Lymphotoxin ß receptor and tertiary lymphoid organs shape acute and chronic allograft rejection.

Solid organ transplantation remains the life-saving treatment for end-stage organ failure, but chronic rejection remains a major obstacle to long-term allograft outcomes and has not improved substantially. Tertiary lymphoid organs (TLO) are ectopic lymphoid structures that form under conditions of chronic inflammation, and evidence from human transplantation suggests that TLO regularly form in allografts undergoing chronic rejection. In this study, we utilized a mouse renal transplantation model and manipulation of the lymphotoxin alpha (LTα) - lymphotoxin beta receptor (LTßR) pathway, which is essential for TLO formation, to define the role of TLO in transplantation. We showed that intragraft TLO are sufficient to activate the alloimmune response and mediate graft rejection in a model where the only lymphoid organs are TLO in the allograft. When transplanted to recipients with a normal set of secondary lymphoid organs, the presence of graft TLO or LTα overexpression accelerated rejection. If the LTßR pathway was disrupted in the donor graft, TLO formation was abrogated, and graft survival prolonged. Intravital microscopy of renal TLO demonstrated that local T and B cell activation in TLOs is similar to that observed in secondary lymphoid organs. In summary, we demonstrated that immune activation in TLO contributes to local immune responses, leading to earlier allograft failure. TLO and the LTαß-LTßR pathway are therefore prime targets to limit local immune responses and prevent allograft rejection. These findings are applicable to other diseases such as autoimmunity or tumors, where either limiting or boosting local immune responses is beneficial and improves disease outcomes.

Real-World Experience With Maribavir for Treatment of Cytomegalovirus Infection in High-Risk Solid Organ Transplant Recipients.

We evaluated use of maribavir (MBV) for treatment of 15 episodes of refractory/resistant cytomegalovirus infection in 13 solid organ transplant recipients. Treatment failure due to treatment-emergent MBV resistance or early virological recurrence after MBV discontinuation occurred in 7 (47%) episodes. Sustained viral clearance was achieved in 6 (40%) episodes.

Comparison of Cardiac Allograft Vasculopathy Incidence Between Simultaneous Multi-Organ and Isolated Heart Transplant Recipients in the United States.

BACKGROUND: Prior studies have shown reduced development of cardiac allograft vasculopathy (CAV) in multi-organ transplant recipients. The aim of this study was to compare the incidence of CAV between isolated heart transplants and simultaneous multi-organ heart transplants in the contemporary era. METHODS: We utilized the Scientific Registry of Transplant Recipients to perform a retrospective analysis of first-time adult heart transplant recipients between January 1, 2010 and December 31, 2019 in the United States. The primary endpoint was the development of angiographic CAV within 5 years of follow-up. RESULTS: Among 20,591 patients included in the analysis, 1,279 (6%) underwent multi-organ heart transplantation (70% heart-kidney, 16% heart-liver, 13% heart-lung, and 1% triple-organ) and 19,312 (94%) were isolated heart transplant recipients. The average age was 53 years and 74% were male. There were no significant between-group differences in cold ischemic time between the groups. The incidence of acute rejection during the first year after transplant was significantly lower in the multi-organ group (18% vs. 33%, p<0.01). The 5-year incidence of CAV was 33% in the isolated heart group and 27% in the multi-organ group (p<0.0001); differences in CAV incidence were seen as early as 1 year after transplant and persisted over time. In multivariable analysis, multi-organ heart transplant recipients had a significantly lower likelihood of CAV at 5 years (hazard ratio=0.76, 95% confidence interval: 0.66-0.88, p<0.01). CONCLUSIONS: Simultaneous multi-organ heart transplantation is associated with significantly lower long-term risk of angiographic CAV compared with isolated heart transplantation in the contemporary era.

