scholarly journals Cytomegalovirus Serology and Replication Remain Associated With Solid Organ Graft Rejection and Graft Loss in the Era of Prophylactic Treatment

2014 ◽  
Vol 98 (9) ◽  
pp. 1013-1018 ◽  
Author(s):  
Martin Stern ◽  
Hans Hirsch ◽  
Alexia Cusini ◽  
Christian van Delden ◽  
Oriol Manuel ◽  
...  
Keyword(s):  
Graft Rejection ◽  
Prophylactic Treatment ◽  
Graft Loss ◽  
Solid Organ ◽  
Organ Graft

scholarly journals The Impact of Culturing the Organ Preservation Fluid on Solid Organ Transplantation: A Prospective Multicenter Cohort Study

2019 ◽  
Vol 6 (6) ◽  
Author(s):  
I Oriol ◽  
N Sabe ◽  
J Càmara ◽  
D Berbel ◽  
M A Ballesteros ◽  
...  
Keyword(s):  
High Risk ◽  
Antibiotic Therapy ◽  
Graft Rejection ◽  
Graft Loss ◽  
Organ Transplant ◽  
Solid Organ Transplant ◽  
Preemptive Therapy ◽  
Solid Organ ◽  
Risk Culture ◽  
Culture Positive

Abstract Background We analyzed the prevalence, etiology, and risk factors of culture-positive preservation fluid and their impact on the management of solid organ transplant recipients. Methods From July 2015 to March 2017, 622 episodes of adult solid organ transplants at 7 university hospitals in Spain were prospectively included in the study. Results The prevalence of culture-positive preservation fluid was 62.5% (389/622). Nevertheless, in only 25.2% (98/389) of the cases were the isolates considered “high risk” for pathogenicity. After applying a multivariate regression analysis, advanced donor age was the main associated factor for having culture-positive preservation fluid for high-risk microorganisms. Preemptive antibiotic therapy was given to 19.8% (77/389) of the cases. The incidence rate of preservation fluid–related infection was 1.3% (5 recipients); none of these patients had received preemptive therapy. Solid organ transplant (SOT) recipients with high-risk culture-positive preservation fluid receiving preemptive antibiotic therapy presented both a lower cumulative incidence of infection and a lower rate of acute rejection and graft loss compared with those who did not have high-risk culture-positive preservation fluid. After adjusting for age, sex, type of transplant, and prior graft rejection, preemptive antibiotic therapy remained a significant protective factor for 90-day infection. Conclusions The routine culture of preservation fluid may be considered a tool that provides information about the contamination of the transplanted organ. Preemptive therapy for SOT recipients with high-risk culture-positive preservation fluid may be useful to avoid preservation fluid–related infections and improve the outcomes of infection, graft loss, and graft rejection in transplant patients.

Post-Transplantation Lymphoproliferative Disorders (PTLD) Management in Solid Organ Transplantation (SOT) Recipients

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4941-4941
Author(s):  
Nikolai A. Podoltsev ◽  
Ivan Bustillo ◽  
Xiaopan Yao ◽  
Haibei Liu ◽  
Dennis L. Cooper
Keyword(s):  
T Cell ◽  
B Cell ◽  
Graft Rejection ◽  
Loss Rate ◽  
Graft Loss ◽  
B Cell Lymphoma ◽  
Proliferative Potential ◽  
Solid Organ ◽  
Combined Approach ◽  
Dose Dense

