Ex Vivo Priming of Naïve T Cells Into EBV-Specific Th1/Tc1 Effector Cells by Mature Autologous DC Loaded with Apoptotic/Necrotic LCL

Posttransplant lymphoproliferative disorders (PTLDs) represent life‐threatening complications of bone marrow and solid organ transplantation (SOTx). These are B‐cell malignancies triggered by Epstein‐Barr Virus (EBV) infection in chronically immunosuppressed (IS) recipients. Immunosuppressed EBV seronegative (EBV^?) organ recipients are at highest risk of developing PTLD owing to the lack of anti‐EBV memory T cells to control subsequent EBV challenges. Our aim is to establish effective anti‐EBV T‐cell generation protocols for prevention or treatment of PTLD encountered in SOTx. We have used autologous dendritic cells (DCs) loaded with apoptotic/necrotic lymphoblastoid cell lines (LCLs) to evaluate the ability of such an approach to activate naïve T cells in vitro. In EBV^? individuals, both CD8+ and CD4+ T‐cell responses were amplified by this approach, as detected by IFN‐γ ELISPOT and cytotoxicity assays. The CD8+ T cells were poly‐specific anti‐EBNA3 A, ‐LMP2 and ‐BMLF1, with uniform reversion to a CD45RO+/RA‐phenotype, decreased CD62L expression, and up‐regulation of the activation markers CD28 and CD69. Addition of rhIL‐12 improved anti‐viral T‐cell responses and reduced the functional differences observed between EBV⁺ and EBV^? responders. In conclusion, the DC/LCL method promotes cross‐presentation of EBV‐associated epitopes and may serve as an effective protocol for the adoptive immunotherapy of PTLD in EBV^? SOTx patients .     

Syk‐Induced Phosphatidylinositol‐3‐Kinase Activation in Epstein–Barr Virus Posttransplant Lymphoproliferative Disorder

Posttransplant lymphoproliferative disorder (PTLD)‐associated Epstein–Barr virus (EBV)+ B cell lymphomas are serious complications of solid organ and bone marrow transplantation. The EBV protein LMP2a, a B cell receptor (BCR) mimic, provides survival signals to virally infected cells through Syk tyrosine kinase. Therefore, we explored whether Syk inhibition is a viable therapeutic strategy for EBV‐associated PTLD. We have shown that R406, the active metabolite of the Syk inhibitor fostamatinib, induces apoptosis and cell cycle arrest while decreasing downstream phosphatidylinositol‐3′‐kinase (PI3K)/Akt signaling in EBV+ B cell lymphoma PTLD lines in vitro. However, Syk inhibition did not inhibit or delay the in vivo growth of solid tumors established from EBV‐infected B cell lines. Instead, we observed tumor growth in adjacent inguinal lymph nodes exclusively in fostamatinib‐treated animals. In contrast, direct inhibition of PI3K/Akt significantly reduced tumor burden in a xenogeneic mouse model of PTLD without evidence of tumor growth in adjacent inguinal lymph nodes. Taken together, our data indicate that Syk activates PI3K/Akt signaling which is required for survival of EBV+ B cell lymphomas. PI3K/Akt signaling may be a promising therapeutic target for PTLD, and other EBV‐associated malignancies.     

Primary Cutaneous Posttransplant Lymphoproliferative Disorders in Solid Organ Transplant Recipients: A Multicenter European Case Series

