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Murine cytomegalovirus dissemination but not reactivation in donor-positive/recipient-negative allogeneic kidney transplantation can be effectively prevented by transplant immune tolerance.

ABSTRACT: Cytomegalovirus (CMV) reactivation from latently infected donor organs post-transplantation and its dissemination cause significant comorbidities in transplant recipients. Transplant-induced inflammation combined with chronic immunosuppression has been thought to provoke CMV reactivation and dissemination, although sequential events in this process have not been studied. Here, we investigated this process in a high-risk donor CMV-positive to recipient CMV-negative allogeneic murine kidney transplantation model. Recipients were either treated with indefinite immunosuppression or tolerized in a donor-specific manner. Untreated recipients served as controls. Kidney allografts from both immunosuppressed and tolerized recipients showed minimal alloimmunity-mediated graft inflammation and normal function for up to day 60 post-transplantation. However, despite the absence of such inflammation in the immunosuppressed and tolerized groups, CMV reactivation in the donor positive kidney allograft was readily observed. Interestingly, subsequent CMV replication and dissemination to distant organs only occurred in immunosuppressed recipients in which CMV-specific CD8 T cells were functionally impaired; whereas in tolerized recipients, host anti-viral immunity was well-preserved and CMV dissemination was effectively prevented. Thus, our studies uncoupled CMV reactivation from its dissemination, and underscore the potential role of robust transplantation tolerance in preventing CMV diseases following allogeneic kidney transplantation.

SUBMITTER: Dangi A

PROVIDER: S-EPMC7311252 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Human Cytomegalovirus Latency and Reactivation in Allogeneic Hematopoietic Stem Cell Transplant Recipients.

Project description:Human cytomegalovirus (HCMV) reactivation is a major infectious cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). HCMV is a ubiquitous beta-herpesvirus which asymptomatically infects immunocompetent individuals but establishes lifelong latency, with the potential to reactivate to a life-threatening productive infection when the host immune system is suppressed or compromised. Opportunistic HCMV reactivation is the most common viral complication following engraftment after HSCT and is associated with a marked increase in non-relapse mortality, which appears to be linked to complex effects on post-transplant immune recovery. This minireview explores the cellular sites of HCMV latency and reactivation in HSCT recipients and provides an overview of the risk factors for HCMV reactivation post-HSCT. The impact of HCMV in shaping post-transplant immune reconstitution and its relationship with patient outcomes such as relapse and graft-versus-host disease will be discussed. Finally, we survey current and emerging strategies to prevent and control HCMV reactivation in HSCT recipients, with recent developments including adoptive T cell therapies to accelerate HCMV-specific T cell reconstitution and new anti-HCMV drug therapy for HCMV reactivation after HSCT.

| S-EPMC6546901 | biostudies-literature

Sequential anti-cytomegalovirus response monitoring may allow prediction of cytomegalovirus reactivation after allogeneic stem cell transplantation.

Project description:BackgroundReconstitution of cytomegalovirus-specific CD3(+)CD8(+) T cells (CMV-CTLs) after allogeneic hematopoietic stem cell transplantation (HSCT) is necessary to bring cytomegalovirus (CMV) reactivation under control. However, the parameters determining protective CMV-CTL reconstitution remain unclear to date.Design and methodsIn a prospective tri-center study, CMV-CTL reconstitution was analyzed in the peripheral blood from 278 patients during the year following HSCT using 7 commercially available tetrameric HLA-CMV epitope complexes. All patients included could be monitored with at least CMV-specific tetramer.ResultsCMV-CTL reconstitution was detected in 198 patients (71%) after allogeneic HSCT. Most importantly, reconstitution with 1 CMV-CTL per µl blood between day +50 and day +75 post-HSCT discriminated between patients with and without CMV reactivation in the R+/D+ patient group, independent of the CMV-epitope recognized. In addition, CMV-CTLs expanded more daramtaically in patients experiencing only one CMV-reactivation than those without or those with multiple CMV reactivations. Monitoring using at least 2 tetramers was possible in 63% (n?=?176) of the patients. The combinations of particular HLA molecules influenced the numbers of CMV-CTLs detected. The highest CMV-CTL count obtained for an individual tetramer also changed over time in 11% of these patients (n?=?19) resulting in higher levels of HLA-B*0801 (IE-1) recognizing CMV-CTLs in 14 patients.ConclusionsOur results indicate that 1 CMV-CTL per µl blood between day +50 to +75 marks the beginning of an immune response against CMV in the R+/D+ group. Detection of CMV-CTL expansion thereafter indicates successful resolution of the CMV reactivation. Thus, sequential monitoring of CMV-CTL reconstitution can be used to predict patients at risk for recurrent CMV reactivation.

| S-EPMC3521740 | biostudies-literature

Recipient and donor genetic variants associated with mortality after allogeneic hematopoietic cell transplantation.

