Posttransplant Lymphoproliferative Disorders in Neuronal Xenotransplanted Macaques

Abstract

Posttransplant lymphoproliferative disorders (PTLDs) are a heterogeneous group of lymphoid proliferations that occur in the setting of depressed T-cell function due to immunosuppressive therapy used following solid organ transplantation, hematopoietic stem cell transplantation, and also xenotransplantation. In the present study, 28 immunosuppressed parkinsonian Macaca fascicularis were intracerebrally injected with wild-type or CTLA4-Ig transgenic porcine xenografts to identify a suitable strategy to enable long-term cell survival, maturation, and differentiation. Nine of 28 (32%) immunosuppressed primates developed masses compatible with PTLD, located mainly in the gastrointestinal tract and/or nasal cavity. The masses were classified as monomorphic PTLD according to the World Health Organization classification. Immunohistochemistry and polymerase chain reaction (PCR) analyses revealed that the PTLDs were associated with macaca lymphocryptovirus as confirmed by double-labeling immunohistochemistry for CD20 and Epstein-Barr nuclear antigen 2 (EBNA-2), where the viral protein was located within the CD20+ neoplastic B cells. In sera from 3 distinct phases of the experimental life of the primates, testing by quantitative PCR revealed a progression of the viral load that paralleled the PTLD progression and no evidence of zoonotic transmission of porcine lymphotropic herpesvirus through xenoneuronal grafts. These data suggest that monitoring the variation of macaca lymphocryptovirus DNA in primates could be used as a possible early diagnostic tool for PTLD progression, allowing preemptive treatment such as immunosuppression therapy reduction.

Experimental co-transmission of Simian Immunodeficiency Virus (SIV) and the macaque homologs of the Kaposi Sarcoma-Associated Herpesvirus (KSHV) and Epstein-Barr Virus (EBV)

“…Previously, cyclosporine has been used to immunosuppress macaques, resulting in a high incidence of lymphomas and post-transplant lymphoproliferative disorders associated with macaque homologs of EBV [ 54 , 69 – 71 ]. To examine the effect of immunosuppression on the RFHVMf and MfaLCV infections, M04203 was treated daily from weeks 26–29 with cyclosporine A intramuscularly at 15 Mgs/Kg ( Fig 3B ).…”

First Successful Delivery after Uterus Transplantation in MHC-Defined Cynomolgus Macaques

“…The incidence of PTLD appears to be tissue specific, with rates as high as 20% in recipients of small intestine transplants, 10% in lung transplants, and 1–6% for heart, liver, and kidney transplants [ 35 ]. The different levels of PTLD that have been reported in cynomolgus macaques are as follows: 9 of 160 (5.6%) in a renal transplantation model [ 36 ]; 9 of 28 (32%) in neuronal xenotransplantation model [ 37 ]; and 5 of 10 (50%) in a composite facia allografts model [ 38 ]. Herein, a high frequency of PTLD was observed in immunosuppressed macaques following UTx; 2 of 5 (40%, case 6 is excluded) in the present study and 1 of 4 (25%) in the previous study.…”

Update on cellular encapsulation

“…49 Nevertheless, immunosuppressive agents are not always well tolerated and lead to a host of deleterious side effects, especially in children. [51][52][53][54] For example, although anti-CD154 monoclonal antibodies have been effective in animal models, they lead to thromboembolic complications and therefore their clinical utility in humans is limited. [45][46][47][55][56][57] Thus, to make cell-based replacement therapies available to the greatest number of patients possible, the need for immunosuppression should be minimized.…”

“…In combination with genetic modifications, recent success has been achieved with an immunosuppressed pig‐to‐non‐human primate heterotropic heart transplant which survived for over 900 days . Nevertheless, immunosuppressive agents are not always well tolerated and lead to a host of deleterious side effects, especially in children . For example, although anti‐CD154 monoclonal antibodies have been effective in animal models, they lead to thromboembolic complications and therefore their clinical utility in humans is limited .…”