Primary cutaneous posttransplant lymphoproliferative disorders (PTLD) are rare. This retrospective, multicenter study of 35 cases aimed to better describe this entity. Cases were (re)‐classified according to the WHO‐EORTC or the WHO 2008 classifications of lymphomas. Median interval between first transplantation and diagnosis was 85 months. Fifty‐seven percent of patients had a kidney transplant. Twenty‐four cases (68.6%) were classified as primary cutaneous T cell lymphoma (CTCL) and 11 (31.4%) as primary cutaneous B cell PTLD. Mycosis fungoides (MF) was the most common (50%) CTCL subtype. Ten (90.9%) cutaneous B cell PTLD cases were classified as EBV‐associated B cell lymphoproliferations (including one plasmablastic lymphoma and one lymphomatoid granulomatosis) and one as diffuse large B cell lymphoma, other, that was EBV‐negative. Sixteen (45.7%) patients died after a median follow‐up of 19.5 months (11 [68.8%] with CTCL [6 of whom had CD30⁺ lymphoproliferative disorders (LPD)] and 5 [31.2%] with cutaneous B cell PTLD. Median survival times for all patients, CTCL and cutaneous B cell PTLD subgroups were 93, 93, and 112 months, respectively. Survival rates for MF were higher than those for CD30⁺ LPD. The spectrum of primary CTCL in organ transplant recipients (OTR) is similar to that in the general population. The prognosis of posttransplant primary cutaneous CD30⁺ LPD is worse than posttransplant MF and than its counterpart in the immunocompetent population. EBV‐associated cutaneous B cell LPD predominates in OTR.     

PI3Kδ Inhibition Augments the Efficacy of Rapamycin in Suppressing Proliferation of Epstein−Barr Virus (EBV)+ B Cell Lymphomas

Posttransplant lymphoproliferative disorder (PTLD) continues to be a devastating and potentially life‐threatening complication in organ transplant recipients. PTLD is associated with EBV infection and can result in malignant B cell lymphomas. Here we demonstrate that the PI3K/Akt/mTOR pathway is highly activated in EBV+ B cell lymphoma lines derived from patients with PTLD. Treatment with the mTORC1 inhibitor Rapamycin (RAPA) partially inhibited the proliferation of EBV+ B cell lines. Resistance to RAPA treatment correlated with high levels of Akt phosphorylation. An mTORC1/2 inhibitor and a PI3K/mTOR dual inhibitor suppressed Akt phosphorylation and showed a greater anti‐proliferative effect on EBV+ B lymphoma lines compared to RAPA. EBV+ B cell lymphoma lines expressed high levels of PI3Kδ. We demonstrate that PI3Kδ is responsible for Akt activation in EBV+ B cell lymphomas, and that selective inhibition of PI3Kδ by either siRNA, or a small molecule inhibitor, augmented the anti‐proliferative effect of RAPA on EBV+ B cell lymphomas. These results suggest that PI3Kδ is a novel, potential therapeutic target for the treatment of EBV‐associated PTLD and that combined blockade of PI3Kδ and mTOR provides increased efficacy in inhibiting proliferation of EBV+ B cell lymphomas.     

Associations of serum EBV DNA and gammopathy with post-transplant lymphoproliferative disease

Abstract: Background: Post‐transplant lymphoproliferative disease (PTLD) is a life‐threatening complication of immunosuppression following transplantation. Epstein–Barr virus (EBV) and gammopathy in serum are associated with PTLD, but these two parameters have not been evaluated in parallel for their association with PTLD. Methods: We evaluated the incidence of EBV load positivity, gammopathy, and protein expression in sera from all PTLD patients diagnosed at our hospital during the past seven yr. Results were compared with those of a control group including matched transplanted patients who did not develop PTLD. Results: Seven of 10 PTLD patients presented EBV⁺ PTLD, for which five patients had detectable serum EBV DNA levels compared with none of 38 controls (RR between two groups =121, p < 0.0001). Five out of 10 patients had gammopathy at PTLD diagnosis compared with 5/38 controls (RR between two groups = 6.6, p = 0.022). Additionally, protein serum analysis by high‐resolution two‐dimensional gel electrophoresis and image examination failed to evidence specific abnormality in patients with PTLD compared with controls. Conclusions: Our results confirm an association between EBV in sera and gammopathy with PTLD, and highlight the high specificity of the former analysis. Whether a combination of both analyses will improve the clinical detection of PTLD remains to be evaluated in a larger prospective cohort study.     

