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Posttransplant Lymphoproliferative Disorders: Studies of Epstein-Barr Virus, Regulatory T Cells and Tumor Origin
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Epstein-Barr virus (EBV) infects almost all humans and establishes lifelong latency in B cells. Posttransplant lymphoproliferative disorder (PTLD) is a rare but serious complication after transplantation triggered by immunosuppression and often related to EBV infection. The aim of this thesis was to study the role of EBV in relation to clinical and histological features of PTLD, regulatory T cells (Tregs), and donor or recipient origin of PTLD.

EBV surveillance after allogeneic hematopoietic stem cell transplantation (allo-HSCT) showed that EBV reactivations were common, but that symptomatic EBV disease (including PTLD) only occurred in the high-risk group (unrelated or mismatched related grafts, reduced-intensity conditioning). A threshold of 1000 copies/ml plasma distinguished EBV disease from asymptomatic reactivations.

In a population-based cohort of 135 PTLDs/lymphomas after solid organ transplantation (SOT) almost half were EBV. EBV+ PTLDs were associated with B cell phenotype, non-germinal center subtype of diffuse large B cell lymphoma (DLBCL), early-onset, graft involvement, antithymocyte globulin treatment, and younger age. EBV PTLDs were associated with T cell phenotype, bone marrow involvement, and hepatitis C. Most PTLDs displayed few or no intratumoral Tregs with the marker FoxP3, possibly due to heavy immuno­suppres­sion. Half of both FoxP3+ and FoxP3PTLDs were EBV+. FoxP3+ PTLDs were associated with B cell phenotype and hepatitis C. All PTLDs for which tumor origin could be determined were recipient-derived and half of them were EBV+. Eight of twelve recipient-derived graft PTLDs were disseminated outside the graft. T cell PTLD and hepatitis C were independently associated with inferior overall survival, whereas subtype of DLBCL, FoxP3-expression, and EBV-status did not influence survival.

In conclusion, monitoring of EBV DNAemia in high-risk patients after allo-HSCT and pre-emptive therapy is valuable for prevention of PTLD. Use of anti­thymocyte globulin increases the risk for EBV+ PTLDs after allo-HSCT and SOT. With long follow-up time, a large proportion of PLTDs after SOT are EBVwith a different clinical presentation. Tregs are rare in PTLD and do not affect survival. The vast majority of PTLDs after SOT is of recipient origin. Graft PTLDs are more likely recipient-derived if disseminated. EBV-status is not associated with intratumoral Tregs or PTLD of recipient origin.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. , 107 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1043
Keyword [en]
PTLD, Lymphoma, Epstein-Barr Virus, EBV DNAemia, FoxP3, Treg, Microenvironment, Cell of Origin, Recipient, Transplantation, Immunosuppression, Hepatitis C, Survival
National Category
Cancer and Oncology Infectious Medicine
Research subject
Medical Science
Identifiers
URN: urn:nbn:se:uu:diva-234130ISBN: 978-91-554-9074-4 (print)OAI: oai:DiVA.org:uu-234130DiVA: diva2:755507
Public defence
2014-11-29, Auditorium Minus, Gustavianum, Akademigatan 3, Uppsala, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2014-11-05 Created: 2014-10-14 Last updated: 2015-02-03
List of papers
1. Post-transplant lymphoproliferative disease and other Epstein-Barr virus diseases in allogeneic haematopoietic stem cell transplantation after introduction of monitoring of viral load by polymerase chain reaction
Open this publication in new window or tab >>Post-transplant lymphoproliferative disease and other Epstein-Barr virus diseases in allogeneic haematopoietic stem cell transplantation after introduction of monitoring of viral load by polymerase chain reaction
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2007 (English)In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 39, no 3, 235-244 p.Article in journal (Refereed) Published
Abstract [en]

