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)

Infusions of donor peripheral blood T cells can induce durable remissions of Epstein-Barr virus (EBV) lymphomas complicating marrow grafts, but they contain alloreactive T cells capable of inducing graft-versus-host disease. EBV-specific T-cell lines or clones avoid this problem but require 30 to 40 days of culture to establish. To accelerate the generation of EBV-specific T cells, we tested whether retroviral vectors, which only integrate in dividing cells, could be used to transduce and select antigen-reactive T cells early after sensitization to autologous EBV-transformed B cells. T cells were transduced with a dicistronic retroviral vector, NIT, which encodes low-affinity nerve growth factor receptor as an immunoselectable marker and herpes simplex virus thymidine kinase as a suicide gene, at different time points after sensitization. EBV-specific cytotoxic T lymphocyte precursor (CTLp) frequencies in purified NIT(+) T-cell fractions transduced on day 8 of culture were comparable to those of EBV-specific T-cell lines cultured for 30 days or more. Alloreactive CTLp frequencies were markedly reduced in the NIT(+) fraction relative to the untransduced T-cell population. NIT(+) fractions transduced on day 8 possessed more CD4(+) T cells than the cell lines at day 30 and exhibited the same selective pattern of reactivity against immunodominant antigens presented by specific HLA alleles. In contrast, T cells transduced with NIT 5 days after stimulation with mitogen and interleukin-2 were relatively depleted of T cells specific for autologous EBV-transformed cells. Thus, retroviral vectors may be used for rapid selection of viral antigen-reactive T cells depleted of alloreactive T cells.
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PMID:Rapid selection of antigen-specific T lymphocytes by retroviral transduction. 1089 38

Expansion of donor-derived lymphocytes after allogeneic stem cell transplantation is a serious and sometimes fatal complication. Lymphoproliferative disorders are reportedly caused mainly by reactivation of Epstein-Barr virus (EBV) and non-EBV-associated secondary lymphoma or leukemia. In this paper, we report massive proliferation of CD4+ lymphocytes in peripheral blood of a patient with chronic graft-versus-host disease (GVHD) following allogeneic bone marrow transplantation (alloBMT) from an HLA-identical sibling donor. The abnormal lymphocytes showed CD3low, CD4+, CD8-, CD2+, CD5+, CD7+, CD25-, CD19-, CD20-, CD21-, CD16-, CD56low, T-cell receptor (TCR)-alpha/beta- and TCR-gamma/delta- phenotypes, and no rearrangement of either TCR-C beta 1 or IG(H)JH was detected from the lymphocytes by Southern blot analysis. EBV was not found in the nuclei of lymphocytes by an immunofluorescence antibody. The lymphoproliferation was resistant against immunosuppressive drugs, administered for the treatment of chronic GVHD, and it effectively inhibited aggravation of the chronic GVHD. Although antithymocyte globulin and cytosine arabinoside were administered later, the patient died of respiratory failure with bilateral pleural effusion and interstitial pneumonia. Because we found no evidence of monoclonality of the abnormal lymphocytes, we could not conclude that this patient had suffered from malignant lymphoproliferation. To our knowledge, this is the first case report of proliferation of CD4+ lymphocytes in a patient with chronic GVHD following alloBMT. In this paper, we discuss the possible pathophysiology of the patient.
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PMID:Proliferation of CD4+ lymphocytes in a patient with chronic graft-versus-host disease after allogeneic bone marrow transplantation. 1090 61