Project description:Many studies have suggested that genetic variants in donors and recipients are associated with survival-related outcomes after allogeneic hematopoietic cell transplantation (HCT), but these results have not been confirmed. Therefore, the utility of testing genetic variants in donors and recipients for risk stratification or understanding mechanisms leading to mortality after HCT has not been established. We tested 122 recipient and donor candidate variants for association with nonrelapse mortality (NRM) and relapse mortality (RM) in a cohort of 2560 HCT recipients of European ancestry with related or unrelated donors. Associations discovered in this cohort were tested for replication in a separate cohort of 1710 HCT recipients. We found that the donor rs1051792 A allele in MICA was associated with a lower risk of NRM. Donor and recipient rs1051792 genotypes were highly correlated, making it statistically impossible to determine whether the donor or recipient genotype accounted for the association. Risks of grade 3 to 4 graft-versus-host disease (GVHD) and NRM in patients with grades 3 to 4 GVHD were lower with donor MICA-129Met but not with MICA-129Val, implicating MICA-129Met in the donor as an explanation for the decreased risk of NRM after HCT. Our analysis of candidate variants did not show any other association with NRM or RM. A genome-wide association study did not identify any other variants associated with NRM or RM.

| S-EPMC7391140 | biostudies-literature

Letermovir for Prevention of Cytomegalovirus Reactivation in Haploidentical and Mismatched Adult Donor Allogeneic Hematopoietic Cell Transplantation with Post-Transplantation Cyclophosphamide for Graft-versus-Host Disease Prophylaxis.

Project description:Cytomegalovirus (CMV) is serious viral infection in allogeneic hematopoietic cell transplantation (allo-HCT) recipients. November 2017, the novel CMV DNA terminase complex inhibitor letermovir was approved for prophylaxis of CMV infection in CMV-seropositive allo-HCT recipients. Here we sought to determine the effectiveness of letermovir in preventing CMV infection in CMV-seropositive patients undergoing haploidentical or mismatched adult unrelated donor allo-HCT using post-transplantation cyclophosphamide-based graft-versus host-disease prophylaxis. Sixty-four patients underwent transplantation between 2014 and 2019, of whom 32 received letermovir and 32 did not receive letermovir. The day 180 cumulative incidence of CMV infection requiring therapy was 45.3% (95% confidence interval [CI], 32.7% to 57.1%) in the entire cohort, 68.8% (95% CI, 48.9% to 82.2%) in the patients who did not receive letermovir, and 21.9% (95% CI, 9.5% to 37.6%; P < .001) in patients who received letermovir. Adjusting for regimen intensity, disease histology, and age, the hazard ratio for CMV infection was .19 (95% CI, .08 to .47; P < .001) in patients who received primary prophylaxis with letermovir. The 1-year cumulative incidence of treatment- related mortality was similar between patients with and without letermovir treatment (16.9% versus 18.9%), as was overall survival (64.0% versus 49.0%). Persistent CMV infection requiring >28 days of therapy was more common in patients who did not receive letermovir (31.2% versus 6.2%; P = .02). In summary, letermovir was effective in preventing CMV infection in this high-risk population of HLA-mismatched allo-HCT recipients.

| S-EPMC8441845 | biostudies-literature

Cytomegalovirus-specific neutralizing antibodies effectively prevent uncontrolled infection after allogeneic hematopoietic stem cell transplantation.

Project description:Cytomegalovirus (CMV) infection remains one of the most frequent and life-threatening infectious complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Herein, we comprehensively compared the immune cells of patients with uncontrolled and controlled CMV infection post-allo-HSCT and found that B-cells were extraordinarily insufficient because of impaired B-cells reconstitution in the uncontrolled infection group. Furthermore, in the controlled infection group, reconstructed B-cells showed signatures of mature B-cells, high expression of CXCR4 and IFITM1, and enrichment of CMV-associated B-cell receptors, which were lacking in the uncontrolled infection group. Consistently, sera from the uncontrolled infection group failed to inhibit CMV infection via neutralizing virus in vitro because of its lower content of anti-CMV-specific immunoglobulin G (IgG) than the controlled infection group. Overall, these results highlighted the contribution of B cells and anti-CMV-specific neutralizing IgGs to the restraint of CMV infection post-allo-HSCT, suggesting their potential as a supplementary treatment to improve outcomes.

| S-EPMC9485910 | biostudies-literature

Paired Donor and Recipient Immunophenotyping in Allogeneic Hematopoietic Stem Cell Transplantation: A Cellular Network Approach.