Impact of COVID-19 on liver transplant recipients: A nationwide cohort study evaluating hospitalization, transplant rejection, and inpatient mortality.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has posed a major public health concern worldwide. Patients with comorbid conditions are at risk of adverse outcomes following COVID-19. Solid organ transplant recipients with concurrent immunosuppression and comorbidities are more susceptible to a severe COVID-19 infection. It could lead to higher rates of inpatient complications and mortality in this patient population. However, studies on COVID-19 outcomes in liver transplant (LT) recipients have yielded inconsistent findings. AIM: To evaluate the impact of the COVID-19 pandemic on hospital-related outcomes among LT recipients in the United States. METHODS: We conducted a retrospective cohort study using the 2019-2020 National Inpatient Sample database. Patients with primary LT hospitalizations and a secondary COVID-19 diagnosis were identified using the International Classification of Diseases, Tenth Revision coding system. The primary outcomes included trends in LT hospitalizations before and during the COVID-19 pandemic. Secondary outcomes included comparative trends in inpatient mortality and transplant rejection in LT recipients. RESULTS: A total of 15720 hospitalized LT recipients were included. Approximately 0.8% of patients had a secondary diagnosis of COVID-19 infection. In both cohorts, the median admission age was 57 years. The linear trends for LT hospitalizations did not differ significantly before and during the pandemic (P = 0.84). The frequency of in-hospital mortality for LT recipients increased from 1.7% to 4.4% between January 2019 and December 2020. Compared to the pre-pandemic period, a higher association was noted between LT recipients and in-hospital mortality during the pandemic, with an odds ratio (OR) of 1.69 [95% confidence interval (CI): 1.55-1.84), P < 0.001]. The frequency of transplant rejections among hospitalized LT recipients increased from 0.2% to 3.6% between January 2019 and December 2020. LT hospitalizations during the COVID-19 pandemic had a higher association with transplant rejection than before the pandemic [OR: 1.53 (95%CI: 1.26-1.85), P < 0.001]. CONCLUSION: The hospitalization rates for LT recipients were comparable before and during the pandemic. Inpatient mortality and transplant rejection rates for hospitalized LT recipients were increased during the COVID-19 pandemic.

Tixagevimab/cilgavimab prophylaxis against COVID-19 in solid organ transplant recipients: a systematic review and meta-analysis.

Background: Tixagevimab/cilgavimab (Tix/Cil) shows promise as a prophylactic treatment against coronavirus disease 2019 (COVID-19) in solid organ transplant recipients (SOTRs). This study was performed to assess the effectiveness of Tix/Cil for preexposure prophylaxis against COVID-19 in this population. Methods: We systematically searched the Cochrane Library, Web of Science, PubMed, and Embase databases to identify articles relevant to our study up to December 15, 2023. Comprehensive Meta-Analysis (ver. 3.0) was used for data analysis. Results: The meta-analysis included seven eligible retrospective studies, encompassing a total of 4,026 SOTRs. The analysis revealed significant differences in SOTRs who received Tix/Cil preexposure prophylaxis relative to those who did not. Specifically, these differences were observed in the incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (odds ratio [OR], 0.30; 95% confidence interval [CI], 0.15-0.60), hospitalization (OR, 0.24; 95% CI, 0.08-0.70), and intensive care unit admission (OR, 0.07; 95% CI, 0.02-0.22). However, mortality rate did not differ significantly between the two groups (P=0.06). Conclusions: The evidence supporting the effectiveness of Tix/Cil as preexposure prophylaxis against SARS-CoV-2 in SOTRs is of a low to moderate level. Further high-quality research is necessary to understand its effects on this population.

Immune response analysis of solid organ transplantation recipients inoculated with inactivated COVID-19 vaccine: A retrospective analysis.

Objective: This study aimed to evaluate the efficacy and safety of solid organ transplantation recipients inoculated with an inactivated COVID-19 vaccine. Methods: We retrospectively analyzed the antibody levels and related adverse events of non-transplantation subjects and solid organ transplant recipients, both pre-transplantation (individuals awaiting organ transplantation) and post-transplantation (individuals who have undergone organ transplantation), who received inactivated COVID-19 vaccines from February 2021 to July 2022. Results: The study included 38 pre-transplantation vaccination group, 129 post-transplantation vaccination group, and 246 non-transplantation group. The antibody titer was assessed monthly within the period of 1-12 months after the last injection. The antibody-positive rate among the three groups were 36.84, 20.30, 61.17% (P < 0.05). The antibody-positive rates among three groups with one, two doses vaccine were not significantly different (P > 0.05), but were significantly different after three doses (P < 0.05). The antibody titers among three groups were significantly different after two doses (P < 0.05). Adverse reactions occurred in six transplant recipients, which were relieved after treatment, and not in the non-transplantation subjects. Conclusion: Inactivated COVID-19 vaccine is safe and effective for solid organ transplantation recipients, at least two doses of which should be completed before organ transplant surgery.