The clinical value of monitoring of Epstein-Barr virus (EBV) viraemia by quantitative polymerase chain reaction during 1 y was evaluated. 39 recipients of allogeneic hematopoietic stem cell transplantation (SCT) were followed. More than 100 EBV genome equivalents (gEq)/ml in blood or plasma were found in 16/39 patients (41%) at 34 d (range 1-139) post-transplant. Seven of these 16 patients developed EBV disease; 3 post-transplant lymphoproliferative disease (PTLD), 1 myelitis, 1 encephalitis and 2 reactivations with fever. EBV diseases were only found in the high-risk group among recipients of mismatched related or unrelated donor grafts or in patients who underwent reduced-intensity conditioning. In this group, 3/20 (15%) developed PTLD. Conditioning with antithymocyte globulin was significantly associated with EBV disease (p<0.01). EBV load in plasma was more strongly associated with EBV disease than viral load in blood. A cut-off level of 1000 gEq/ml plasma distinguished EBV disease from asymptomatic viraemia, but not PTLD from other EBV diseases. Weekly monitoring of EBV load in plasma in high-risk patients in the first 3 months following SCT seems to be of value for prediction of EBV disease. Therapy for PTLD including rituximab was evaluated during 2 y and showed response in 4/6 cases.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-14286 (URN)10.1080/00365540600978906 (DOI)000245235300008 ()17366054 (PubMedID)
Available from: 2008-06-03 Created: 2008-06-03 Last updated: 2017-12-11Bibliographically approved
2. A population-based study of 135 lymphomas after solid organ transplantation: The role of Epstein-Barr virus, hepatitis C and diffuse large B-cell lymphoma subtype in clinical presentation and survival.
Open this publication in new window or tab >>A population-based study of 135 lymphomas after solid organ transplantation: The role of Epstein-Barr virus, hepatitis C and diffuse large B-cell lymphoma subtype in clinical presentation and survival.
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2014 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 53, no 5, 669-679 p.Article in journal (Refereed) Published
Abstract [en]

Background. Epstein-Barr virus (EBV) plays a major role in the development of post-transplant lymphoproliferative disorder (PTLD), but there is an increasing awareness of EBV-negative PTLD. The clinical presentation of EBV-negative PTLD has not been as well characterised as EBV-positive cases. Further, there is limited knowledge on the clinical importance of diffuse large B-cell lymphoma (DLBCL) cell of origin subtype post-transplant. Materials and methods. We studied the role of EBV, hepatitis C (HCV) and DLBCL subtype in clinical presentation and survival in 135 post-transplant lymphomas diagnosed 1980-2006 in a population-based cohort of 10 010 Swedish solid organ transplant recipients. The lymphomas were re-evaluated according to WHO 2008, examined for EBV, and clinical data were collected from medical records. Results. Lymphoma incidence rate was 159/100 000 person-years and is also reported by lymphoma subtype. EBV-negative lymphomas constituted 48% and were associated with HCV infection (p = 0.02), bone marrow involvement (p < 0.001), and T-cell phenotype (p = 0.002). Among DLBCL, 78% were of non-germinal centre subtype, which was associated with EBV-positivity (69%, p = 0.001), early occurrence (p = 0.03), heart/liver/lung/pancreas recipients (p = 0.02), anti-T-cell globulin (p = 0.001), and tacrolimus treatment (p = 0.02). DLBCL subtypes had similar overall survival. Five-year overall survival was 42% in all treated patients. Independent poor prognostic factors were older age, B symptoms, ECOG 2-4, kidney/pancreas/heart recipients, T-cell lymphoma, and HCV-infection. Conclusions. With long follow-up, a large part of PTLD is EBV-negative, due to a high proportion of T-cell lymphomas and low of polymorphic PTLD. EBV-negative PTLD have a different clinical presentation. HCV may play an aetiological role in late-onset PTLD and was revealed as a new prognostic factor for inferior survival that needs to be confirmed in larger studies. The heavier immunosuppression in non-kidney transplantations seems to play a role in the development of non-germinal centre DLBCL. DLBCL cell of origin subtype lacks prognostic importance in the transplant setting.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-214933 (URN)10.3109/0284186X.2013.844853 (DOI)000334740000013 ()24164103 (PubMedID)
Available from: 2014-01-09 Created: 2014-01-09 Last updated: 2017-12-06Bibliographically approved
3. Expression of Intratumoral Forkhead Box Protein 3 in Posttransplant Lymphoproliferative Disorders: Clinical Features and Survival Outcomes
Open this publication in new window or tab >>Expression of Intratumoral Forkhead Box Protein 3 in Posttransplant Lymphoproliferative Disorders: Clinical Features and Survival Outcomes
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2015 (English)In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 99, no 5, 1036-1042 p.Article in journal (Refereed) Published
Abstract [en]

Background. The infiltration of regulatory T cells (Tregs) in lymphomas is associated with better prognosis for some types of lymphomas, but knowledge of their role in posttransplant lymphoproliferative disorders (PTLDs) is limited. We therefore investigated the association between the expression of the Treg marker forkhead box protein 3 (FoxP3) in biopsies of PTLDs and survival, PTLD subtype, and clinical characteristics.