IL‐6 and IL‐10 in post‐transplant lymphoproliferative disorders development and maintenance: a longitudinal study of cytokine plasma levels and T‐cell subsets in 38 patients undergoing treatment

IL‐6 and IL‐10 have previously been implicated in the pathogenesis of post‐transplant lymphoproliferative disorders (PTLD) and, like peripheral lymphocyte populations, are markers of immune status that are amenable to study in vivo. Thus, we analyzed cytokine plasma levels as well as lymphocyte subsets in a longitudinal analysis of 38 adult transplant recipients undergoing treatment for PTLD. Pretherapeutically, we found significantly elevated IL‐6 (13.8 pg/ml) and IL‐10 plasma levels (54.7 pg/ml) – in the case of IL‐10, even higher in treatment nonresponders than in responders (116 vs. 14 pg/ml). Over time, however, IL‐10 levels did not correlate with the course of disease, whereas those of IL‐6 did, falling in responders and rising in nonresponders. These findings were independent of histological EBV‐status, treatment type, and total peripheral T‐cell counts, which were significantly reduced in patients with PTLD. Our observations support the idea that although IL‐10 is important for creating a permissive environment for post‐transplant lymphoma development, IL‐6 is associated with PTLD proliferation. The analysis of lymphocyte subsets further identified HLA‐DR+ CD8+ lymphocyte numbers as significantly different in non‐PTLD controls (33%), treatment responders (44%) and nonresponders (70%). Although the specificity of these cells is unclear, their increase might correlate with the impaired tumor‐specific cytotoxic‐T‐lymphocyte (CTL)‐response in PTLD.     

Dual blockade of the PI3K/Akt/mTOR pathway inhibits posttransplant Epstein‐Barr virus B cell lymphomas and promotes allograft survival

Posttransplant lymphoproliferative disorder (PTLD) is a serious complication of organ transplantation that often manifests as Epstein‐Barr virus (EBV)‐associated B cell lymphomas. Current treatments for PTLD have limited efficacy and can be associated with graft rejection or systemic toxicities. The mTOR inhibitor, rapamycin, suppresses tumor growth of EBV+ B cell lymphoma cells in vitro and in vivo; however, the efficacy is limited and clinical benefits of mTOR inhibitors for PTLD are variable. Here, we show constitutive activation of multiple nodes within the PI3K/Akt/mTOR pathway in EBV+ PTLD‐derived cell lines. Inhibition of either PI3K or Akt, with specific inhibitors CAL‐101 and MK‐2206, respectively, diminished growth of EBV+ B cell lines from PTLD patients in a dose‐dependent manner. Importantly, rapamycin combined with CAL‐101 or MK‐2206 had a synergistic effect in suppressing cell growth as determined by IC₅₀ isobolographic analysis and Loewe indices. Moreover, these combinations were significantly more effective than rapamycin alone in inhibiting tumor xenograft growth in NOD‐SCID mice. Finally, both CAL‐101 and MK‐2206 also prolonged survival of heterotopic cardiac allografts in C57BL/6 mice. Thus, combination therapy with rapamycin and a PI3K inhibitor, or an Akt inhibitor, can be an efficacious treatment for EBV‐associated PTLD, while simultaneously promoting allograft survival.     

Post‐transplant lymphoproliferative disorders,Epstein‐Barr virus infection,and disease in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice

These updated guidelines from the American Society of Transplantation Infectious Diseases Community of Practice review the diagnosis, management, and prevention of post‐transplant lymphoproliferative disorders (PTLD) and other Epstein‐Barr virus (EBV) syndromes after solid organ transplantation. PTLD are a heterogeneous spectrum of predominantly B‐cell disorders, often extra‐nodal, with complex distinct pathogeneses and variable clinical presentations determined by pathologic subtype. Recent epidemiologic studies report a decrease in early EBV‐positive (+) PTLD and an increase in late EBV‐negative (?) PTLD. Pre‐transplant EBV‐seronegativity and primary EBV infection, often from donor‐transmitted infection, are an important risk factors for EBV syndromes and early EBV + PTLD. Low‐quality evidence supports preemptive prevention strategies for early EBV + PTLD in EBV‐seronegative recipients that involve EBV DNA measurement in peripheral blood using assays requiring further result harmonization, combined with interventions to lower viral load. Reduction in immunosuppression (RIS) is the best validated intervention. WHO pathology classification of a tissue biopsy remains the gold standard for PTLD diagnosis; optimal staging procedures are uncertain. Treatment of CD20⁺ PTLD with the response‐dependent sequential use of RIS, rituximab, and cytotoxic chemotherapy is recommended. Evidence gaps requiring future research and alternate treatment strategies including immunotherapy are highlighted.     

