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)

There is now clear clinical evidence that adoptive cellular immunotherapy can eradicate hematologic malignancy and cure otherwise lethal viral infections. With this knowledge comes the challenge of improving the effectiveness and safety of the approach and of simplifying the methodologies required whilst still meeting appropriate federal regulatory guidelines. This review provides an overview of the current status of cellular immunotherapies and addresses how they may be implemented and the future directions they are likely to take. In Section I, Dr. Brenner with Drs. Rossig and Sili reviews the clinical experience to date with adoptive transfer of viral antigen-specific T cells for the successful treatment of Epstein-Barr virus-associated malignancies as well as viral infectious diseases. Genetic modification of the T cell receptor of the infused cells to potentiate such T cells as well as modifications to improve safety of the infusions are described. In Section II, Dr. Young describes the hematopoietic lineages of human dendritic cells and some of their immunotherapeutic applications. The critical importance of dendritic cells to T cell immunity and the capacity to generate dendritic cells in large numbers has spawned enormous interest in the use of these specialized leukocytes to manipulate cellular immunity. Successful cytokine-driven differentiation of dendritic cells reveal two types, myeloid- and plasmacytoid or lymphoid-related dendritic cells. The effects of maturation on phenotype and function of the dendritic cells and their use as immune adjuvants in dendritic cell vaccines to elicit antitumor and antiviral immunity are reviewed. In Section III, Professor Goulmy illustrates some current and future approaches towards tumor-specific cellular therapy of hematopoietic malignancy. Minor histocompatibility antigen (mHag) disparities between HLA-matched bone marrow donor and recipient can induce allo-responses that may participate in post bone marrow transplantation (BMT) graft-versus-leukemia (GVL) reactivities. A lack of such allo-reactivity may result in relapse of leukemia after BMT. In these patients, adoptive immunotherapy with cytotoxic T cells (CTLs) specific for hematopoietic system-restricted mHags may be used as an extension of current efforts using immunotherapy with donor lymphocyte infusions. Adoptive immunotherapy with CTLs specific for the hematopoietic system-restricted mHags, however, offers the prospect of greater and more predictable effectiveness in the absence of graft-versus-host disease.
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PMID:Transfusion Medicine: New Clinical Applications of Cellular Immunotherapy. 1170 51

Epstein-Barr virus (EBV) is closely associated with the progressive and often fatal lymphoproliferative disorders (LPD) in post bone marrow transplantation (BMT) and immunocompromised hosts. The incidence increases significantly when alternative donors or manipulation of marrow graft are used. A total of 318 consecutive BMT from partially mismatched related family donors (PMRD) were performed between February 1993 and June 1998. Known risk factors for the development of EBV-LPD were analyzed which included HLA mismatches, T cell depletion, antithymocyte globulin (ATG), and graft-versus-host disease (GVHD). Eighteen patients (5.7%) developed EBV-LPD at a median of 137 days post BMT (range 48-617). The estimated probability of developing EBV-LPD was 0.13 (95% CI 0.07-0.19) at 5 years. The incidence of grade II to IV GVHD was 19.2%, which translated into an increased trend of EBV-LPD. No correlation with other risk factors was observed. Treatment consisted of supportive antiviral agents, tapering of immunosuppressive regimens, donor leukocyte infusions and radiation. Three patients are alive and disease-free at a median follow-up of 69 months (range 36-71). We observed a lower than expected incidence of EBV-LPD despite existing multiple high-risk factors. We believe prevention and early control of GVHD may contribute to this finding.
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PMID:Epstein-Barr virus-associated B cell lymphoproliferative disorder following mismatched related T cell-depleted bone marrow transplantation. 1180 52

We report a case of Epstein-Barr virus-associated lymphoproliferative disorder (EBV-LPD) after allogeneic bone marrow transplantation (allo-BMT) from a partially mismatched related donor for acute lymphocytic leukemia, which was treated successfully by donor lymphocyte infusion (DLI). A 54-year-old woman in first complete remission from acute lymphocytic leukemia received an unmanipulated bone marrow transplant from an HLA-A 1-locus-mismatched sibling donor after preconditioning with cyclophosphamide and total body irradiation. Prophylaxis against graft-versus-host disease (GVHD) was done with tacrolimus and short-term methotrexate. Skin GVHD (grade I) occurred on day 36, but this subsided spontaneously without treatment. On day 61, rapidly progressive cervical lymphadenopathy with fever developed. Lymph node biopsy revealed lymphoid cell proliferation, which was positive for LCA, L26 and LMP-1. A diagnosis of EBV-LPD was made. After withdrawal of the tacrolimus, DLI (1 x 10(6) CD3 cells/kg) resulted in remission. This case suggests that even in the absence of risk factors such as severe GVHD, intensive immunosuppressive therapy and ATG administration, allo-BMT from an HLA 1-locus-mismatched related donor can be complicated by EBV-LPD, and that reduction of immunosuppressive therapy and DLI can be an effective treatment for it.
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PMID:[Successful donor lymphocyte infusion for Epstein-Barr virus-associated lymphoproliferative disorder after allogeneic bone marrow transplantation from an HLA 1-locus-mismatched sibling donor in a patient with acute lymphocytic leukemia]. 1180 79