Abstract Abstract 4941 Introduction: PTLD are lymphoid proliferations that develop as a consequence of immunosuppression in 1% of SOT recipients. The majority of PTLD are associated with Epstein-Barr virus (EBV) infection, as therapeutic immunosuppression causes decreased T-cell surveillance, increasing the proliferative potential of EBV in latently infected B-cells. PTLD may manifest as early lesions including polyclonal plasmacytic hyperplasia and infectious mononucleosis-like PTLD as well as monoclonal polymorphic PTLD. Patients who develop polymorphic PTLD, universally associated with EBV and occurring early after transplant, usually have good prognosis and respond well to reduction of immunosuppression and antiviral therapy. Monomorphic PTLD is indistinguishable from a subset of B-cell and much less frequently T-cell lymphomas that occur in immunocompetent individuals. Monomorphic PTLD in SOT patients frequently involve extranodal sites as well as the allograft and causes significant morbidity and mortality in this group of patients. There is no universally accepted treatment strategy for monomorphic PTLD as randomized trials are lacking with most of the data coming from prospective and retrospective cohort trials evaluating heterogeneous populations of patients. Standard therapy consists of a stepwise treatment approach, aimed at partially restoring cellular immunity by reduction of immunosuppression (RI) sometimes in combination with or followed by rituximab. If there is no response chemotherapy is initiated. However, this strategy is vague as there are no clear rules for how much and for how long immunosuppression is reduced and may be associated with both graft loss and disease progression. We believe that aggressive monomorphic PTLD patients can be successfully treated by employing aggressive chemo-immunotherapy and withdrawal of standard immunosuppressive agents. We prefer to use “dose dense” administration schedule to 1) provide intensive therapy and 2) provide strong enough immunosuppression to prevent rejection. This retrospective study was designed to assess the outcome of such a strategy in monomorphic PTLD patients treated at the Yale Cancer Center (YCC) over a 15 year period. Patients and Methods: We identified patients with the PTLD after SOT by searching Yale Tumor Registry. Patients were eligible for selection if they were diagnosed with PTLD after SOT between January 1st of 1995 and December 31st of 2009 provided they were 18 years of age or older at the time of diagnosis (diagnosis criteria). We planned to analyze the outcomes among patients treated with combined approach (treatment criteria). Sixteen patients met inclusion criteria. Results: Out of 16 identified patients 11 received kidney, 1 kidney and pancreas, 3 heart and 1 liver transplants. Thirteen patients (81%) were diagnosed with diffuse large B cell lymphoma (DLBCL), 3 with Burkitt or Burkitt-like lymphoma (19%). All patients were treated with a combined approach with most of the patients (n=11, 69%) receiving CHOP-R every 2 weeks (“dose dense”). 10 out of the 16 patients had EBV positive lymphoma (62%). Only one patient had early PTLD (< 1 year after SOT) which was EBV positive. 6 out of 15 patients with late PTLD had EBV negative tumors. 9 (56%) patients had an advanced stage disease and 13 (81%) had extranodal involvement. One patient who developed PTLD after kidney transplantation had graft involvement with PTLD. Complete response (CR) was seen in all but one patient (94%). Median overall survival and median progression free survival were 5.39 years. Only 3 patients died due to PTLD and median cause specific survival time has not been reached. Out of the 16 patients, 4 had graft rejection and graft loss due to PTLD. Both the PTLD related-graft-rejection rate and graft loss rate were 25% with 95% CI (0.07-0.52). Conclusion: Combined therapy approach utilized at the YCC yields excellent results for patients with monomorphic PTLD after SOT. High CR rate, low number of PTLD-related deaths and low graft rejection /graft loss rate make this strategy an appealing option in the treatment armamentarium for this disease. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The role of TGF-β1 gene polymorphisms in the development of post-transplant complications

2021 ◽  
Vol 23 (3) ◽  
pp. 180-185
Author(s):  
R. M. Kurabekova ◽  
O. E. Gichkun ◽  
S. V. Meshcheryakov ◽  
O. P. Shevchenko
Keyword(s):  
Transforming Growth Factor Beta ◽  
Graft Rejection ◽  
Gene Polymorphisms ◽  
Transforming Growth Factor ◽  
Meta Analysis ◽  
Organ Transplant ◽  
Solid Organ ◽  
Post Transplant ◽  
Transplant Complications ◽  
Tgf Β1