A critical role for donor‐derived IL‐22 in cutaneous chronic GVHD

Graft‐versus‐host disease (GVHD) is the major cause of nonrelapse morbidity and mortality after allogeneic stem cell transplantation (allo‐SCT). Prevention and treatment of GVHD remain inadequate and commonly lead to end‐organ dysfunction and opportunistic infection. The role of interleukin (IL)‐17 and IL‐22 in GVHD remains uncertain, due to an apparent lack of lineage fidelity and variable and contextually determined protective and pathogenic effects. We demonstrate that donor T cell–derived IL‐22 significantly exacerbates cutaneous chronic GVHD and that IL‐22 is produced by highly inflammatory donor CD4⁺ T cells posttransplantation. IL‐22 and IL‐17A derive from both independent and overlapping lineages, defined as T helper (Th)22 and IL‐22⁺ Th17 cells. Donor Th22 and IL‐22⁺ Th17 cells share a similar IL‐6–dependent developmental pathway, and while Th22 cells arise independently of the IL‐22⁺Th17 lineage, IL‐17 signaling to donor Th22 directly promotes their development in allo‐SCT. Importantly, while both IL‐22 and IL‐17 mediate skin GVHD, Th17‐induced chronic GVHD can be attenuated by IL‐22 inhibition in preclinical systems. In the clinic, high levels of both IL‐17A and IL‐22 expression are present in the skin of patients with GVHD after allo‐SCT. Together, these data demonstrate a key role for donor‐derived IL‐22 in patients with chronic skin GVHD and confirm parallel but symbiotic developmental pathways of Th22 and Th17 differentiation.     

Circulating Epstein‐Barr virus DNA to monitor lymphoproliferative disease following pediatric liver transplantation

Abstract Epstein‐Barr virus (EBV) infection can induce uncontrolled lymphocyte B proliferation in immunosuppressed transplant patients. Monitoring circulating EBV‐infected lymphocytes can help in identifying patients at risk of post‐transplant lymphoproliferative disease (PTLD). Circulating EBV genome levels were determined in 54 liver transplant pediatric recipients. Ten patients had more than 500 EBV genome/10⁵ peripheral blood lymphocytes (PBL) and exhibited clinical manifestations of EBV infection; three developed PTLD. To treat EBV infection, the level of immunosuppression was reduced and acute rejection developed in 4 patients. Three were treated with steroid and one had to be switched from cyclosporine to tacrolimus. Treatment of acute rejection was associated with increases in circulating EBV genome. None of the patients with less than 500 EBV genome/10⁵ PBL developed PTLD or EBV infection. Monitoring of EBV DNA is useful in the management of EBV infection and PTLD following pediatric liver transplantation. EBV infection should be treated in ways which do not expose patients to the risk of rejection.     

