Integrated Immunologic Monitoring in Solid Organ Transplantation: The Road Toward Torque Teno Virus-guided Immunosuppression

Jaksch, Péter; Görzer, Irene; Puchhammer‐Stöckl, Elisabeth; Bond, Gregor

doi:10.1097/tp.0000000000004153

Cited by 44 publications

(80 citation statements)

References 91 publications

(174 reference statements)

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“…The highly prevalent and non-pathogenic TTV is an emerging marker to monitor immunosuppression ( 17 , 18 ). Median average TTV loads from week eight until 24 in the IgG apheresis group were 4.0 x 10 4 (IQR: 5.6 x 10 3 , 9.1 x 10 4 ) and 5.2 x 10 4 (IQR: 2.9 x 10 4 , 2.6 x 10 5 ) copy numbers in the LDL apheresis group.…”

Section: Resultsmentioning

confidence: 99%

“…Our study cohort comprises a mixed repertoire of immunocompromised patients, either due to comorbidities, such as liver or metabolic disease, or due to additional immunosuppressive medications. TTV, a highly prevalent and non-pathogenic small nonenveloped DNA virus, is an emerging marker to monitor immunosuppression in recipients of solid organ transplantations ( 17 , 20 ) and in patients with rheumatologic disease ( 21 ). Moreover, TTV is associated with immunocompetence in patients with HIV ( 22 ) and with response to SARS-CoV-2 vaccination in immunocompromised patients ( 18 , 23 ).…”

Section: Discussionmentioning

confidence: 99%

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SARS-CoV-2 IgG spike protein antibody response in mRNA-1273 Moderna® vaccinated patients on maintenance immunoapheresis – a cohort study

et al. 2022

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BackgroundThe SARS-CoV-2 pandemic increased mortality and morbidity among immunocompromised populations. Vaccination is the most important preventive measure, however, its effectiveness among patients depending on maintenance immunoglobulin G (IgG) apheresis to control autoimmune disease activity is unknown. We aimed to examine the humoral immune response after mRNA-1273 Moderna® vaccination in immunoapheresis patients.MethodsWe prospectively monitored SARS-CoV-2 IgG spike (S) protein antibody levels before and after each IgG (exposure) or lipid (LDL) apheresis (controls) over 12 weeks and once after 24 weeks. Primary outcome was the difference of change of SARS-CoV-2 IgG S antibody levels from vaccination until week 12, secondary outcome was the difference of change of SARS-CoV-2 IgG S antibody levels by apheresis treatments across groups.ResultsWe included 6 IgG and 18 LDL apheresis patients. After 12 weeks the median SARS-CoV-2 IgG S antibody level was 115 (IQR: 0.74, 258) in the IgG and 1216 (IQR: 788, 2178) in the LDL group (p=0.03). Median SARS-CoV-2 IgG S antibody reduction by apheresis was 76.4 vs. 23.7% in the IgG and LDL group (p=0.04). The average post- vs. pre-treatment SARS-CoV-2 IgG S antibody rebound in the IgG group vs. the LDL group was 46.1 and 6.44%/week from prior until week 12 visit.ConclusionsIgG apheresis patients had lower SARS-CoV-2 IgG S antibody levels compared to LDL apheresis patients, but recovered appropriately between treatment sessions. We believe that IgG apheresis itself probably has less effect on maintaining the immune response compared to concomitant immunosuppressive drugs. Immunization is recommended independent of apheresis treatment.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 IgG spike protein antibody response in mRNA-1273 Moderna® vaccinated patients on maintenance immunoapheresis – a cohort study

et al. 2022

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“…There is increasing evidence on the usefulness of TTV as a surrogate marker of the immune status in a variety of clinical scenarios ( Martin-Lopez et al, 2020 ; Honorato et al, 2021 ; Studenic et al, 2021 ), in particular SOT ( Fernandez-Ruiz et al, 2019 ; Redondo et al, 2022a ; Eldar-Yedidia et al, 2022 ; Jaksch et al, 2022 ), under the rationale that the T-cell-mediated immunity plays an instrumental role in controlling viral replication. Nevertheless, the relative contribution of the innate system—and its genetic determinants—has not been characterized so far.…”

Section: Discussionmentioning

confidence: 99%

“…The precise underlying mechanisms on how this immune control is carry out largely remain to be determined, although a major role has been proposed for the cellular arm. Belonging to the Alphatorquevirus genus and discovered in 1997 ( Nishizawa et al, 1997 ), Torque teno virus (TTV) has been proven by us and others to serve as a convenient surrogate marker of the overall status of immunosuppression after solid organ (SOT) and allogeneic hematopoietic stem cell transplantation (HSCT) ( Fernandez-Ruiz et al, 2019 ; Rezahosseini et al, 2019 ; Mouton et al, 2020 ; Redondo et al, 2022a ; Jaksch et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

“…The innate immunity acts as a frontline defense against viruses through an orchestrated response, that is, triggered upon recognition of viral motifs by pathogen recognition receptors (PRRs) present in macrophages and dendritic cells ( Takeuchi and Akira, 2010 ). The rationale for the use of TTV DNAemia as a biomarker of immune competence after SOT lies on the assumption that the viral kinetics is mainly dictated by the T-cell-mediated immunity ( Redondo et al, 2022a ; Jaksch et al, 2022 ). Indeed, various studies have shown a direct correlation between TTV DNA loads and calcineurin inhibitors trough levels ( Gorzer et al, 2014 ; Jaksch et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