Transforming growth factor beta 1 (TGF-β1) is an immunosuppressive and profibrogenic cytokine capable of influencing the development of graft rejection and graft fibrosis in solid organ recipients. The TGF-β gene has a significant polymorphism that may cause individual protein expression levels and be associated with post-organ transplant complications. It is believed that three TGFB1 polymorphic variants (rs1800469, rs1800470 and rs1800471) may be associated with the development of graft rejection, graft fibrosis and chronic dysfunction of a heart, liver or kidney transplant. A review of current literature presents the results of studies on the relationship between TGF-β1 gene polymorphisms and post-transplant complications in solid organ recipients. The findings of various studies of TGF-β1 gene polymorphism in solid organ recipients are not always unambiguous, and their results are often difficult to generalize even with the help of meta-analysis. Samples included in studies vary in terms of ethnicity, gender, age, and underlying medical conditions, while results are highly dependent on sample structure or latent relatedness. Currently available data suggest that TGFB1 polymorphism may determine a predisposition to the development of graft rejection, graft fibrosis and graft dysfunction in solid organ recipients, but this is not conclusive and requires further, larger studies.

Multi-center phase 1 safety and efficacy study of nivolumab in renal transplant patients with metastatic malignancy.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2567-2567
Author(s):  
John Raymond Zalcberg ◽  
Michael J. Boyer ◽  
Anne Elizabeth Taylor ◽  
Thean Hsiang Tan ◽  
Bronwyn Hockley ◽  
...  
Keyword(s):  
Graft Rejection ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Graft Loss ◽  
Organ Transplant ◽  
Case Series ◽  
Incurable Cancer ◽  
No Donor ◽  
Organ Rejection ◽  
Rejection Rates

2567 Background: Organ Transplant Recipients (OTR) are generally excluded from trials of immune checkpoint inhibitors (ICI) due to the reported risk of allograft rejection. A recent systematic review of published case series includes only 65 cases. Transplant organ rejection rates of 41% are reported with cancer response rates of 39%. The majority of OTR treated with ICI have had reduction/cessation of immunosuppression (IS) prior to ICI. Isolated IS reduction is associated with organ rejection and therefore either IS manipulation alone and/or ICI could induce organ rejection episodes. Methods: Renal OTR with incurable cancer, for whom ICI would normally be used in the general population (without an organ transplant), were eligible if creatinine < 180 umol/l, no donor specific HLA antibodies and ECOG < 2. Treatment was with nivolumab (3mg/kg q 14 days for 5 doses, then 480 mg q 28 days), without manipulation of IS and pre-ICI-exposure alloimmune risk assessment. Treatment continued till progression, patient refusal, or graft rejection. Primary endpoint was rate of irretrievable renal graft rejection. Results: 15 patients (9 male:6 female; median age 66.6 years) were enrolled and treated with a median (range) 3(1-42) infusions and with median (range) follow-up of 128 (11-784) days. Tumour types included:1 melanoma; 2 renal tract; 1 hepatocellular carcinoma; 1 Merkel cell; 1 adenocarcinoma lung; 1 MSI high colorectal, 8 squamous cell carcinoma (SCC) head and neck. 2 patients experienced rejection; one at day 28 (2 infusions); one at day 36 (3 infusions). Both had SCC and have had a CR. One is on haemodialysis and alive at 2 years the other a creatinine 450 umol/l. Both rejections treated with steroid, plasma-exchange and anti-thymocyte-globulin (ATG). 1 patient (metastatic bladder cancer) experienced graft loss (at 300 days) due to ureteric-stent bleed and BK-nephritis indirectly related to nivolumab- this patient died of progressive disease at 65 days after nivolumab cessation. Median (range) progression free disease (PD) with ≥ 2 infusions was 300 (68-784+) days. There were 5 CR (1 MSI high colorectal, 4 SCC) median duration of response 13 months and 2 PR (1 SCC 1 bladder)- 1 without PD. Conclusions: In this interim analysis, rejection rates in OTR with incurable cancers treated with ICI was 2/15 (13%) when IS is maintained and there is pre exposure alloimmune assessment. The combined CR and PR rate was 7/15 (47%). Clinical trial information: 12617000741381.

