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Donor or Recipient Origin of Posttransplant Lymphoproliferative Disorders Following Solid Organ Transplantation
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
Vise andre og tillknytning
2014 (engelsk)Inngår i: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 14, nr 12, s. 2838-2845Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
Wiley-Blackwell, 2014. Vol. 14, nr 12, s. 2838-2845
Emneord [en]
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
HSV kategori
Forskningsprogram
Medicinsk vetenskap
Identifikatorer
URN: urn:nbn:se:uu:diva-234076DOI: 10.1111/ajt.12990ISI: 000345294300022PubMedID: 25307322OAI: oai:DiVA.org:uu-234076DiVA, id: diva2:755451
Tilgjengelig fra: 2014-10-14 Laget: 2014-10-14 Sist oppdatert: 2017-12-05bibliografisk kontrollert
Inngår i avhandling
1. Posttransplant Lymphoproliferative Disorders: Studies of Epstein-Barr Virus, Regulatory T Cells and Tumor Origin
Åpne denne publikasjonen i ny fane eller vindu >>Posttransplant Lymphoproliferative Disorders: Studies of Epstein-Barr Virus, Regulatory T Cells and Tumor Origin
2014 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2014. s. 107
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1043
Emneord
PTLD, Lymphoma, Epstein-Barr Virus, EBV DNAemia, FoxP3, Treg, Microenvironment, Cell of Origin, Recipient, Transplantation, Immunosuppression, Hepatitis C, Survival
HSV kategori
Forskningsprogram
Medicinsk vetenskap
Identifikatorer
urn:nbn:se:uu:diva-234130 (URN)978-91-554-9074-4 (ISBN)
Disputas
2014-11-29, Auditorium Minus, Gustavianum, Akademigatan 3, Uppsala, 09:00 (svensk)
Opponent
Veileder
Tilgjengelig fra: 2014-11-05 Laget: 2014-10-14 Sist oppdatert: 2015-02-03

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