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Impact of polymorphisms in genes orchestrating innate immune responses on replication kinetics of Torque teno virus after kidney transplantation

et al. 2022

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Background: Torque teno virus (TTV) DNAemia has been proposed as a surrogate marker of immunosuppression after kidney transplantation (KT), under the assumption that the control of viral replication is mainly exerted by T-cell-mediated immunity. However, Tthe impact on post-transplant TTV kinetics of single genetic polymorphisms (SNPs) in genes orchestrating innate responses remains unknown. We aimed to characterize the potential association between 14 of these SNPs and TTV DNA levels in a single-center cohort of KT recipients.Methods: Plasma TTV DNAemia was quantified by real-time PCR in 221 KT recipients before transplantation (baseline) and regularly through the first 12 post-transplant months. We performed genotyping of the following SNPs: CTLA4 (rs5742909, rs231775), TLR3 (rs3775291), TLR9 (rs5743836, rs352139), CD209 (rs735240, rs4804803), IFNL3 (rs12979860, rs8099917), TNF (rs1800629), IL10 (rs1878672, rs1800872), IL12B (rs3212227) and IL17A (rs2275913).Results: The presence of the minor G allele of CD209 (rs4804803) in the homozygous state was associated with undetectable TTV DNAemia at the pre-transplant assessment (adjusted odds ratio: 36.96; 95% confidence interval: 4.72–289.67; p-value = 0.001). After applying correction for multiple comparisons, no significant differences across SNP genotypes were observed for any of the variables of post-transplant TTV DNAemia analyzed (mean and peak values, areas under the curve during discrete periods, or absolute increments from baseline to day 15 and months 1, 3, 6 and 12 after transplantation).Conclusion: The minor G allele of CD209 (rs4804803) seems to exert a recessive protective effect against TTV infection in non-immunocompromised patients. However, no associations were observed between the SNPs analyzed and post-transplant kinetics of TTV DNAemia. These negative results would suggest that post-transplant TTV replication is mainly influenced by immunosuppressive therapy rather than by underlying genetic predisposition, reinforcing its clinical application as a biomarker of adaptive immunity.

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Assessment of the potential value of plasma Torque Teno virus DNA load monitoring to predict cytomegalovirus DNAemia in patients with hematological malignancies treated with small molecule inhibitors: A proof‐of‐concept study

Asunción

Giménez

Hernández‐Boluda

et al. 2023

Journal of Medical Virology

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It is unknown whether Torque Teno virus (TTV) DNA load monitoring could anticipate the development of infectious events in hematological patients undergoing treatment with small molecular targeting agents. We characterized the kinetics of plasma TTV DNA in patients treated with ibrutinib or ruxolitinib and assessed whether TTV DNA load monitoring could predict the occurrence of Cytomegalovirus (CMV) DNAemia or the magnitude of CMV‐specific T‐cell responses. Multicenter, retrospective, observational study, recruiting 20 patients treated with ibrutinib and 21 with ruxolitinib. Plasma TTV and CMV DNA loads were quantified by real‐time PCR at baseline and days +15, +30, +45, +60, +75, +90, +120, +150, and +180 after treatment inception. Enumeration of CMV‐specific interferon‐γ (IFN‐γ)‐producing CD8+ and CD4+ T‐cells in whole blood was performed by flow cytometry. Median TTV DNA load in ibrutinib‐treated patients increased significantly (p = 0.025) from baseline (median: 5.76 log10 copies/mL) to day +120 (median: 7.83 log10 copies/mL). A moderate inverse correlation (Rho = −0.46; p < 0.001) was found between TTV DNA load and absolute lymphocyte count. In ruxolitinib‐treated patients, TTV DNA load quantified at baseline was not significantly different from that measured after treatment inception (p ≥ 0.12). TTV DNA load was not predictive of the subsequent occurrence of CMV DNAemia in either patient group. No correlation was observed between TTV DNA loads and CMV‐specific IFN‐γ‐producing CD8+ and CD4+ T‐cell counts in either patient group. The data did not support the hypothesis that TTV DNA load monitoring in hematological patients treated with ibrutinib or ruxolitinib could be useful to predict either the occurrence of CMV DNAemia or the level of CMV‐specific T‐cell reconstitution; nevertheless, due to the small sample size, further studies involving larger cohorts are warranted to elucidate this issue.

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Integrated Immunologic Monitoring in Solid Organ Transplantation: The Road Toward Torque Teno Virus-guided Immunosuppression

Abstract: CLINICAL PROBLEM AND INTRODUCTIONAllograft transplantation (TX) is the preferred treatment for patients with end-stage solid organ disease.

Cited by 44 publications

References 91 publications

SARS-CoV-2 IgG spike protein antibody response in mRNA-1273 Moderna® vaccinated patients on maintenance immunoapheresis – a cohort study

SARS-CoV-2 IgG spike protein antibody response in mRNA-1273 Moderna® vaccinated patients on maintenance immunoapheresis – a cohort study

Impact of polymorphisms in genes orchestrating innate immune responses on replication kinetics of Torque teno virus after kidney transplantation

Assessment of the potential value of plasma Torque Teno virus DNA load monitoring to predict cytomegalovirus DNAemia in patients with hematological malignancies treated with small molecule inhibitors: A proof‐of‐concept study

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