scholarly journals BZLF1-DEC205 Fusion Protein Enhances EBV-Protective Immunity in a Spontaneous Model of EBV-Driven Lymphoproliferative Disease

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 342-342 ◽  
Author(s):  
Elshafa Hassan Ahmed ◽  
Eric Brooks ◽  
Shelby Sloan ◽  
Sarah Schlotter ◽  
Frankie Jeney ◽  
...  
Keyword(s):  
T Cell ◽  
Fusion Protein ◽  
Graft Rejection ◽  
Lymphoproliferative Disease ◽  
T Cell Response ◽  
Effector Memory ◽  
P Value ◽  
Autologous Tumor ◽  
Solid Organ ◽  
Early Protein

Abstract Epstein-Barr virus (EBV) is a human herpes virus that infects over 90% of the world's population and is linked with cancer development. In immune-competent individuals, EBV-infection is controlled by a highly efficient virus-specific T cell response. Following primary infection, the virus achieves lifelong persistence within the human host. Risk of EBV-driven cancers increases with immune suppression (IS). Solid organ transplant recipients receive IS medications to prevent graft rejection and are at highest risk of developing EBV-associated lymphomas known as post-transplant lymphoproliferative disease (PTLD). PTLD represents a serious complication of organ transplantation, associated with poor prognosis. Currently, no standard approach for prevention or treatment exists. Reducing the level of IS medication may control PTLD but often leads to graft-rejection. In order to promote long-term protection from EBV-driven cancers, we have developed a vaccine to bolster EBV-specific immunity by targeting the EBV immediate early protein, BZLF1. BZLF1 initiates the activation of lytic stage in EBV-infected cells and promotes B-cell transformation. Work by our group has shown BZLF1-specific T cell expansion following reduction in IS medications correlates with PTLD tumor regression and improved patient survival. Here we specifically delivered the protein (BZLF1) to dendritic cells (DCs) through its endocytic receptor DEC205. DCs were generated from HLA-B8+ donor monocytes incubated with interleukin-4 (IL4) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Mature DCs were then loaded with DEC205-BZLF1 fusion protein or control protein (DEC205-Human Chorionic Gonadotropin (DEC205-HCG)). Antigen-loaded DCs were co-cultured with autologous peripheral blood mononuclear cells (PBMCs) in the presence of IL-2 for 10 days. Cells were analyzed by flow cytometry using HLA-tetramers to detect and quantify antigen-specific cytotoxic T leukocyte (CTL) response. To test the EBV vaccine in-vivo, we utilized a human-murine chimeric model of EBV-driven lymphoproliferative disease (EBV-LPD). Severe combined immune deficient (SCID) mice were engrafted with PBMCs from EBV+ donors (Hu-PBL-SCID model). The spontaneous EBV-LPD that develops in this model is comprised of human CD20+, EBV+ lymphoblasts that closely resembles PTLD. Mice were immunized with DCs loaded with DEC205-BZLF1 or DEC205-HCG at the time of PBMC transplant and received booster doses at day 14 and 28. Splenocyte from vaccinated mice were stimulated with autologous tumor (lymphoblastoid cells line, (LCL)) pulsed with BZLF1 pepmix, BZLF1 pepmix alone, and anti-CD3. Secretion of IFNg by stimulated splenocytes was detected using Human IFNg Enzyme-Linked Immunosorbent Spot (ELISpot). In vitro co-cultures treated with DEC205-BZLF1-loaded DCs showed increased expansion of EBV-specific CTLs (p-value: 0.0002) capable of abundant IFNg production and potent cytotoxicity against autologous tumor. This vaccine significantly improved survival in vaccinated mice (p-value: 0.035). Splenocytes from mice in the DEC205-BZLF1 vaccination group revealed higher responsiveness to autologous LCLs and BZLF1 pepmix compared to controls as determined by ELISpot. Human cells recovered from mouse spleen will be analyzed by mass cytometry using a multi-parametric antibody panel to evaluate central/effector memory status, CD4+ Th, CD8+ CTL, NK, and monocyte subsets. These results further support pre-clinical and clinical development of vaccine approaches utilizing the BZLF1 protein as an immunogen to harness adaptive cellular responses to prevent EBV-associated LPD in vulnerable patient populations. Disclosures No relevant conflicts of interest to declare.