Homozygosity in any HLA locus is a risk factor for specific antibody production: the taboo concept 2.0.

Objective: In a cooperative study of the University Hospital Leipzig, University of Leipzig, and the Charité Berlin on kidney transplant patients, we analysed the occurrence of HLA-specific antibodies with respect to the HLA setup of the patients. We aimed at the definition of specific HLA antigens towards which the patients produced these antibodies. Methods: Patients were typed for the relevant HLA determinants using mainly the next-generation technology. Antibody screening was performed by the state-of-the-art multiplex-based technology using microspheres coupled with the respective HLA alleles of HLA class I and II determinants. Results: Patients homozygous for HLA-A*02, HLA-A*03, HLA-A*24, HLA-B*07, HLA-B*18, HLA-B*35, HLA-B*44, HLA-C*03, HLA-C*04, and HLA-C*07 in the class I group and HLA-DRB1*01, HLA-DRB1*03, HLA-DRB1*07, HLA-DRB1*15, HLA-DQA1*01, HLA-DQA1*05, HLA-DQB1*02, HLA-DQB1*03(7), HLA-DQB1*06, HLA-DPA1*01, and HLA-DPB1*04 in the class II group were found to have a significant higher antibody production compared to the heterozygous ones. In general, all HLA determinants are affected. Remarkably, HLA-A*24 homozygous patients can produce antibodies towards all HLA-A determinants, while HLA-B*18 homozygous ones make antibodies towards all HLA-B and selected HLA-A and C antigens, and are associated with an elevation of HLA-DRB1, parts of DQB1 and DPB1 alleles. Homozygosity for the HLA class II HLA-DRB1*01, and HLA-DRB1*15 seems to increase the risk for antibody responses against most of the HLA class I antigens (HLA-A, HLA-B, and HLA-C) in contrast to HLA-DQB1*03(7) where a lower risk towards few HLA-A and HLA-B alleles is found. The widely observed differential antibody response is therefore to be accounted to the patient's HLA type. Conclusion: Homozygous patients are at risk of producing HLA-specific antibodies hampering the outcome of transplantation. Including this information on the allocation procedure might reduce antibody-mediated immune reactivity and prevent graft loss in a patient at risk, increasing the life span of the transplanted organ.

The question of screening organ donors for hepatitis e virus: a case report of transmission by kidney transplantation in France and a review of the literature.

BACKGROUND: Hepatitis E is a potentially serious infection in organ recipients, with an estimated two-thirds of cases becoming chronic, and with a subsequent risk of cirrhosis and death. In Europe, transmission occurs most often through the consumption of raw or undercooked pork, more rarely through blood transfusion, but also after solid organ transplantation. Here we describe a case of Hepatitis E virus (HEV) infection transmitted following kidney transplantation and review the literature describing cases of HEV infection transmitted by solid organ transplantation. CASE PRESENTATION: Three weeks after kidney transplantation, the patient presented with an isolated minimal increase in GGT and hepatic cytolysis 6 months later, leading to the diagnosis of genotype 3c hepatitis E, with a plasma viral load of 6.5 log10IU/mL. In retrospect, HEV RNA was detected in the patient's serum from the onset of hepatitis, and in the donor's serum on the day of donation, with 100% identity between the viral sequences, confirming donor-derived HEV infection. Hepatitis E had a chronic course, was treated by ribavirin, and relapsed 10 months after the end of treatment. DISCUSSION: Seven cases of transmission of HEV by solid organ transplantation have been described since 2012 without systematic screening for donors, all diagnosed at the chronic infection stage; two patients died. HEV organ donor transmission may be underestimated and there is insufficient focus on immunocompromised patients in whom mild liver function test impairment is potentially related to hepatitis E. However, since HEV infection is potentially severe in these patients, and as evidence accumulates, we believe that systematic screening of organ donors should be implemented for deceased and living donors regardless of liver function abnormalities, as is already the case in the UK and Spain. In January 2024, the French regulatory agency of transplantation has implemented mandatory screening of organ donors for HEV RNA.