Project description:Success and complications of allogeneic hematopoietic stem cell transplantation (alloHSCT) are closely connected to the transferred graft and immune reconstitution post alloHSCT. Due to the variety of immune cells and their distinct roles, a broad evaluation of the immune cellular network is warranted in mobilization and reconstitution studies in alloHSCT. Here, we propose a comprehensive phenotypic analysis of 26 immune cell subsets with multicolor flow cytometry from only 100µl whole blood per time point. Using this approach, we provide an extensive longitudinal analysis of almost 200 time points from 21 donor-recipient pairs. We observe a broad mobilization of innate and adaptive immune cell subsets after granulocyte-colony stimulating factor (G-CSF) treatment of healthy donors. Our data suggest that the relative quantitative immune cell subset composition in recipients approaches that of healthy donors from day +180 post alloHSCT onwards. Correlation of donor and recipient cell counts reveals distinct association patterns for different immune cell subsets and hierarchical clustering of recipient cell counts identifies distinct reconstitution groups in the first month after transplantation. We suggest our comprehensive immune subset analysis as a feasible and time efficient approach for a broad immune assessment for future clinical studies in the context of alloHSCT. This comprehensive cell composition assessment can be a critical step towards personalized graft composition strategies and individualized therapy management in areas such as GvHD prophylaxis in the highly complex immunological setting of alloHSCT.

| S-EPMC9168993 | biostudies-literature

Effects of donor/recipient human leukocyte antigen mismatch on human cytomegalovirus replication following liver transplantation.

Project description:BackgroundNatural immunity against cytomegalovirus (CMV) can control virus replication after solid organ transplantation; however, it is not known which components of the adaptive immune system mediate this protection. We investigated whether this protection requires human leukocyte antigen (HLA) matching between donor and recipient by exploiting the fact that, unlike transplantation of other solid organs, liver transplantation does not require HLA matching, but some donor and recipient pairs may nevertheless be matched by chance.MethodsTo further investigate this immune control, we determined whether chance HLA matching between donor (D) and recipient (R) in liver transplants affected a range of viral replication parameters.ResultsIn total, 274 liver transplant recipients were stratified according to matches at the HLA A, HLA B, and HLA DR loci. The incidence of CMV viremia, kinetics of replication, and peak viral load were similar between the HLA matched and mismatched patients in the D+/R+ and D-/R+ transplant groups. D+/R- transplants with 1 or 2 mismatches at the HLA DR locus had a higher incidence of CMV viremia >3000 genomes/mL blood compared to patients matched at this locus (78% vs. 17%; P = 0.01). Evidence was seen that matching at the HLA A locus had a small effect on peak viral loads in D+/R- patients, with median peak loads of 3540 and 14,706 genomes/mL in the 0 and combined (1 and 2) mismatch groups, respectively (P = 0.03).ConclusionOverall, our data indicate that, in the setting of liver transplantation, prevention of CMV infection and control of CMV replication by adaptive immunity is minimally influenced by HLA matching of the donor and recipient. Our data raise questions about immune control of CMV in the liver and also about the cells in which the virus is amplified to give rise to CMV viremia.

| S-EPMC4345424 | biostudies-literature

Increasing Proportion of High-risk Cytomegalovirus Donor-positive/Recipient-negative Serostatus in Solid Organ Transplant Recipients.

Project description:BackgroundCytomegalovirus (CMV) donor-positive/recipient-negative (D+R-) serostatus is independently associated with worse allograft and patient survival across solid organ transplant (SOT) types. We characterized trends in CMV D+R- serostatus among adult SOT recipients performed in the United States.MethodsDonor (D) and recipient (R) CMV serostatus and demographic factors were obtained from the Scientific Registry of Transplant Recipients for persons ≥18 y undergoing a first SOT between January 1, 2000, and December 31, 2020. The proportions of D+R- SOTs over time were assessed using Chi square for trend and modeled through 2040. Factors associated with D/R seropositivity were assessed using logistic models.ResultsAmong 472 549 SOTs, the average proportion of D+R- SOTs increased significantly among kidney, liver, heart, and lung between 2000 to 2009 and 2010 to 2020: 18.0% to 18.3% ( P = 0.034), 19.4% to 21.8% ( P < 0.001), 22.2% to 25.5% ( P < 0.001), and 23.6% to 27.0% ( P < 0.001), respectively. The increased proportion over time resulted from a disproportionate increase in R- (34.9% to 37.0% for all organ types, P < 0.001) and a smaller corresponding change in D+ (60.8% to 60.3%, P < 0.001).ConclusionsThe proportion of high-risk CMV D+R- SOTs increased significantly across all organs and is projected to continue to increase. These findings inform population-level strategies to mitigate the negative impact of CMV D+R- in SOT.