scholarly journals Epitope-Level Matching—A Review of the Novel Concept of Eplets in Transplant Histocompatibility

2021 ◽  
Vol 2 (3) ◽  
pp. 336-347
Author(s):  
André Renaldo ◽  
Adriel Roa-Bautista ◽  
Elena González-López ◽  
Marcos López-Hoyos ◽  
David San Segundo
Keyword(s):  
De Novo ◽  
Graft Loss ◽  
Solid Organ Transplantation ◽  
Human Leukocyte ◽  
Future Research ◽  
Solid Organ ◽  
Leukocyte Antigen ◽  
Definition Of ◽  
Novel Concept ◽  
Hla Compatibility

The development of de novo donor-specific antibodies is related to the poor matching of the human leukocyte antigen (HLA) between donor and recipient, which leads to dismal clinical outcomes and graft loss. However, new approaches that stratify the risks of long-term graft failure in solid organ transplantation have emerged, changing the paradigm of HLA compatibility. In addition, advances in software development have given rise to a new structurally based algorithm known as HLA Matchmaker, which determines compatibility at the epitope rather than the antigen level. Although this technique still has limitations, plenty of research maintains that this assessment represents a more complete and detailed definition of HLA compatibility. This review summarizes recent aspects of eplet mismatches, highlighting the most recent advances and future research directions.

scholarly journals Long-Term Outcomes in 831 Kidney Transplant Recipients with 20 Years of Graft Function

2021 ◽  
Vol 8 ◽  
Author(s):  
Varvara Kirchner ◽  
Kristen Gillingham ◽  
Oscar Serrano ◽  
Srinath Chinnakotla ◽  
Ty Dunn ◽  
...  
Keyword(s):  
Kidney Transplant ◽  
Graft Survival ◽  
Interstitial Fibrosis ◽  
Graft Loss ◽  
Graft Function ◽  
Solid Organ ◽  
Kidney Transplant Recipients ◽  
Long Term Outcomes ◽  
Tubular Atrophy

An understanding of long-term outcomes for kidney transplant(KTx) recipients who survive with graft function beyond a specific time posttransplant is the first step in creating protocols to optimize care for current and improve outcomes for future recipients. We studied 831KTx recipients-580 living donor(LD); 251 deceased donor(DD)—with graft survival(GS) >20 years.  For primary LD recipients, 25-year patient survival(PS) was 83%; 35-year, 59%.  Their 25-year death-censored graft survival(DCGS) was 89%; 35-year, 72%.   DD recipients had lower PS(P<0.01), DCGS(P<0.01).   After 20 years, two major causes of graft loss(GL) were death with function(DwF)(58%, LD; 58%, DD) and interstitial fibrosis and tubular atrophy(IFTA)(22%, LD; 23%, DD).  Two major causes of DwF were cancer(31%, LD; 31%, DD) and cardiovascular disease(CVD)(19%, LD;17%, DD).  Per multivariate analysis(MVA), risk factors for GL after 20 years in pre–calcineurin inhibitor(CNI) era were human leukocyte antigen(HLA) mismatches >3 antigens, pretransplant type 1 diabetes mellitus(DM1); in CNI era, a history of rejection, female gender.  New comorbidities after 20 years were common: CVD(13%, non-DM1;18%, DM1), infections(27%, non-DM1;37%, DM1), 20-29 years posttransplant.  Cancer after 20 years included: nonmelanotic skin cancer,22%; solid organ,7%; post-transplant lymphoproliferative disease(PTLD),2%.  To improve long-term outcomes, clinical trials on prevention, recognition, and treatment of new comorbidities are needed.

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