Dysfunction of infiltrating cytotoxic CD8+ T cells within the graft promotes murine kidney allotransplant tolerance.

Tolerance of mouse kidney allografts arises in grafts that develop regulatory Tertiary Lymphoid Organs (rTLOs). scRNAseq data and adoptive transfer of alloreactive T cells post-transplant showed that cytotoxic CD8+ T cells are reprogrammed within the accepted graft to an exhausted/regulatory-like phenotype mediated by IFN-γ. Establishment of rTLOs was required since adoptive transfer of alloreactive T cells prior to transplantation results in kidney allograft rejection. Despite intragraft CD8+ cells with a regulatory phenotype, they were not essential for the induction and maintenance of kidney allograft tolerance since renal allotransplantation into CD8 KO recipients resulted in acceptance and not rejection. Analysis of scRNAseq data from allograft kidneys and malignant tumors identified similar regulatory-like cell types within the T cell clusters and trajectory analysis showed that cytotoxic CD8+ T cells are reprogrammed into an exhausted/regulatory-like phenotype intratumorally. Induction of cytotoxic CD8+ T cell dysfunction of infiltrating cells appears to be a beneficial mechanistic pathway that protects the kidney allotransplant from rejection through a process we call "defensive tolerance." This pathway has implications for our understanding of allotransplant tolerance and tumor resistance to host immunity.

Challenges for the improvement of valganciclovir prophylaxis in solid organ transplantation and the possible role of therapeutic drug monitoring in adults.

Cytomegalovirus (CMV) infection frequently occurs after solid organ transplantation and is associated with an increased morbidity and mortality. Fortunately, the development of valganciclovir prophylaxis has lowered the incidence of CMV infection and its complications in immunosuppressed solid organ transplant recipients. However, breakthrough infections during valganciclovir prophylaxis and late CMV infection after cessation of valganciclovir prophylaxis still occur with the current prophylactic strategy. Additionally, valganciclovir resistance has emerged among CMV strains, which complicates the treatment of CMV infections. Furthermore, the use of valganciclovir is associated with myelotoxicity, which can lead to the premature withdrawal of prophylaxis. It is important to address these current issues in order to improve the standard care after solid organ transplantation. This paper will therefore discuss the clinical practice of valganciclovir prophylaxis, elaborate on its issues and suggest how to improve the current prophylactic strategy with a possible role for therapeutic drug monitoring.

The Public Health Service "Increased Risk" 2020 Policy Change Has not Improved Organ Utilization in the United States: A Nationwide Cohort Study.

Objective: To assess the effects of the 2020 United States Public Health Service (PHS) "Increased Risk" Guidelines update. Background: Donors labeled as "Increased Risk" for transmission of infectious diseases have been found to have decreased organ utilization rates despite no significant impact on recipient survival. Recently, the PHS provided an updated guideline focused on "Increased Risk" organ donors, which included the removal of the "Increased Risk" label and the elimination of the separate informed consent form, although the actual increased risk status of donors is still ultimately transmitted to transplant physicians. We sought to analyze the effect of this update on organ utilization rates. Methods: This was a retrospective analysis of the Organ Procurement and Transplantation Network database which compared donor organ utilization in the 2 years before the June 2020 PHS Guideline update for increased-risk donor organs (June 2018-May 2020) versus the 2 years after the update (August 2020-July 2022). The organ utilization rate for each donor was determined by dividing the number of organs transplanted by the total number of organs available for procurement. Student t test and multivariable logistic regression models were used for analysis. Results: There were 17,272 donors in the preupdate cohort and 17,922 donors in the postupdate cohort; of these, 4,977 (28.8%) and 3,893 (21.7%) donors were considered "Increased Risk", respectively. There was a 2% decrease in overall organ utilization rates after the update, driven by a 3% decrease in liver utilization rates and a 2% decrease in lung utilization rates. After multivariable adjustment, donors in the postupdate cohort had 10% decreased odds of having all organs transplanted. Conclusions: The 2020 PHS "Increased Risk" Donor Guideline update was not associated with an increase in organ utilization rates in the first 2 years after its implementation, despite a decrease in the proportion of donors considered to be at higher risk. Further efforts to educate the community on the safe usage of high-risk organs are needed and may increase organ utilization.

