The Clinical Spectrum, Pathology, and Clonal Analysis of Epstein-Barr Virus–Associated Lymphoproliferative Disorders in Heart–Lung Transplant Recipients

Randhawa, Parmjeet; Yousem, Samuel A.; Paradis, Irwin L.; Dauber, James A.; Griffith, Bartley P.; Locker, Joseph

doi:10.1093/ajcp/92.2.177

Cited by 129 publications

(31 citation statements)

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“…Posttransplantation lymphoproliferative disorder (PTLD) is a potentially lethal complication of immunosuppression in solid organ transplant (SOT) and bone marrow transplant (BMT) recipients, [1][2][3] mostly associated with the proliferation of Epstein-Barr virus (EBV)-infected B cells whose expansion in immunocompetent individuals is controlled by cytotoxic T lymphocytes (CTLs). 4 There is ample evidence that an adoptive immunotherapy approach with transfer of lymphocytes or EBV-specific CTLs of donor origin is effective as prophylaxis and/or treatment of EBV-related PTLD in recipients of T-cell-depleted BMT [5][6][7][8] ; data have shown that anti-CD20 monoclonal antibody can be an equally useful therapeutic strategy when donor-derived EBV CTLs are not available.…”

Section: Introductionmentioning

confidence: 99%

Infusion of autologous Epstein-Barr virus (EBV)–specific cytotoxic T cells for prevention of EBV-related lymphoproliferative disorder in solid organ transplant recipients with evidence of active virus replication

Comoli

Labirio

Basso

et al. 2002

Blood

233

159

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Epstein-Barr virus (EBV)-associated posttransplantation lymphoproliferative disorders (PTLDs) are a well-recognized complication of immunosuppression in solid organ transplant recipients. The reported therapeutic approaches are frequently complicated by rejection, toxicity, and other infectious pathologies, and overall mortality in patients with unresponsive PTLD remains high. Thus, low-toxicity treatment options or, preferably, some form of prophylactic/preemptive intervention are warranted to improve PTLD outcome in this setting. We assessed whether transfer of EBV-specific cytotoxic T lymphocytes (CTLs) generated in vitro from the peripheral blood of allograft recipients receiving immunosuppression could increase EBV-specific killing in vivo without augmenting the probability of graft rejection. Autologous EBV-specific CTLs were generated for 23 patients who were identified as being at risk of developing PTLD through the finding of elevated EBV DNA load. Of the 23 patients, 7 received 1 to 5 infusions of EBV-specific CTLs. CTL transfer was well tolerated, and none of the patients showed any evidence of rejection. An increase of the EBV-specific cytotoxicity was observed after infusion, notwithstanding continuation of immunosuppressive therapy. EBV DNA levels had a 1.5-to 3-log decrease in 5 patients, whereas in the other 2 graft recipients CTL transfer had no apparent stable effect on EBV load. Our data suggest that the infusion of autologous EBVspecific CTLs obtained from peripheral blood mononuclear cells recovered at the time of viral reactivation is able to augment virus-specific immune response and to reduce viral load in organ transplant recipients. This approach may, therefore, be safely used as prophylaxis of EBV-related lymphoproliferative disorders in these patients, following a strategy of preemptive therapy guided by EBV DNA levels. (Blood. 2002;99: 2592-2598

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Section: Introductionmentioning

confidence: 99%

Infusion of autologous Epstein-Barr virus (EBV)–specific cytotoxic T cells for prevention of EBV-related lymphoproliferative disorder in solid organ transplant recipients with evidence of active virus replication

Comoli

Labirio

Basso

et al. 2002

Blood

233

159

View full text Add to dashboard Cite

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“…1,[3][4][5][6] These tumors frequently involve extranodal sites and generally regress with reduction or withdrawal of immunosuppressive therapy, but some of them progress independently from the restoration of the immune system. It has been hypothesized that PT-LPDs arise from a polyclonal expansion of Epstein-Barr virus (EBV)-infected B cells and can evolve into a lymphoid tumor with the emergence of an oligoclonal or monoclonal dominant population.…”