B cell–derived IL‐1β and IL‐6 drive T cell reconstitution following lymphoablation

Understanding the mechanisms of T cell homeostatic expansion is crucial for clinical applications of lymphoablative therapies. We previously established that T cell recovery in mouse heart allograft recipients treated with anti‐thymocyte globulin (mATG) critically depends on B cells and is mediated by B cell–derived soluble factors. B cell production of interleukin (IL)‐1β and IL‐6 is markedly upregulated after heart allotransplantation and lymphoablation. Neutralizing IL‐1β or IL‐6 with mAb or the use of recipients lacking mature IL‐1β, IL‐6, IL‐1R, MyD88, or IL‐6R impair CD4⁺ and CD8⁺ T cell recovery and significantly enhance the graft‐prolonging efficacy of lymphoablation. Adoptive co‐transfer experiments demonstrate a direct effect of IL‐6 but not IL‐1β on T lymphocytes. Furthermore, B cells incapable of IL‐1β or IL‐6 production have diminished capacity to mediate T cell reconstitution and initiate heart allograft rejection upon adoptive transfer into mATG treated B cell deficient recipients. These findings reveal the essential role of B cell–derived IL‐1β and IL‐6 during homeostatic T cell expansion in a clinically relevant model of lymphoablation.     

Risk factors for post‐transplant lymphoproliferative disorder after Thymoglobulin‐conditioned hematopoietic cell transplantation

Epstein‐Barr virus (EBV)‐induced post‐transplant lymphoproliferative disorder (PTLD) occurs frequently when rabbit antithymocyte globulin (ATG) is used in hematopoietic cell transplant (HCT) conditioning. We retrospectively studied 554 patients undergoing ATG‐conditioned myeloablative HCT. Strategies used to minimize mortality due to PTLD were either therapy of biopsy‐diagnosed PTLD in the absence of EBV DNAemia monitoring (n = 266) or prompt therapy of presumed PTLD (based on clinical/radiologic signs and high EBV DNAemia, in the setting of weekly EBV DNAemia monitoring) (n = 199). Both strategies resulted in similar mortality due to PTLD (0.7% vs 1% at 2 years, P = .43) and similar overall survival (63% vs 67% at 2 years, P = .23) even though there was a trend toward higher PTLD incidence with the prompt therapy. Donor positive with recipient negative EBV (D+R?) serostatus was a risk factor for developing PTLD. Older patient age, HLA‐mismatched donor, and graft‐versus‐host disease were not associated with increased risk of PTLD. In summary, in ATG‐conditioned HCT, D+R? serostatus, but not older age, mismatched donor or GVHD is a risk factor for developing PTLD. EBV DNAemia monitoring may be a weak risk factor for developing/diagnosing PTLD; the monitoring coupled with prompt therapy does not improve survival.     

Induction of porcine‐specific regulatory T cells with high specificity and expression of IL‐10 and TGF‐β1 using baboon‐derived tolerogenic dendritic cells

Background

Regulatory T cells (Treg) play an important role in maintenance of homeostasis in vivo. Treg application to alleviate allo‐organ rejection is being studied extensively. However, natural Treg (nTreg) expansion in vitro is laborious and expensive. Antigen‐specific Treg are more effective and require lower cell numbers than use of nTreg for immune control. The baboon, as a non‐human primate experimental animal model, is widely used in xenotransplantation research. An effective method to generate baboon xeno‐specific Treg would benefit research on immune tolerance in xenotransplantation using this model system.

Method

Baboon tolerogenic dendritic cells (tolDC) were generated in 3 days from monocytes isolated from baboon peripheral blood mononuclear cells in medium supplemented with anti‐inflammatory cytokines. After loading with porcine‐specific (PS) in vitro‐transcribed RNA (ivtRNA), tolDC were used to induce CD4⁺ T cells to become porcine‐specific Treg (PSTreg) in cocultures supplemented with IL‐2 and rapamycin for 10 days. Anti‐inflammatory and inflammatory cytokine expression was evaluated at the mRNA and protein levels in both baboon tolDC and PSTreg. Functional assays, suppression of activation markers on porcine‐specific effector T cells (PSTeff) and inhibition of PSTeff proliferation, were used to test PSTreg specificity.

