Application of Operational Tolerance Signatures Are Limited by Variability and Type of Immunosuppression in Renal Transplant Recipients: A Cross-Sectional Study

Bottomley, Matthew J.; Chen, Mian; Fuggle, S; Harden, Paul; Wood, Kathryn J.

doi:10.1097/txd.0000000000000638

Cited by 25 publications

(30 citation statements)

References 45 publications

(61 reference statements)

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“…Recent data suggest that the type and dose of immunosuppressive therapy may interfere with the induction of CD19 + CD24 hi CD38 hi transitional B lymphocytes (Bregs) (21,22). In a crosssectional study of 117 transplant recipients, Bottomley et al found no significant association between steroids and Bregs (21), whereas in the Genetic Analysis of Molecular Biomarkers of Immunological Tolerance (GAMBIT) study, Rebollo-Mesa et al observed slightly higher Breg percentages in patients with reduced or no steroids (22). To address this issue, we identified transplanted control patients on immunosuppressive therapy comparable to that for MIC-treated patients and analyzed their Breg frequencies retrospectively.…”

Section: Discussionmentioning

confidence: 99%

Phase I trial of donor-derived modified immune cell infusion in kidney transplantation

Morath¹,

Schmitt²,

Kleist³

et al. 2020

Journal of Clinical Investigation

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BACKGROUND.Preclinical experiments have shown that donor blood cells, modified in vitro by an alkylating agent (modified immune cells [MICs]), induced long-term specific immunosuppression against the allogeneic donor. METHODS.In this phase I trial, patients received either 1.5 × 10 6 MICs per kg BW on day -2 (n = 3, group A), or 1.5 × 10 8 MICs per kg BW on day -2 (n = 3, group B) or day -7 (n = 4, group C) before living donor kidney transplantation in addition to posttransplantation immunosuppression. The primary outcome measure was the frequency of adverse events (AEs) until day 30 (study phase) with follow-up out to day 360. RESULTS. MIC infusions were extremely well tolerated. During the study phase, 10 treated patients experienced a total of 69 AEs that were unlikely to be related or not related to MIC infusion. No donor-specific human leukocyte antigen Abs or rejection episodes were noted, even though the patients received up to 1.3 × 10 10 donor mononuclear cells before transplantation. Group C patients with low immunosuppression during follow-up showed no in vitro reactivity against stimulatory donor blood cells on day 360, whereas reactivity against third-party cells was still preserved. Frequencies of CD19 + CD24 hi CD38 hi transitional B lymphocytes (Bregs) increased from a median of 6% before MIC infusion to 20% on day 180, which was 19-and 68-fold higher, respectively, than in 2 independent cohorts of transplanted controls. The majority of Bregs produced the immunosuppressive cytokine IL-10. MIC-treated patients showed the Immune Tolerance Network operational tolerance signature. CONCLUSION. MIC administration was safe and could be a future tool for the targeted induction of tolerogenic Bregs.

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Section: Discussionmentioning

confidence: 99%

Phase I trial of donor-derived modified immune cell infusion in kidney transplantation

Morath¹,

Schmitt²,

Kleist³

et al. 2020

Journal of Clinical Investigation

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“…Edward Geissler, David Sachs, and Kenneth Newell. There was a consensus that graft injury and loss in these trials should be no greater than in standard of care patients, and prevention can be improved by use of biopsies just before drug minimization, and the use of biomarkers of tolerance [14][15][16][17][18][19][20][21][22][23][24] .…”

Section: Discussion Of Immunosuppressive Drug Minimization and Of Dismentioning

confidence: 99%

Summary of the Third International Workshop on Clinical Tolerance

Kawai

Leventhal

Wood

et al. 2019

American Journal of Transplantation

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The Third International Workshop on Clinical Tolerance was held in Stanford, California, September 8-9, 2017. This is a summary of Workshop presentations of clinical trials designed to withdraw or minimize immunosuppressive (IS) drugs in kidney and liver transplant patients without subsequent evidence of rejection. All clinical protocols had in common the use of donor or recipient cell therapy combined with organ transplantation. Tolerance to HLA matched and mismatched living donor kidney transplants with complete withdrawal of IS drugs without subsequent rejection for up to 14 years of observation was achieved in more than 50 patients enrolled in trials in four medical centers after the establishment of transient or persistent chimerism. Complete IS drug withdrawal without chimerism was reported in a prospective trial of liver transplantation combined with injection of regulatory T cells. IS drug minimization without rejection was reported in recipients of living donor kidney transplants enrolled in the One Study consortium after injection of recipient regulatory T cells, or injection of donor regulatory monocytes or dendritic cells. In conclusion, considerable progress has been made in achieving IS drug withdrawal after cell therapy in recipients of organ transplants.

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“…The relative proportions of these distinct morphologic and presumably molecular phenotypes in any data set will affect any putative disease-associated transcriptome signatures that can be derived from these tissues. In the study by Sigdel et al, 9 , 54 an attempt was made to match BKPyVN and control biopsies for major clinical variables such as donor/recipient age, % living donor kidneys, time posttransplant, and immunosuppression usage. However, there were insufficient numbers of BKPyVN biopsies to separately study individual disease phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Polyomavirus BK Nephropathy-Associated Transcriptomic Signatures: A Critical Reevaluation

Pan

Lyu

Adam

et al. 2018

Transplantation Direct

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BackgroundRecent work using DNA microarrays has suggested that genes related to DNA replication, RNA polymerase assembly, and pathogen recognition receptors can serve as surrogate tissue biomarkers for polyomavirus BK nephropathy (BKPyVN).MethodsWe have examined this premise by looking for differential regulation of these genes using a different technology platform (RNA-seq) and an independent set 25 biopsies covering a wide spectrum of diagnoses.ResultsRNA-seq could discriminate T cell–mediated rejection from other common lesions seen in formalin fixed biopsy material. However, overlapping RNA-seq signatures were found among all disease processes investigated. Specifically, genes previously reported as being specific for the diagnosis of BKPyVN were found to be significantly upregulated in T cell–mediated rejection, inflamed areas of fibrosis/tubular atrophy, as well as acute tubular injury.ConclusionsIn conclusion, the search for virus specific molecular signatures is confounded by substantial overlap in pathogenetic mechanisms between BKPyVN and nonviral forms of allograft injury. Clinical heterogeneity, overlapping exposures, and different morphologic patterns and stage of disease are a source of substantial variability in “Omics” experiments. These variables should be better controlled in future biomarker studies on BKPyVN, T cell–mediated rejection, and other forms of allograft injury, before widespread implementation of these tests in the transplant clinic.

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Application of Operational Tolerance Signatures Are Limited by Variability and Type of Immunosuppression in Renal Transplant Recipients: A Cross-Sectional Study

Abstract: Supplemental digital content is available in the text.

Cited by 25 publications

References 45 publications

Phase I trial of donor-derived modified immune cell infusion in kidney transplantation

Phase I trial of donor-derived modified immune cell infusion in kidney transplantation

Summary of the Third International Workshop on Clinical Tolerance

Polyomavirus BK Nephropathy-Associated Transcriptomic Signatures: A Critical Reevaluation

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