Glucocorticoids remain the standard approach to initial systemic management of acute graft-versus-host disease (aGVHD). For patients refractory to steroids, antithymocyte globulin (ATG) is frequently used as salvage therapy. We decided to test whether the combination of corticosteroids and equine ATG would improve the outcome of initial management of aGVHD, especially in high-risk patients such as recipients of unrelated donor (URD) transplants. One hundred patients with grade II to IV aGVHD having undergone a related or URD marrow transplant were enrolled in the study. Of the patients, 46 were randomly assigned to therapy with prednisone (60 mg/m2 per day x 7 days) and 50 received ATG/prednisone (15 mg/kg ATG bid plus 20 mg/m2 prednisone bid x 5 days, each followed by an 8-week prednisone taper). An intent-to-treat analysis of the overall response at day 42 revealed equivalent complete plus partial response rates of 76% in both the prednisone and ATG/prednisone therapy groups (P > .80). In univariate analysis, patient age, donor type, site of involvement, or aGVHD stage did not influence overall response to therapy (all P > .2). When treatment arms were studied separately, no single clinical feature predicted outcome in either group. Complications were more frequent in the ATG/prednisone arm; patients experienced more infections with cytomegalovirus (44% versus 22%; P = .02) and more frequent pneumonitis, both infectious and noninfectious (50% versus 24%; P < .01). Epstein-Barr virus lymphoproliferative disease was uncommon (4 cases) and comparable in both arms (P = .35). There was no significant difference in survival at day 100, 6 months, and 2 years between the 2 treatment arms. The more intensive immunosuppressive combination of ATG/prednisone failed to improve control of aGVHD and may have affected survival by causing more infectious complications. Combination therapy with ATG should thus be reserved as second-line therapy in the management of aGVHD.
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PMID:A randomized trial comparing prednisone with antithymocyte globulin/prednisone as an initial systemic therapy for moderately severe acute graft-versus-host disease. 1097 13

Post-transplantation lymphoproliferative disorder is a well-documented complication of solid organ or bone marrow transplantation. Histologically, it is characterized by an abnormal proliferation of lymphocytes, which can range from benign B-cell hyperplasia to malignant lymphoma. Non-Hodgkin's lymphoma (NHL) is associated with several risk factors, such as congenital or acquired immunodeficiency states, autoimmune disorders, and infectious agents (eg, Epstein-Barr virus). Primary sites of presentation in the head and neck are Waldeyer's ring, paranasal sinuses, salivary glands, the oral cavity, and the larynx. Clinical appearance of gingival NHL varies but is usually found to be an asymptomatic gingival enlargement or mass resembling a pyogenic granuloma. We present a patient with a gingival ulceration that was subsequently diagnosed as Epstein-Barr virus malignant lymphoma resulting from the immunosuppression needed to prevent graft-versus-host disease after bone marrow transplantation.
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PMID:Unusual gingival presentation of post-transplantation lymphoproliferative disorder: a case report and review of the literature. 1102 79

Administration of donor T cells expressing the herpes simplex-thymidine kinase (HS-tk) with a hematopoietic stem cell (HSC) transplantation could allow, if graft-versus-host disease (GVHD) was to occur, a selective in vivo depletion of these T cells by the use of ganciclovir (GCV). The study evaluates the feasibility of such an approach. Escalating numbers of donor HS-tk-expressing CD3(+) gene-modified cells (GMCs) are infused with a T-cell-depleted bone marrow transplantation (BMT). Twelve patients with hematological malignancies received 2 x 10(5) (n = 5), 6 x 10(5) (n = 5), or 20 x 10(5) (n = 2) donor CD3(+) GMCs/kg with a BMT from a human leukocyte antigen (HLA)-identical sibling. No acute toxicity was associated with GMC administration. An early increase of circulating GMCs followed by a progressive decrease and long-lasting circulation of GMCs was documented. GCV treatment resulted in significant rapid decrease in circulating GMCs. Three patients developed acute GVHD, with a grade of at least II, while one patient developed chronic GVHD. Treatment with GCV alone was associated with a complete remission (CR) in 2 patients with acute GVHD, while the addition of glucocorticoids was necessary to achieve a CR in the last case. Long-lasting CR occurred with GCV treatment in the patient with chronic GVHD. Unfortunately, Epstein-Barr virus-lymphoproliferative disease occurred in 3 patients. Overall, the administration of low numbers of HS-tk-expressing T cells early following an HLA-identical BMT is associated with no acute toxicity, persistent circulation of the GMCs, and GCV-sensitive GVHD. Such findings open the way to the infusion of higher numbers of gene-modified donor T cells to enhance post-BMT immune competence while preserving GCV-sensitive alloreactivity.
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PMID:Administration of herpes simplex-thymidine kinase-expressing donor T cells with a T-cell-depleted allogeneic marrow graft. 1113 43