Results

TolDC generated with this method exhibited a tolerogenic phenotype, expressed CCR7 and produced high levels of IL‐10 and TGF‐β1, whereas IL‐12p40 and IFN‐γ were not expressed. PSTreg were successfully generated in cocultures of CD4⁺ T cells and PS ivtRNA‐loaded tolDC. They exhibited a CD3⁺ CD4⁺ CD25⁺ CD127^low/? CD45RA^low Foxp3⁺ phenotype and were characterized by high expression of IL‐10 and TGF‐β1 mRNA and protein. They showed upregulated expression of EBI3 and GARP mRNA. PSTreg exhibited highly suppressive effects toward PSTeff, secreting high amounts of IL‐10 and TGF‐β1 cytokine upon interaction with PSTeff and suppressing IFN‐γ expression on PSTeff.

Conclusion

In this study, a fast 3‐day method to generate baboon‐derived tolDC is provided that allows subsequent induction of PSTreg displaying high porcine‐antigen specificity and expression of IL‐10 and TGF‐β1. Porcine‐specific baboon Treg can be used in porcine solid organ or cell xenotransplantation studies through adoptive cell transfer into host baboons.     

IL‐22 is required for the induction of bronchus‐associated lymphoid tissue in tolerant lung allografts

Long‐term survival after lung transplantation remains profoundly limited by graft rejection. Recent work has shown that bronchus‐associated lymphoid tissue (BALT), characterized by the development of peripheral nodal addressin (PNAd)‐expressing high endothelial venules and enriched in B and Foxp3⁺ T cells, is important for the maintenance of allograft tolerance. Mechanisms underlying BALT induction in tolerant pulmonary allografts, however, remain poorly understood. Here, we show that the development of PNAd‐expressing high endothelial venules within intragraft lymphoid follicles and the recruitment of B cells, but not Foxp3⁺ cells depends on IL‐22. We identify graft‐infiltrating gamma‐delta (γδ) T cells and Type 3 innate lymphoid cells (ILC3s) as important producers of IL‐22. Reconstitution of IL‐22 at late time points through retransplantation into wildtype hosts mediates B cell recruitment into lymphoid follicles within the allograft, resulting in a significant increase in their size, but does not induce PNAd expression. Our work has identified cellular and molecular requirements for the induction of BALT in pulmonary allografts during tolerance induction and may provide a platform for the development of new therapies for lung transplant patients.     

Quantitative Epstein-Barr virus shedding and its correlation with the risk of post-transplant lymphoproliferative disorder

We postulated that quantitative monitoring of Epstein–Barr virus (EBV) shedding after transplantation could distinguish EBV‐associated illnesses and predict clinical outcome. EBV DNA was measured in solid organ (SOT) and hematopoietic cell transplants (HCT) using our own real‐time TaqMan EBV PCR. The proportion of patients who had EBV DNAemia post‐transplant was significantly lower in HCT vs. SOT (p < 0.001). Over a 7.5‐yr period, post‐transplant lymphoproliferative disorder (PTLD) occurred in 66 (5.8%) of 1131 patients who met adequate monitoring criteria. SOT recipients developed PTLD significantly later than HCT recipients (median, 2.8 yr vs. 121 d; p < 0.001). PTLD was documented in 53 (14%) of 376 patients who had EBV in ≥1 whole blood sample vs. 13 (2%) of 755 patients who had at least three EBV‐negative blood samples and were never positive. PTLD risk in viremic patients increased with the peak quantity of EBV DNAemia (p < 0.001). PTLD occurred in 37/333 (11%) of patients with peak blood levels 10³–10⁵ copies/mL vs. 16/43 (37%) of patients with levels >10⁵ (p < 0.001). EBV PCR was predictive in 29 (78%) of 37 patients tested within three wk prior to tissue diagnosis of PTLD, and thus, we conclude that EBV PCR with careful attention paid to changes in EBV DNAemia could lead to earlier diagnosis and treatment of PTLD.     

