Posttransplant lymphoproliferative disorder associated with an Epstein-Barr-related virus in cynomolgus monkeys.
BACKGROUND
Human posttransplant lymphoproliferative disorder (PTLD) has been shown to be associated with Epstein-Barr virus (EBV) infection. Primate animal models of PTLD and the use of molecular markers in its diagnosis have not been reported. This study was designed to evaluate the frequency, pathology, and molecular characteristics of PTLD in cynomolgus kidney allograft recipients.


METHODS
Over a 5-year period (January 1995 to November 2000), 160 primate renal transplants were performed at the Massachusetts General Hospital (MGH). Of these, all cases (n=9) that developed PTLD were included. H&E stained paraffin sections of all available tissue samples from the cases were evaluated for the presence of PTLD. Immunoperoxidase staining for T cells (CD3), B cells (CD20), kappa and lambda light chains as well as EBV nuclear antigens (EBNA2) and latent membrane proteins (EBV LMP-1) was done on paraffin sections using standard immunohistochemical (IHC) methods. In situ hybridization for EBV encoded RNA (EBER) was performed in all tissue samples with atypical lymphoid proliferations, using a novel EBER nucleotide probe based on consensus gene sequences from EBV and the related herpes lymphocryptoviruses (LCV) infecting baboons and rhesus macaques.


RESULTS
Of 160 consecutive primate renal transplants performed at MGH, 5.6% developed PTLD 28-103 days after transplantation. In all cases, the lymph nodes were involved and effaced by an atypical polymorphous lymphoid proliferation of EBER+ B cells, diagnostic for PTLD. Focal staining for EBNA-2 was noted in tumor cells. In 67% (six of nine) the PTLD infiltrates were present in extra nodal sites, notably liver (56%), lung (44%), heart (44%), renal allograft (44%), and native kidney (22%). The spleen was involved by PTLD in all four animals that had not undergone a pretransplant splenectomy. The PTLD morphology was similar in all cases and predominantly of the polymorphous type, however, some of these showed areas that appeared minimally polymorphous. No cases of monomorphic PTLD were seen.


CONCLUSIONS
By in situ hybridization, expression of the RNA product, homologous for EBV-encoded RNA (EBER) was identified in the PTLD tumor cells of all cases, indicating latent primate EBV- related infection. This report identifies a novel animal model of EBV associated PTLD in the setting of kidney transplantation, with valuable implications for managing and understanding human PTLD and oncogenesis.
Schmidtko
Jan
J
Department of Pathology and Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, USA.
Wang
Ruojie
R
Wu
Chin-Lee
CL
Mauiyyedi
Shamila
S
Harris
Nancy L
NL
Della Pelle
Patricia
P
Brousaides
Nicole
N
Zagachin
Luba
L
Ferry
Judith A
JA
Wang
Fred
F
Kawai
Tatsuo
T
Sachs
David H
DH
Cosimi
Benedict A
BA
Colvin
Robert B
RB
D000818:Animals; D020031:Epstein-Barr Virus Infections / Q000150:complications*; D005500:Follow-Up Studies; D004854:Herpesvirus 4, Human / Q000235:genetics; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D016030:Kidney Transplantation / Q000009:adverse effects*; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D008232:Lymphoproliferative Disorders / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology / Q000821:virology*; D008252:Macaca fascicularis; D015138:RNA, Nuclear / Q000032:analysis; D012367:RNA, Viral / Q000032:analysis
D015138:RNA, Nuclear; D012367:RNA, Viral