Uncontrolled expansion of donor-derived Epstein-Barr virus (EBV)-infected B cells has become a significant problem in recipients of allogeneic hematopoietic stem cell transplantations. Major risk factors for the early development of posttransplantation lymphoproliferative disease include the use of unrelated or HLA-mismatched related donors, selective T-cell depletion of donor marrow, and the use of antithymocyte globulin or monoclonal anti-T-cell antibodies for the prophylaxis and treatment of acute graft-versus-host disease. Over the past few years, the administration of in vitro-generated EBV-specific cytotoxic T cells or anti-B-cell monoclonal antibodies has provided effective options for the prophylaxis or treatment of posttransplantation lymphoproliferative disease. Advances in quantitative polymerase chain reaction-based assays allow both the precise measurement of EBV load in peripheral blood samples and the identification of high-risk patients for early initiation of therapy. A major remaining challenge is to assess the significance of an elevated EBV load posttransplantation and to determine the indications for preemptive treatment.
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PMID:Diagnosis and treatment of posttransplantation lymphoproliferative disease after hematopoietic stem cell transplantation. 1184 51

Visilizumab is a humanized anti-CD3 monoclonal antibody characterized by a mutated IgG2 isotype, lack of binding to Fcgamma-receptors, and ability to induce apoptosis selectively in activated T cells. To test pharmacokinetics, safety, and immunosuppressive activity of visilizumab, 17 patients with glucocorticoid-refractory acute graft-versus-host disease (GVHD) were enrolled in a phase 1 study. Six patients were given 7 doses of visilizumab (0.25 or 1.0 mg/m(2)) on days 1, 3, 5, 7, 9, 11, and 13. Because multiple doses of 1 mg/m(2) caused delayed visilizumab accumulation and prolonged lymphopenia, the next 11 patients received a single dose of 3.0 mg/m(2) on day 1. GVHD improved in all patients; 15 were evaluable through day 42. Multiple dosing resulted in 1 of 6 complete responses (CRs) and 5 partial responses (PRs), but all 6 patients died at a median of 87 days after starting visilizumab therapy. Single dosing resulted in 6 of 9 CRs, 3 PRs, and 7 of 11 patients surviving after 260 to 490 days (median, 359 days; P =.03). There were no allergic reactions and 3 grade 1 acute infusional toxicities. Plasma Epstein-Barr virus (EBV) DNA titers more than 1000 copies/mL and posttransplant lymphoproliferative disease (PTLD) developed in 2 of the first 7 patients. Based on rising EBV DNA titers, 5 of the next 10 patients were given the B cell-specific monoclonal antibody, rituximab. EBV DNA became undetectable and no overt PTLD developed. Visilizumab is well tolerated and has activity in advanced GVHD. A phase 2 study incorporating preemptive therapy for PTLD is warranted to determine the efficacy of visilizumab in GVHD.
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PMID:A humanized non-FcR-binding anti-CD3 antibody, visilizumab, for treatment of steroid-refractory acute graft-versus-host disease. 1192 57

We report here a patient who developed multiple central nervous system (CNS) space-occupying lesions 6 months after bone marrow transplantation from an HLA-matched unrelated donor. He had extensive chronic graft-versus-host disease and severe thrombocytopenia. Posttransplantation lymphoproliferative disorder (PTLD) was diagnosed after biopsy of the lesion was facilitated by the transfusion of 40 units of platelets. Epstein-Barr virus (EBV) DNA was not initially detected in the peripheral blood by real-time polymerase chain reaction, and the blood became positive for EBV at a low level only after more than 6 weeks had passed since the initial identification of detectable intracranial lesions. The patient died of cerebral herniation while donor leukocyte infusion was being prepared, and an autopsy confirmed the diagnosis of EBV-associated PTLD restricted to the CNS.
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PMID:Failure to detect Epstein-Barr virus (EBV) DNA in plasma by real-time PCR in a case of EBV-associated posttransplantation lymphoproliferative disorder confined to the central nervous system. 1204 75