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confidence: 99%

Expression of p16/INK4a in Posttransplantation Lymphoproliferative Disorders

Martin

Baran-Marzak²,

Mansouri³

et al. 2000

The American Journal of Pathology

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It was recently demonstrated that classification of posttransplantation lymphoproliferative disorders (PT-LPDs) into morphological and molecular categories is clinically relevant. It was also reported that PT-LPD not associated with Epstein-Barr virus (EBV) had a more aggressive course than most lesions associated with EBV. Because the cyclin-dependent kinase inhibitor p16/INK4a has been reported to be frequently inactivated in high-grade lymphomas, we evaluated 17 PT-LPD to determine whether p16/ INK4a expression could be correlated to morphology, EBV detection, and a Ki-67 labeling index. We demonstrated that tumors with no p16/INK4a expression (n ‫؍‬ 8) had a predominantly monomorphic appearance, and most were EBV negative (respectively, 7/8 and 5/8), whereas lesions with p16/INK4a expression (n ‫؍‬ 9) were mostly polymorphic PT-LPD (6/9) (P ‫؍‬ 0.049) and associated with EBV (9/9) (P ‫؍‬ 0.015). In particular, strong p16/INK4a expression was observed in atypical immunoblasts and ReedSternberg-like cells. Furthermore, the proliferation index was significantly higher in tumors lacking p16/ INK4a expression than in other lesions (P ‫؍‬ 0.0008). Lymphoproliferative disorders (LPDs) are a major cause of morbidity in organ transplant recipients receiving immunosuppression, 1,2 varying between 1 and 12% of the graftees, for the most part according to the dose and duration of immunosuppressive therapy and the organ transplanted. 1,3-6 These tumors frequently involve extranodal sites and generally regress with reduction or withdrawal of immunosuppressive therapy, but some of them progress independently from the restoration of the immune system. It has been hypothesized that PT-LPDs arise from a polyclonal expansion of Epstein-Barr virus (EBV)-infected B cells and can evolve into a lymphoid tumor with the emergence of an oligoclonal or monoclonal dominant population. 7 PT-LPDs are usually classified into two subgroups, according to their appearance: polymorphic and monomorphic. 3 The latter closely resembles the diffuse large B-cell lymphoma (DLCL) of the Revised European American Lymphoma (REAL) classification. 8 Based on morphological and molecular analysis, Knowles et al 7 distinguished three main subgroups: 1) plasmacytic hyperplasia, 2) polymorphic B-cell hyperplasia and polymorphic B-cell lymphomas, and 3) malignant lymphoma or multiple myeloma, with the latter group being more frequently associated with genetic alterations, such as the inactivation of tumor suppressor gene p53 and the activation of c-myc and N-ras oncogenes. Moreover, Chadburn et al 9 recently showed the clinical relevance of this classification, as no response to aggressive clinical intervention was more frequently seen in patients with the lesions from the last group than those with the other tumors. Some patients with PT-LPDs that are not associated with EBV have a shorter survival time than those with EBV-positive lesions. 10 Expansion of B cells after organ transplantation should involve an excessive activation of the cell cycle, as in man...

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“…Integration of EBV into B-lymphocytes might result in some risk for the development of lymphoproliferative disorders later in life. EBV-associated diffuse lymphoid proliferations have been observed to occur in the lungs of patients treated with immunosuppressive therapy after organ transplantation [24,25]. Patients with various types of immunodeficiency are at increased risk for the development of potentially fatal EBV-related lymphoproliferative diseases, B lymphomas, and severe atypical EBV infections; most notably, this includes male children with the x-linked lymphoproliferative syndrome [26].…”

Section: Discussionmentioning

confidence: 99%

Chronic interstitial lung disease due to Epstein-Barr virus infection in two infants

Pfleger¹,

Eber²,

Popper³

et al. 2000

Eur Respir J

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This case study reports on two infants, 5 and 6 months of age, respectively, with chronic interstitial lung disease who presented with failure to thrive, tachypnoea, rales and mild hypoxaemia.Epstein-Barr virus (EBV) was detected by in situ hybridization in lung biopsy specimens and by EBV-deoxyribonucleic acid-polymerase chain reaction (PCR) in bronchoalveolar lavage (BAL) fluid in one patient and by in situ hybridization and PCR analysis in BAL fluid in the second patient. There was serological evidence of immunoglobulin G antibodies to EBV capsid antigen by indirect immunofluorescence in both patients.After 7 months of respiratory symptoms one patient was successfully treated with a 10 day course of intravenous ganciclovir followed by oral acyclovir for 20 days. The other patient became symptom free after 3.5 months of respiratory symptoms, without any specific antiviral medication. During a follow-up of 2 and 1.5 yrs, respectively, both infants remained symptom free and showed normal physical development. Eur Respir J 2000; 15: 803±806.

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The Clinical Spectrum, Pathology, and Clonal Analysis of Epstein-Barr Virus–Associated Lymphoproliferative Disorders in Heart–Lung Transplant Recipients

Cited by 129 publications

References 0 publications

Infusion of autologous Epstein-Barr virus (EBV)–specific cytotoxic T cells for prevention of EBV-related lymphoproliferative disorder in solid organ transplant recipients with evidence of active virus replication

Infusion of autologous Epstein-Barr virus (EBV)–specific cytotoxic T cells for prevention of EBV-related lymphoproliferative disorder in solid organ transplant recipients with evidence of active virus replication

Expression of p16/INK4a in Posttransplantation Lymphoproliferative Disorders

Chronic interstitial lung disease due to Epstein-Barr virus infection in two infants

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