In contrast to solid organ transplantation (Tx), the incidence of post-transplant lymphoproliferative disease (PTLD) after hematopoietic stem cell Tx (HSCT) is generally low. This risk, however, is significantly elevated in patients receiving human leukocyte antigen (HLA) mis-matched or T-cell-depleted grafts, or after treatment for severe graft-versus-host disease (GvHD). An 18-yr-old patient with positive Epstein-Barr virus (EBV) serology received a fully matched, unmanipulated bone marrow graft from an unrelated EBV-positive donor for treatment of acute myeloid leukemia (AML) in second complete remission. GvHD prophylaxis was performed with cyclosporin A (CsA) and a short course of methotrexate. Four months after Tx, the patient developed ulcerative tonsillitis that was unresponsive to antibiotic treatment. Diarrhea appearing simultaneously was interpreted as gastrointestinal GvHD and steroids were added to CsA. A few days later the patient was admitted to hospital because of generalized seizure and pneumonia. Despite reduction of immunosuppression, intensification of anti-viral treatment, and subsequent mechanical ventilation, the patient died of acute respiratory distress 6 days later. Autopsy demonstrated disseminated EBV-induced, multi-nodular lymphoma infiltration of the entire colon but no signs of GvHD. Moreover, both lungs, paratracheal lymph nodes, kidneys, thyroid gland, and liver were infiltrated with large B-cell non-Hodgkin's lymphomas. This case underlines the rapid and aggressive course of EBV-induced disseminated PTLD after HSCT, initially mimicking intestinal GvHD because of massive colonic lymphoma infiltration. Tissue biopsies should be performed early for establishing correct diagnosis, thus enabling specific therapy, e.g. infusion of donor leukocytes with cytotoxic T-lymphocytes.
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PMID:Epstein-Barr virus-associated post-transplant lymphoproliferative disease after bone marrow transplantation mimicking graft-versus-host disease. 1127 9

We recently found that sperm protein 17 (Sp17), a spermatozoa-restricted protein, is aberrantly expressed on the tumor cells in patients with multiple myeloma (MM). It may therefore be possible to generate donor-derived Sp17-specific CTL for administration following allogeneic stem cell transplant to augment graft-versus-myeloma (GVM) effect without inducing a global GVHD. To assess this approach, we have produced recombinant Sp17 protein and used Sp17 protein-pulsed dendritic cells to generate HLA class I-restricted Sp17-specific CTL from a previously unimmunized healthy donor. These CTL were able to lyse autologous Epstein-Barr virus-transformed lymphoblastoid cells in a Sp17-dependent manner. Target lysis was HLA-A1 and HLA-B27 restricted. Cytotoxicity could be blocked by antibodies against monomorphic HLA class I, HLA-A1 and HLA-B27 molecules but not HLA class II molecules. Most importantly, the CTL lysed HLA class I-matched Sp17-positive tumor cells, suggesting that Sp17 is processed and presented in association with the HLA class I molecules in Sp17-positive tumor cells in a concentration and configuration that could be recognized by recombinant protein-primed CTL. Analysis by flow cytometry of the CTL indicated that they were predominantly CD8 in phenotype and they produced IFN-gamma and very little IL-4. Our results suggest the potential for the generation and administration of donor-derived Sp17-specific CTL to augment GVM without inducing GVHD following allogeneic stem cell transplant for MM.
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PMID:Sperm protein 17 (Sp17) in multiple myeloma: opportunity for myeloma-specific donor T cell infusion to enhance graft-versus-myeloma effect without increasing graft-versus-host disease risk. 1147 39