Methods. Seventy-four cases of PTLD after solid organ transplantation with sufficient material for further analysis were included from a population-based study of PTLDs in Sweden. The PTLD biopsies were reevaluated and stained with the 236A/E7 antibody to detect FoxP3 in lymphoma tissue. Detailed clinical data were collected retrospectively from medical records.

Results. Based on a cutoff level of 29 FoxP3+ cells per mm2, most (80%) of the PTLDs were FoxP3-. Forty-seven of 74 PTLDs displayed no FoxP3+ cells at all. The frequency of FoxP3+ cells did not influence median overall survival. The FoxP3- PTLDs were more frequently of T-cell phenotype (P=0.04), located at the graft (P=0.03), occurred earlier after transplantation (P=0.04), were more likely to develop in lung recipients (P=0.04), and in patients that had received anti T-cell globulin as induction therapy (P=0.02). The FoxP3+ PTLDs were associated with hepatitis C seropositivity (P=0.03). In multivariate analysis, B-cell PTLD and hepatitis C infection were independent predictors of FoxP3 positivity.

Conclusion. Our findings suggest that intratumoral FoxP3+ Tregs do not influence survival in patients with PTLD. FoxP3+ Tregs are rare in PTLD, possibly because of heavy immunosuppression.

Place, publisher, year, edition, pages
Lippincott Williams & Wilkins, 2015
Keyword
Regulatory T cell, FoxP3, Posttransplant lymphoproliferative disorders, lymphoma, microenvironment, survival, clinical features, hepatitis C, Treg, immunosuppression, antithymocyte globulin
National Category
Cancer and Oncology
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-234073 (URN)10.1097/TP.0000000000000415 (DOI)000353962700030 ()25211518 (PubMedID)
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2014-10-14 Created: 2014-10-14 Last updated: 2017-12-05Bibliographically approved
4. Donor or Recipient Origin of Posttransplant Lymphoproliferative Disorders Following Solid Organ Transplantation
Open this publication in new window or tab >>Donor or Recipient Origin of Posttransplant Lymphoproliferative Disorders Following Solid Organ Transplantation
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2014 (English)In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 14, no 12, 2838-2845 p.Article in journal (Refereed) Published
Abstract [en]

Previous studies of donor or recipient origin of posttransplant lymphoproliferative disorders (PTLDs) following solid organ transplantation (SOT) have either been small or with selected patient groups. We studied tumor origin in a population-based cohort of 93 patients with PTLD following SOT. Tumor origin of PTLD tissue was analyzed by fluorescence in situ hybridization of the sex chromosomes in cases of sex mismatch between donor and recipient (n=41), or HLA genotyping in cases of identical sex but different HLA type (n=52). Tumor origin of PTLD could be determined in 67 of the 93 cases. All 67 PTLDs were of recipient origin. They were found in recipients of kidney (n=38), liver (n=12), heart (n=10) and lung (n=7). The most common recipient-derived lymphomas were monomorphic B-cell PTLDs (n=45), monomorphic T cell PTLDs (n=9), indolent lymphomas (n=6), and polymorphic PTLD (n=4). Half of the recipient-derived PTLDs were Epstein–Barr virus-positive. Twelve of the recipient-derived PTLDs were located in the grafts: in four cases exclusively and in eight cases in combination with disseminated disease outside the graft. Tumor origin was indeterminable in 26 cases, probably due to low DNA quality. We conclude that the vast majority of PTLDs after SOT was of recipient origin.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2014
Keyword
Posttransplant lymphoproliferative disorders, PTLD, Cell of origin, Donor, Recipient, Solid Organ Transplantation, Graft, Loss of Y chromosome, fluorescence in situ hybridization, HLA typing, Epstein-Barr virus
National Category
Cancer and Oncology
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-234076 (URN)10.1111/ajt.12990 (DOI)000345294300022 ()25307322 (PubMedID)
Available from: 2014-10-14 Created: 2014-10-14 Last updated: 2017-12-05Bibliographically approved

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