GVHD are often difficult to distinguish. However, an accurate diagnosis is important since the treatments for these conditions are different. It is known that MxA protein is specifically induced in patients with several viral infections. We investigated the cytoplasmic expression of MxA in the peripheral blood mononuclear cells (PBMCs) of patients with fever after allogeneic SCT using a newly generated monoclonal antibody (KM1135) and flow cytometry. The level of MxA expression was significantly higher in patients diagnosed with viral infections (n=6, cytomegalovirus in three, Epstein-Barr virus in one, human herpesvirus-6 in one, adenovirus in one) than control individuals (n=9) (P<0.05, Mann-Whitney test). The level of MxA in patients with aGVHD (n=7) was identical to that in controls. The level of MxA correlated well with the amount of the cytomegalovirus antigen-positive cells in the presence of acute GVHD in two patients. The measurement of MxA is simple and useful in distinguishing viral disease from acute GVHD after allogeneic SCT.
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PMID:MxA expression in patients with viral infection after allogeneic stem cell transplantation. 1285 4

T cell depletion (TCD) of marrow is a proven method of graft-versus-host disease (GVHD) prophylaxis in allogeneic bone marrow transplantation (BMT). Nonetheless, TCD is associated with an increased risk of developing post transplant lymphoproliferative disorder (PTLD). Between 1986 and 1998, 241 pediatric patients at the University of Iowa underwent BMT using ex vivo TCD of marrow from mismatched related or matched unrelated donors. Additional GVHD prophylaxis included antithymocyte globulin (ATG) or anti lymphocyte globulin (ALG) post transplant (in vivo TCD). A total of 30 cases of PTLD were identified based upon a combination of clinical, histological, and immunological features. Nearly all cases occurred within 3 months post BMT. A statistically significant increase in PTLD incidence was noted for patients treated with ATG vs ALG (33 vs 9%). While grade I-II acute GVHD was more common in patients receiving ATG vs ALG, no difference in grade III-IV GVHD or overall survival was noted between the two groups. Assessment of immune recovery at various times post BMT revealed significantly fewer T cells in the ATG-treated group, suggesting the deleterious effect of ATG may be due to excessive depletion of donor-derived Epstein-Barr virus-specific cytotoxic T cells. Thus, caution should be exercised in the use of anti-T-cell antibody therapy for additional GVHD prophylaxis in the setting of TCD BMT.
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PMID:Effect of in vivo lymphocyte-depleting strategies on development of lymphoproliferative disorders in children post allogeneic bone marrow transplantation. 1294 1

We previously constructed human peripheral blood lymphocyte (hu-PBL)/severe combined immunodeficiency mouse (SCID) chimeras and induced human B-cell lymphomas associated with Epstein-Barr virus (EBV) in SCID mice. However, a number of SCID mice died of graft-versus-host disease (GVHD) during the early experimental course. The aim of this study was to test the efficacy of cyclosporine A (CSA) for prevention of GVHD and to define how CSA inhibits the occurrence of GVHD and the production of soluble interleukin (IL) 2 receptor (sIL-2R) in hu-PBL/SCID mice. No mouse died in the active EBV infection group with CSA administration, while 17 mice in three groups without CSA administration died of GVHD. Mortalities in these three groups were 55.56% (5/9), 30.43% (7/23), and 27.78% (5/18), and the medium life span was 17 days. Over the first 33 days after hu-PBL transplantation, serum level of human sIL-2R in hu-PBL/SCID chimeras was stable in the active EBV infection plus CSA group, while sIL-2R concentration gradually increased in the sera of mice with active EBV infection without CSA administration and peaked at 22 days. Thirty-two mice developed tumors among the 43 surviving SCID mice. There was no significant difference of tumor incidence between the active EBV infection groups with CSA and without CSA administration (P > 0.05). From their morphological and immunohistochemical features, as well as detection of human Alu-sequence and EBV in tumor cells, these EBV-induced tumors were identified as human B-cell lymphomas. Thus, CSA can strikingly inhibit GVHD in hu-PBL/SCID chimeras, and should therefore be effective to establish a stable SCID mouse model of human lymphoma associated with EBV. Treatment with CSA had no effect on the tumor incidence in hu-PBL/SCID chimeras after active EBV infection. Accordingly, serum level of sIL-2R is a valuable indicator of GVHD occurrence in hu-PBL/SCID chimeras.
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PMID:Cyclosporine A effectively inhibits graft-versus-host disease during development of Epstein-Barr virus-infected human B cell lymphoma in SCID mouse. 1296 78