Reactivation of the Epstein-Barr virus (EBV) after allogeneic stem cell transplantation (allo-SCT) may evoke a protective cellular immune response or may be complicated by the development of EBV-lymphoproliferative disease (EBV-LPD). So far, very little is known about the incidence, recurrence, and sequelae of EBV reactivation following allo-SCT. EBV reactivation was retrospectively monitored in 85 EBV-seropositive recipients of a T-cell--depleted (TCD) allo-SCT and 65 EBV-seropositive recipients of an unmanipulated allo-SCT. Viral reactivation (more than 50 EBV genome equivalents [gEq]/mL) was monitored frequently by quantitative real-time plasma polymerase chain reaction until day 180 after SCT. Probabilities of developing viral reactivation were high after both unmanipulated and TCD-allogeneic SCT (31% +/- 6% versus 65% +/- 7%, respectively). A high CD34(+) cell number of the graft appeared as a novel significant predictor (P =.001) for EBV reactivation. Recurrent reactivation was observed more frequently in recipients of a TCD graft, and EBV-LPD occurred only after TCD-SCT. High-risk status, TCD, and use of antithymocyte globulin were predictive for developing EBV-LPD. Plasma EBV DNA quantitatively predicted EBV-LPD. The positive and negative predictive values of a viral load of 1000 gEq/mL were, respectively, 39% and 100% after TCD. Treatment-related mortality did not differ significantly between TCD and non-TCD transplants, but the incidence of chronic graft-versus-host disease was significantly less in TCD patients. It is concluded that EBV reactivation occurs frequently after TCD and unmanipulated allo-SCT, especially in recipients of grafts with high CD34(+) cell counts. EBV-LPD, however, occurred only after TCD, and EBV load quantitatively predicted EBV-LPD in recipients of a TCD graft. (Blood. 2001;98:972-978)
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PMID:Epstein-Barr virus (EBV) reactivation is a frequent event after allogeneic stem cell transplantation (SCT) and quantitatively predicts EBV-lymphoproliferative disease following T-cell--depleted SCT. 1149 41

Umbilical cord blood (UCB) is being increasingly used for transplantation, but the ability of neonatal T cells to regulate Epstein-Barr virus (EBV)-associated lymphoproliferation is unknown. Because UCB transplantation (UCBT) is associated with a relatively low infused dose of donor T cells, frequent donor-recipient HLA disparity, and use of antithymocyte globulin during conditioning, we hypothesized that the risk of EBV-associated posttransplantation lymphoproliferative disorders (EVB-PTLD) after UCBT may be increased. To investigate the incidence of EBV-PTLD after UCBT, we analyzed 272 unrelated-donor UCBTs performed from August 1993 to December 1999 at Duke University Medical Center and the University of Minnesota. Five cases of EBV-PTLD were identified, with a cumulative incidence of 2% (95% confidence interval, 0.3%-3.7%) at 2 years. EBV-PTLD affected UCB recipients aged 1 to 49 years (median, 8 years), with 4 patients undergoing transplantation for leukemia and 1 for immunodeficiency. Patients received UCB grafts that were HLA matched (n = 1) or mismatched at 1 (n = 1) or 2 (n = 3) HLA loci. Diagnoses occurred at 4 to 14 months (median, 6 months) after UCBT, with 4 of 5 patients having preceding grade II to IV acute graft-versus-host disease and 1 being diagnosed at autopsy. Treatment of 4 patients consisted of withdrawal of immunosuppressive treatment and administration of rituximab, with 2 of 4 patients responding. Thus, the incidence of EBV-PTLD after unrelated-donor UCBT appears similar to that observed after transplantation using unrelated bone marrow (BM) and compares favorably with unrelated-donor T-cell-depleted BM transplantation. Because adoptive immunotherapy with donor lymphocytes is not an available option for recipients of unrelated-donor UCBT, new therapeutic strategies are needed, and rituximab appears promising.
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PMID:Low incidence of Epstein-Barr virus-associated posttransplantation lymphoproliferative disorders in 272 unrelated-donor umbilical cord blood transplant recipients. 1152 90

We encountered 2 patients with pneumococcal arthritis following bone marrow transplantation (BMT). Both patients received grafts from unrelated human lymphocyte antigen (HLA)-matched donors and had suffered from chronic graft-versus-host disease (GVHD). One, a 10-year-old boy, suffered from Epstein-Barr virus-related lymphoproliferative disease (EB-LPD) and received oral 6-mercaptopurine and methotrexate to manage lymphadenopathy. Twenty-four months after BMT and 7 months after the onset of EB-LPD, pneumococcal arthritis occurred in both knee joints. The other patient, a 10-year-old girl, received multiagent immunosuppressive therapy for her chronic GVHD. At 51 months following BMT, pneumococcal arthritis occurred in her left knee joint. Chronic GVHD of the skin delayed the recovery from the arthritis in both patients. This complication is quite rare but can be very serious, in regard to the patient's performance status following BMT. Although vaccination against pneumococcus or preventive antibiotics should be administered to high-risk patients, early diagnosis and treatment may be the best strategy for pneumococcal arthritis.
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PMID:Pneumococcal arthritis affects performance status in patients with chronic GVHD of the skin following allogeneic bone marrow transplantation. 1153 Aug 13


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