Infectious Diseases Physician Management of Cryptococcal Meningitis in North America-Is Single High-Dose Liposomal Amphotericin B Being Used?

Background: Several recent randomized trials have been conducted in resource-limited settings for cryptococcal meningitis that have rapidly innovated international guidelines. The 2010 Infectious Diseases Society of America (IDSA) cryptococcal meningitis guideline has not been updated with recent trials. The 2022 AMBITION-cm trial found that a single 10-mg/kg dose of liposomal amphotericin B plus daily flucytosine and fluconazole for 2 weeks was noninferior to 1 week of amphotericin B deoxycholate with flucytosine. It is unknown whether physicians in high-resource settings are using this regimen or more traditional regimens. Methods: We developed an electronic survey in June 2023 to better understand whether physician members of the IDSA Emerging Infections Network (EIN) and Mycoses Study Group Education and Research Consortium (MSG-ERC) had used the AMBITION-cm induction regimen, would use the regimen in hypothetical clinical scenarios, and what perceived barriers to use existed. Results: A total of 242 of 561 (43%) physicians responded to the survey, of whom 205 provided care for persons with cryptococcal meningitis in the last year. Overall, 29 (14%) had used the AMBITION-cm regimen, and 176 (86%) had not. In various hypothetical clinical scenarios, only ∼10% of 209 respondents selected the AMBITION-cm regimen as preferred. Perceived barriers to uptake included the applicability of trials performed in low-resource settings to high-resource settings, that the regimen is not recommended in the 2010 IDSA guidelines, and the applicability to persons without HIV. Conclusions: Most respondents had not used the single-dose liposomal amphotericin B regimen, but the regimen is being used. Further study of this regimen in other patient populations and settings is necessary.

Ethical and Equity Guidance for Transplant Programs Considering Thoracoabdominal Normothermic Regional Perfusion (TA-NRP) for Procurement of Hearts.

Donation after circulatory determination of death (DCDD) is an accepted practice in the United States, but heart procurement under these circumstances has been debated. Although the practice is experiencing a resurgence due to the recently completed trials using ex vivo perfusion systems, interest in thoracoabdominal normothermic regional perfusion (TA-NRP), wherein the organs are reanimated in situ prior to procurement, has raised many ethical questions. We outline practical, ethical, and equity considerations to ensure transplant programs make well-informed decisions about TA-NRP. We present a multidisciplinary analysis of the relevant ethical issues arising from DCDD-NRP heart procurement, including application of the Dead Donor Rule and the Uniform Definition of Death Act, and provide recommendations to facilitate ethical analysis and input from all interested parties. We also recommend informed consent, as distinct from typical "authorization," for cadaveric organ donation using TA-NRP.

An Ethics Committee's Evaluation of Normothermic Regional Perfusion (NRP) in 2018-Unsatisfactory Answers Then-and Now.

An adult university hospital ethics committee evaluated a proposed TA-NRP protocol in the fall of 2018. The protocol raised ethical concerns about violation of the Uniform Determination of Death Act and the prohibition known as the Dead Donor Rule, with potential resultant legal consequences. An additional concern was the potential for increased mistrust by the community of organ donation and transplantation. The ethics committee evaluated the responses to these concerns as unable to surmount the ethical and legal boundaries and the ethics committee declined to endorse the procedure. These concerns endure.

Restoring the Organism as a Whole: Does NRP Resurrect the Dead?

The introduction of normothermic regional perfusion (NRP) in controlled donation after circulatory determination of death (cDCDD) protocols is by some regarded as controversial and ethically troublesome. One of the main concerns that opponents have about introducing NRP in cDCDD protocols is that reestablishing circulation will negate the determination of death by circulatory criteria, potentially resuscitating the donor. In this article, I argue that this is not the case. If we take a closer look at the concept of death underlying the circulatory criterion for determination of death, we find that the purpose of the criterion is to show whether the organism as a whole has died. I argue that this purpose is fulfilled by the circulatory criterion in cDCDD protocols, and that applying NRP does not negate the determination of death or resuscitate the donor.

Genomic full-length sequence of the novel HLA-C*06:364 allele.

HLA-C*06:364 differs from HLA-C*06:02:01:01 by a non-synonymous nucleotide substitution in exon 3.