| S-EPMC10050221 | biostudies-literature

Prediction of Three-Year Mortality After Deceased Donor Kidney Transplantation in Adults with Pre-Transplant Donor and Recipient Variables.

Project description:BACKGROUND Prognostic models for 3-year mortality after kidney transplantation based on pre-transplant donor and recipient variables may avoid futility and thus improve donor organ allocation. MATERIAL AND METHODS There were 1546 consecutive deceased-donor kidney transplants in adults (January 1, 2000 to December 31, 2012) used to identify pre-transplant donor and recipient variables with significant independent influence on long-term survival (Cox regression modelling). Detected factors were used to develop a prognostic model for 3-year mortality in 1289 patients with follow-up of >3 years (multivariable logistic regression). The sensitivity and specificity of this model's prognostic ability was assessed with the area under the receiver operating characteristic curve (AUROC). RESULTS Highly immunized recipients [hazard ratio (HR: 2.579, 95% CI: 1.272-4.631], high urgency recipients (HR: 3.062, 95% CI: 1.294-6.082), recipients with diabetic nephropathy (HR: 3.471, 95% CI: 2.476-4.751), as well as 0, 1, or 2 HLA DR mismatches (HR: 1.349, 95% CI: 1.160-1.569) were independent and significant risk factors for patient survival. Younger recipient age ≤42.1 years (HR: 0.137, 95% CI: 0.090-0.203), recipient age 42.2-52.8 years (HR: 0.374, 95% CI: 0.278-0.498), recipient age 52.9-62.8 years (HR: 0.553, 95% CI: 0.421-0.723), short cold ischemic times ≤11.8 hours (HR: 0.602, 95% CI: 0.438-0.814) and cold ischemic times 11.9-15.3 hours (HR: 0.736, 95% CI: 0.557-0.962) reduced this risk independently and significantly. The AUROC of the derived model for 3-year post-transplant mortality with these variables was 0.748 (95% CI: 0.689-0.788). CONCLUSIONS Older, highly immunized or high urgency transplant candidates with anticipated longer cold ischemic times, who were transplanted with the indication of diabetic nephropathy should receive donor organs with no HLA DR mismatches to improve their mortality risk.

| S-EPMC6540619 | biostudies-literature

Adult Living-Donor Kidney Transplantation, Donor Age, and Donor-Recipient Age.

Project description:IntroductionOwing to organ shortage, the number of kidney transplantation (KT) involving older adult living donors is increasing. We aimed to investigate the effects of living-donor age and donor-recipient age differences on KT outcomes.MethodsThis single-center, retrospective cohort study involved 853 adult LDKTs performed between January 2008 and December 2018. Recipients were stratified into the following 5 groups based on donor age and donor-recipient age difference: donor age, 30 to 49 years and age difference, -10 to 15 years; donor age, 50 to 69 years and age difference, -10 to 15 years; donor age, 50 to 69 years and age difference, 15 to 40 years; donor age, 70 to 89 years and age difference, -10 to 15 years; and donor age, 70 to 89 years and age difference, 15 to 40 years (groups 1, 2, 3, 4, and 5, respectively). As a primary outcome, the risk of graft loss was investigated. The secondary outcomes were postoperative estimated glomerular filtration rates (eGFRs) and mortality rates of recipients.ResultsGroup 4, representing KT between older adult donors and older adult recipients, had the highest graft loss risk and mortality. The eGFRs of the recipients from donors aged 70 to 89 years (groups 4 and 5) were significantly lower than those from donors in the other groups. Although the differences in the eGFR between groups 4 and 5 were not significant, the eGFR of group 4 was lower than that of group 5 at 6 months post-KT.ConclusionLDKTs from older adult donors to older adult recipients resulted in the worst graft survival and mortality rates.

| S-EPMC8640566 | biostudies-literature

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