Post‐transplant lymphoproliferative disorders with naso‐ and oropharyngeal manifestation

The nasopharyngeal/oropharyngeal lymphatic tissues represent the anatomical site of Epstein–Barr virus (EBV) entry. Post‐transplant lymphoproliferative disorders (PTLD) are often associated with EBV, but little is known about the characteristics of nasopharyngeal/oropharyngeal mass‐forming PTLD. Retrospective evaluation of our own PTLD database (n = 79) and the PubMed^® database (n = 61) has been performed. Sinonasal/oro‐/nasopharyngeal lymphatic masses were early lesions (n = 54/140, 38.5%), polymorphic PTLD (n = 32/140, 23%), monomorphic B‐PTLD (n = 47/140, 33.5%) and T‐PTLD (n = 7/140, 5%). One‐fourth of lesions manifested as masses in the Waldeyer's ring, and in two‐thirds of cases, swelling of tonsils was related to manifestation of benign early lesions. Tonsil infiltration by polymorphic PTLD and monomorphic PTLD was present in one‐third of cases. Extratonsillar masses were mainly monomorphic PTLD. Meta‐analysis of our data in combination with previously published data revealed that lung transplantation and young patients are at a higher risk for earlier manifestation of monomorphic PTLD. Therapy is similar to PTLD therapy strategies, in general reduced immunosuppression and chemotherapy for polymorphic and monomorphic PTLD, and diagnostic and therapeutic surgical gross tumour resection of tonsillar/adenoid lesions. In summary, it is relevant for the clinical differential diagnosis that oro‐/nasopharyngeal aggressive PTLD manifested in ~30% as tonsillar masses and >90% at extratonsillar sites.     

Epstein–Barr Virus‐Related Post‐Transplant Lymphoproliferative Disorders: Pathogenetic Insights for Targeted Therapy

Post‐transplant lymphoproliferative disorder (PTLD) is a spectrum of major, life‐threatening lymphoproliferative diseases occurring in the post‐transplant setting. The majority of PTLD is of B‐cell origin and is associated with several risk factors, the most significant being Epstein‐Barr virus (EBV) infection. EBV's in vitro transforming abilities, distinctive latency, clonality within the malignant cells and response to targeted therapies implicate a critical role in the biology of PTLD. This minireview focuses on EBV‐related PTLD pathogenesis, in particular the interplay between aspects of the EBV life cycle and latency with nonviral factors resulting in the wide spectrum of histology and clinical presentations encountered in PTLD. With the increased prevalence of transplantation a rise in the incidence of PTLD may be expected. Therefore the importance of laboratory and animal models in the understanding of PTLD and the development of novel therapeutic approaches is discussed.     

Post‐transplant lymphoproliferative disease in lung transplantation: A nested case‐control study

Post‐transplant lymphoproliferative disorder (PTLD) may compromise long‐term outcome of lung transplant (LTx) recipients. A case‐control study was performed, comparing LTx recipients with PTLD (n=31) to matched recipients without PTLD (Controls, n=62). Risk factors for PTLD and post‐transplant outcomes were assessed. PTLD prevalence was 3.9%, time to PTLD 323 (166‐1132) days; and 54.8% had early‐onset PTLD versus 45.2% late‐onset PTLD. At LTx, more Epstein‐Barr virus (EBV)‐seronegative patients were present in PTLD (42%) compared to Controls (5%) (P<.0001); most of whom had undergone EBV seroconversion upon PTLD diagnosis. EBV viral load was higher in PTLD versus Controls (P<.0001). Overall, lower hemoglobin and higher C‐reactive protein levels were present in PTLD versus Controls (P<.0001). EBV status at LTx (P=.0073) and EBV viral load at PTLD (P=.0002) were the most important risk determinates for later PTLD. Patients with PTLD demonstrated shorter time to onset of chronic lung allograft dysfunction (CLAD) (P=.0006) and poorer 5‐year survival post‐LTx (66.6% versus 91.5%), resulting in worse CLAD‐free survival (HR 2.127, 95%CI 1.006‐4.500; P=.0483) and overall survival (HR 3.297 95%CI 1.473‐7.382; P=.0037) compared to Controls. Late‐onset PTLD had worse survival compared to early‐onset PTLD (P=.021). Primary EBV infection is a risk for PTLD; which is associated with worse long‐term outcome post‐LTx.