Effect of Irradiation on Incidence of Post-Transplant Lymphoproliferative Disorder after Hematopoietic Cell Transplantation in Miniature Swine

Abstract

Post-transplant lymphoproliferative disease (PTLD) is a major complication of clinical organ and cell transplantation. Conditioning and immunosuppressive regimens that significantly impair T cell immunity, including depleting antibodies and calcineurin inhibitors, increase the risk of PTLD after transplantation. Swine PTLD has been shown to closely resemble human PTLD in morphology, histology, and viral-driven reactivation of B cells. Previously, we reported high incidences of PTLD after hematopoietic cell transplantation (HCT) in miniature swine recipients conditioned with thymic irradiation (TI) in addition to T cell depletion and cyclosporine A monotherapy after transplantation. Replacement of TI with 100 cGy of total body irradiation resulted in similar numbers of B cells early post-transplantation, greater numbers of T cells at day 0, and markedly decreased incidence of PTLD, suggesting that a threshold number of T cells may be necessary to prevent subsequent B cell proliferation and development of overt PTLD. Results from this large cohort of animals provide insight into the important effect of irradiation and T cell immunity on the incidence of PTLD after HCT and reinforce the pig model as a valuable tool for the study of PTLD and HCT.

Epstein-Barr Virus-Related Post-Transplantation Lymphoproliferative Disorders After Allogeneic Hematopoietic Stem Cell Transplantation

“…In one study that analyzed 288 adults who underwent umbilical cord blood transplantation in a single center, the 3-year cumulative incidence of EBV-PTLDs was 12.9% in recipients of an RIC regimen and 2.6% in recipients of a myeloablative conditioning regimen (P < .0001) [11], suggesting RIC as a potential risk factor for EBV-PTLDs. In another study, conditioning with thymic irradiation (1000 cGy) and T cell depletion using pCD3-CRM9 followed by a short course of cyclosporine A (30 to 60 days) resulted in a high incidence of PTLDs at 34.4% (10 of 29) in a miniature swine study due to impaired T cell immunity [23].…”

Myeloid Leukemias and Virally Induced Lymphomas in Miniature Inbred Swine: Development of a Large Animal Tumor Model

“…In contrast, swine have been shown to be an excellent model for the study of PTLD. Immunosuppressed swine undergoing HCT or SOT develop B-cell expansions with a clinical presentation that closely resembles human PTLD ( Huang et al, 2001 ; Matar et al, 2015 ). Similarly to human PTLD’s association with EBV, swine PTLD is associated with primary infection or reactivation of a gamma herpesvirus, porcine lymphotropic herpesvirus-1 (PLHV-1; Doucette et al, 2007 ).…”

“…Similarly to human PTLD’s association with EBV, swine PTLD is associated with primary infection or reactivation of a gamma herpesvirus, porcine lymphotropic herpesvirus-1 (PLHV-1; Doucette et al, 2007 ). In a model of haploidentical HCT, immunosuppressive regimens consisting of T-cell depletion using CD3-immunotoxin, 1000 cGy of thymic irradiation, and a 30–60 days course of cyclosporine A consistently (40–50%) resulted in the development of B cell lymphomas post-transplant ( Cho et al, 2004 ; Cina et al, 2006 ; Matar et al, 2015 ). When thymic irradiation was eliminated as part of the conditioning regimen, only 1/23 animals developed PTLD.…”

“…100 cGy of TBI was added to the conditioning regimen in an attempt to decrease the incidence of PTLD while allowing for stem cell engraftment. Subsequently, only 15% developed PTLD, while the majority of animals successfully engrafted ( Matar et al, 2015 ). Matar et al (2015) recently explored the effect of thymic and TBI on the incidence of PTLD in this model and concluded that thymic irradiation was a risk factor for PTLD development via its depleting effect on the absolute number of T cells.…”

“…Subsequently, only 15% developed PTLD, while the majority of animals successfully engrafted ( Matar et al, 2015 ). Matar et al (2015) recently explored the effect of thymic and TBI on the incidence of PTLD in this model and concluded that thymic irradiation was a risk factor for PTLD development via its depleting effect on the absolute number of T cells. Further, the use of LDH as a serum marker for swine PTLD was validated ( Figure 1 ).…”