Post-transplant lymphoproliferative disorder associated with immunosuppressive therapy for renal transplantation in rhesus macaques (Macaca mulatta)

Abstract

Human post-transplant lymphoproliferative disorder (PTLD) is an abnormal lymphoid proliferation that arises in 1–12% of transplant recipients as a consequence of prolonged immunosuppression and Epstein–Barr viral infection (EBV). Nonhuman primates, primarily rhesus macaques (Macaca mulatta), have been used extensively in research models of solid organ transplantation, as the nonhuman primate immune system closely resembles that of the human. Lymphocryptovirus of rhesus monkeys has been characterized and shown to be very similar to EBV in humans in regards to its cellular tropism, host immune response, and ability to stimulate B lymphocyte proliferation and lymphomagenesis. Thus, it appears that the NHP may be an appropriate animal model for EBV-associated lymphoma development in humans. The clinical management of post-transplant nonhuman primates that are receiving multiple immunosuppressive agents can be complicated by the risk of PTLD and other opportunistic infections. We report 3 cases of PTLD in rhesus macaques that illustrate this risk potential in the setting of potent immunosuppressive therapies for solid organ transplantation.

Animal Models for Gammaherpesvirus Infections: Recent Development in the Analysis of Virus-Induced Pathogenesis

“…The development of NHP models of organ transplantation concurrently provided NHP models for EBV-associated post-transplant lymphoproliferative disorder (PTLD). A fraction of old-world NHPs that were treated with immunosuppressive drugs and received allogeneic grafts were found to develop LPDs that harbored their inherent LCVs [28,37,38]. Schmidtko and others reported that among 160 consecutive renal transplant recipients of cynomolgus monkeys (Macaca fascicularis), 5.6% developed lymphoproliferative lesions similar to human PTLD in incidence, morphology, and immunophenotype [37].…”

Nonhuman Primates

“…Coinfections with rhesus LCV (Macacine herpesvirus 4) and SIV in macaques have been associated with malignant B cell lymphomas and oral lesions resembling hairy leukoplakia (Feichtinger et al, 1992;Baskin et al, 1995). A posttransplantation lymphoproliferative disorder has been described in cynomolgus macaques following renal transplantation and has a predilection for extranodal involvement (Schmidtko et al, 2002;Page et al, 2013).…”

Total Recall: Can We Reshape T Cell Memory by Lymphoablation?

“…Such is an example is provided in an NHP renal transplantation study using T cell depletion combined with costimulatory blockade. All eight recipients in this study had viral infections, and three of eight developed posttransplant lymphoproliferative disorder (46). Considering the potential effects on the protective memory T cell pool is critical when improving the efficacy of lymphoablation in transplant recipients.…”

“…To reduce the risk of opportunistic infections, prophylactic therapies are often used to counterbalance the negative effects of lymphoablation (45). All eight recipients in this study had viral infections, and three of eight developed posttransplant lymphoproliferative disorder (46). Such is an example is provided in an NHP renal transplantation study using T cell depletion combined with costimulatory blockade.…”