Human leucocyte antigen (HLA)-Cw-reactive cytotoxic T lymphocytes (CTL) were generated from cord blood (CB) lymphocytes of two cases used for cord blood stem cell transplantation (CBSCT). In both cases, the CTL were cytotoxic against the patient's leukaemic cells, as well as the patient's Epstein-Barr virus (EBV)-lymphoblastoid cell line (EBV-LCL) and phytohaemagglutinin blasts, and the cytotoxicity was blocked by anti-HLA-class I monoclonal antibodies. In the first case, the CTL recognized Cw 3 (Cw 9 and Cw 10)-positive EBV-LCL, while in the second case, the CTL recognized Cw1 and/or Cw7. These cases suggest that CB T cells may be competent enough for generating CTL to induce a graft-versus-leukaemia effect and/or graft-versus-host disease in patients with CBSCT and that the mismatching of Cw antigens between patient and CB may be related to the outcome of CBSCT.
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PMID:Human leucocyte antigen-Cw-specific cytotoxic T lymphocytes generated from naive cord blood used for cord blood stem cell transplantation. 1206 Jan 28

Post-transplant lymphoproliferative disorder (PTLD) represents a spectrum of Epstein-Barr virus-related (EBV) clinical diseases, from a benign mononucleosis-like illness to a fulminant non-Hodgkin's lymphoma. In the setting of hematopoietic stem cell transplantation, PTLD is an often-fatal complication occurring relatively early after transplant. Risk factors for the development of PTLD are well established, and include HLA-mismatching, T-cell depletion, and the use of antilymphocyte antibodies as conditioning or treatment of graft-versus-host disease. Early recognition of PTLD is particularly important in the SCT setting, because PTLD in these patients tends to be rapidly progressive. Familiarity with the clinical features of PTLD and a heightened level of suspicion are critical for making the diagnosis. Surveillance techniques with EBV antibody titers and/or polymerase chain reaction (PCR) may have a role in some high-risk settings. Immune-based therapies such as monoclonal anti-B-cell antibodies, interferon-alpha, and EBV-specific donor T cells, either as treatment for PTLD or as prophylaxis in high-risk patients, represent promising new directions in the treatment of this disease.
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PMID:Post-transplant lymphoproliferative disorder: a review. 1262 74

Homogeneous immunoglobulins are frequently detected in the serum of patients undergoing allogeneic bone marrow transplantation (BMT). The aim of the present study was to further characterize the incidence of this phenomenon and its correlations with laboratory and clinical data. Serum samples were gathered from 29 patients undergoing allogeneic or syngeneic BMT for chronic myeloid leukemia (CML), and serial protein (IgG, IgA and IgM) quantification, electrophoresis and immunofixation were performed. Transient mono- or oligoclonal gammopathies were observed in 23 out of 29 patients between days 20 and 1,750 following transplantation. The presence of homogeneous immunoglobulins was not correlated with the following clinical parameters: graft-versus-host disease, bacterial sepsis, Epstein-Barr virus or cytomegalovirus infection or invasive fungal infection. Therefore, the development of mono- or oligoclonal immunoglobulins may represent a complex disorder of B cell regeneration which may be caused by an intrinsic B cell defect, or a failure in the regenerating T cell system, or both, manifesting itself in a restricted antibody diversity after allogeneic BMT.
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PMID:Homogeneous immunoglobulins following allogeneic bone marrow transplantation. 1271 21

Poor immune reconstitution after haploidentical stem cell transplantation results in a high mortality from viral infections and relapse. One approach to overcome this problem is to selectively deplete the graft of alloreactive cells using an immunotoxin directed against the activation marker CD25. However, the degree of depletion of alloreactive cells is variable following stimulation with recipient peripheral blood mononuclear cells (PBMCs), and this can result in graft versus host disease (GVHD). We have refined this approach using recipient Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs) as stimulators to activate donor alloreactive T cells. Our studies demonstrate that allodepletion with an anti-CD25 immunotoxin following stimulation with HLA-mismatched host LCLs more consistently depleted in vitro alloreactivity than stimulation with host PBMCs, as assessed in primary mixed lymphocyte reactions (MLRs). Allodepletion using this approach specifically abrogates cytotoxic T-cell responses against host LCLs. In interferon-gamma (IFN-gamma) enzyme-linked immunospot (ELISPOT) assays, antiviral responses to adenovirus and cytomegalovirus (CMV) were preserved following allodepletion. Likewise, using HLA-A2-pp65 tetramers, we have shown that the frequency of CMV-specific T cells is unaffected by allodepletion. Moreover, the donor anti-EBV response is partially retained by recognition of EBV antigens through the nonshared haplotype. Finally, we studied whether allodepletion affects the response to candidate tumor antigens in myeloid malignancies. Using HLA-A2-PR1 tetramer analysis, we found that the frequency of T cells recognizing the PR1 epitope of proteinase 3 was not significantly different in allodepleted and unmanipulated PBMCs from patients with chronic myeloid leukemia (CML) undergoing transplantation. Based on these data, we have embarked on a phase 1 clinical trial of addback of allo-LCL-depleted donor T cells in the haplo-identical setting.
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PMID:Selective depletion of donor alloreactive T cells without loss of antiviral or antileukemic responses. 1276 37


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