The construction and use of Class I human leucocyte antigen (HLA) tetramers has, for the first time, allowed the direct enumeration of CD8(+) T lymphocytes specific for the antigen of interest. Tetramer staining can be combined with functional assays of antigen-specific T cells measuring their production of intracellular cytokines after short-term stimulation with antigen. The advantages of flow cytometric tetramer-based assays are their short turn-around time and their amenability to standardisation. Currently, their main limitation is that only a limited number of Class I HLA tetramers are available. This situation may bias the information derived from such studies. Nevertheless, clinically useful information has been obtained in tetramer-based studies of the regeneration of cytomegalovirus (CMV) and Epstein-Barr virus (EBV)-specific CD8(+) T cells after allogeneic stem cell transplantation (SCT). Following myeloablative cytoreductive therapy and SCT, a period of deep cellular immunodeficiency follows until the donor-derived immune system has sufficiently regenerated. As a result of the lack of immunosurveillance, endogenous viruses such as CMV and EBV may reactivate and cause disease. In order to prevent these complications, pre-emptive therapeutic interventions are made, in which antiviral treatment is administered based on frequent viral load measurements. In this way, overtreatment associated with prophylactic strategies is reduced; however, a subgroup of patients developing recurrent reactivations and/or disease remains. Interventions aimed at the prevention of graft versus host disease (GVHD) and the reduction of its severity greatly reduce the rate of (virus-specific) T-cell reconstitution and hence, increase the frequency and severity of viral reactivations. Specifically, T-cell depletion of SCT and the use of antithymocyte globulin as part of the conditioning regimen reduces the (virus-specific) T lymphocytes transferred with the graft, which otherwise would have contributed to the first phase of T-cell regeneration post-SCT. Consequently, patients whose CMV- and EBV-specific CD8(+) T cells fail to regenerate to levels detectable by tetramer-based flow cytometry during the first 3-6 months post-SCT were at highly increased risk for CMV disease and EBV(+) B-lymphoproliferative disease, respectively. Furthermore, delayed reconstitution of the CD4(+) T-cell compartment results in the lack of adequate help for the generation of sufficient antiviral CD8(+) T cells. Conversely, adoptive immunotherapy using CMV- or EBV-specific T cells results in the swift restoration of virus-specific T-cell immunity and the reduction of viral load, unless corticosteroids have to be administered to treat concurrent GVHD. Studies have shown the clinical utility of tetramer-based immune monitoring in the setting of allogeneic SCT and indicate that such assays, extended by functional studies of the virus-specific T cells, may constitute a valuable extension of current viral load monitoring strategies.
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PMID:Clinical utility of tetramer-based immune monitoring in allogeneic stem cell transplantation. 1449 63

Posttransplantation lymphoproliferative disease (PTLD) presenting as an Epstein-Barr-virus (EBV)-related nasal plasmacytoma developed in a renal-allograft recipient 13 years after transplantation. Systemic dissemination occurred despite immunosuppression withdrawal, surgery, irradiation, and chemotherapy. A nonmyeloablative hematopoietic-stem-cell-transplantation (HSCT) with peripheral blood HSC from the kidney donor was performed. With the onset of graft-versus-host disease, resolution of the systemic disease was demonstrated clinically and molecularly by serial quantification of plasma EBV-DNA. Isolated relapse occurred in the central nervous system (CNS), a known tumour sanctuary site, ultimately leading to death. Nonmyeloablative HSCT might be considered a cellular therapy for PTLD, but possible CNS relapse must be effectively tackled.
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PMID:Treatment of postrenal transplantation lymphoproliferative disease manifesting as plasmacytoma with nonmyeloablative hematopoietic stem cell transplantation from the same kidney donor. 1463 12

The Third Workshop on reduced intensity conditioning allogeneic stem cell transplants (RIC-HSCT) was convened by EBMT/AMGEN in Zurich in February 2003. Three general issues were addressed: the age effect, graft-versus-host disease (GvHD) and donor lymphocyte infusions (DLI). An age effect is seen and has a negative impact on survival; GvHD remains an issue that needs to be addressed, and DLI were shown to be a powerful tool against minimal residual disease, but not with rapidly progressing leukemia. The role of host antigen-presenting cells in the development of acute GvHD was outlined and discussed in the animal model. The emerging importance of Epstein Barr Virus infections was also discussed. Retrospective and prospective studies from the EBMT, national groups and single institutions included over 1800 patients: the incidence of acute GvHD grade III-IV was 11% extensive chronic GvHD 22% and TRM 20%. Most conditioning regimens include fludarabine in association with a reduced dose of a myeloablative agent (busulfan, TBI, thiotepa or melphalan). Most transplants were from HLA-identical siblings (77%), and used peripheral blood (90%) as a stem cell source. A consensus discussion on current evidence in RIC transplants is reported in this paper.
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PMID:Third EBMT/AMGEN Workshop on reduced-intensity conditioning allogeneic haemopoietic stem cell transplants (RIC-HSCT), and panel consensus. 1475 22

Cellular inactivation through killer immunoglobulin-like receptors (KIRs) may allow neoplastic cells to evade host natural killer (NK) cell-mediated immunity. Recently, alloreactive NK cells were shown to mediate antileukemic effects against acute myelogenous leukemia (AML) after mismatched transplantation, when KIR ligand incompatibility existed in the direction of graft-versus-host disease (GVHD). Therefore, we investigated whether solid tumor cells would have similar enhanced susceptibility to allogeneic KIR-incompatible NK cells compared with their KIR-matched autologous or allogeneic counterparts. NK populations enriched and cloned from the blood of cancer patients or healthy donors homozygous for HLA-C alleles in group 1 (C-G1) or group 2 (C-G2) were tested in vitro for cytotoxicity against Epstein-Barr virus-transformed lymphoblastic cell lines (EBV-LCLs), renal cell carcinoma (RCC), and melanoma (MEL) cells with or without a matching KIR-inhibitory HLA-C ligand. Allogeneic NK cells were more cytotoxic to tumor targets mismatched for KIR ligands than their KIR ligand-matched counterparts. Bulk NK populations (CD3(-)/CD2(+)/CD56(+)) expanded 10(4)-fold from patients homozygous for C-G1 or C-G2 had enhanced cytotoxicity against KIR ligand-mismatched tumor cells but only minimal cytotoxicity against KIR ligand-matched targets. Further, NK cell lines from C-G1 or C-G2 homozygous cancer patients or healthy donors expanded but failed to kill autologous or KIR-matched MEL and RCC cells yet had significant cytotoxicity (more than 50% lysis at 20:1 effector-target [E/T] ratio) against allogeneic KIR-mismatched tumor lines. These data suggest immunotherapeutic strategies that use KIR-incompatible allogeneic NK cells might have superior antineoplastic effects against solid tumors compared with approaches using autologous NK cells.
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PMID:Enhanced cytotoxicity of allogeneic NK cells with killer immunoglobulin-like receptor ligand incompatibility against melanoma and renal cell carcinoma cells. 1501 54

Nonselective T-cell depletion reduces the incidence of severe graft-versus-host disease after allogeneic hematopoietic stem cell transplantation, but the cost is delayed and disordered antigen-specific immune reconstitution and increased infection. We use a method of selective depletion of alloreactive T cells expressing the activation marker CD69 after coculture with stimulator cells in a modified or standard mixed lymphocyte reaction. The technique has been shown to reduce alloreactivity while retaining third-party responses in vitro and, in a mismatched murine model, led to donor T-cell engraftment with a virtual absence of graft-versus-host disease and increased survival. We show in a human HLA-mismatched and unrelated HLA-identical setting that this technique retains >80% of specific cellular antiviral activity by cytomegalovirus-tetramer analysis and cytomegalovirus/Epstein-Barr virus peptide-stimulated interferon-gamma ELISpot assay. Furthermore, CD4(+) CD25(+) T-regulatory cells are not removed by this method of selective allodepletion and retain their function in suppressing allogeneic proliferative responses. Preservation of antiviral cytotoxic T lymphocytes in selectively allodepleted stem cell grafts would lead to improved antiviral immunity after transplantation. The retention of immunosuppressive CD4(+) CD25(+) T-regulatory cells could lead to more ordered immune reconstitution and further suppress alloreactive responses after transplantation.
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PMID:Antiviral immunity and T-regulatory cell function are retained after selective alloreactive T-cell depletion in both the HLA-identical and HLA-mismatched settings. 1507 24

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