The imbalance of <scp>T</scp> helper 17/regulatory <scp>T</scp> cells and memory <scp>B</scp> cells during the early post‐transplantation period in peripheral blood of living donor liver transplantation recipients under calcineurin inhibitor‐based immunosuppression

Kim, Hee Yeon; Cho, Mi‐La; Jhun, Joo Yeon; Byun, Jae Kyeong; Kim, Min Jung; Yim, Ye Been; Chung, Byung Ha; Yoon, Seung Kew; Bae, Si Hyun; Kim, Dong Goo; Yang, Chul Woo; Choi, Jong Young

doi:10.1111/imm.12021

Cited by 22 publications

(20 citation statements)

References 30 publications

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“…The observation that CsA may drive a Th17-mediated immune response -as observed in this study -was already reported in an animal model of posttransplant obliterative airway disease [37] and in a model of liver transplantation [38] . In patients with Vogt-Koyanagi-Harada disease, IL-27 expression was decreased and Th17 response higher during the active phase of the disease.…”

Section: Discussionsupporting

confidence: 79%

Behavioral Conditioning of Immune Responses with Cyclosporine A in a Murine Model of Experimental Autoimmune Uveitis

Bauer

Busch²,

Pacheco-López³

et al. 2017

Neuroimmunomodulation

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Objective: We examined the role of behavioral conditioning of immune responses with cyclosporine A (CsA) on the development of Th1/Th17-driven experimental autoimmune uveoretinitis (EAU). Methods: Mice received a 0.2% w/v saccharin solution as conditioned stimulus combined with CsA (20 mg/kg) in 6 association trials at 72-h intervals. For evocation periods, conditioned mice were reexposed to saccharin, whereas the conditioned but not reexposed group received water only. Animals were immunized with human interphotoreceptor-retinoid-binding protein peptide 161-180 (hIRBP_p161-180) peptide in complete Freund adjuvant (CFA) and a concomitant injection of pertussis toxin. Results: In naïve mice subjected to the behavioral conditioning regimen, mitogen-induced interleukin (IL)-2 production was decreased in conditioned mice compared to conditioned but not reexposed animals. Incidence and severity of EAU were not significantly lower in behaviorally conditioned and immunized mice. ELISA analysis of splenocytes revealed a reduced interferon (IFN)-γ/IL-17 ratio in CsA-treated, conditioned but not reexposed, and conditioned animals. The adoptive transfer of antigen-specific splenocytes from animals behaviorally conditioned with CsA to naïve mice decreased the severity of EAU in recipient mice compared to the control group. In vitro activation of splenocytes isolated from immunized mice with agonists targeting TLR2 and NOD2 together with β₂-adrenergic activation (induced by epinephrine, norepinephrine, or salbutamol) resulted in decreased IFN-γ but increased IL-17 immune responses. The β₂-adrenergic antagonist propranolol could restore IFN-γ production, whereas only the norepinephrine-induced increase in IL-17 production was abrogated. Conclusions: We conclude that CsA conditioning in the EAU model mitigates Th1 but enhances Th17 immune responses, and does not ameliorate disease. The results imply that in EAU the mechanism of immune conditioning interacts with CFA components during active immunization, most likely via the TLR2/NOD2 pathway, and induces differentiation of Th17 cells that drive autoimmune diseases.

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Section: Discussionsupporting

confidence: 79%

Behavioral Conditioning of Immune Responses with Cyclosporine A in a Murine Model of Experimental Autoimmune Uveitis

Bauer

Busch²,

Pacheco-López³

et al. 2017

Neuroimmunomodulation

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“…Conventional immunosuppression as applied to our patients affects effector T cells and regulatory T cells (Tregs; CD4 + CD25 high FOXP3 + T cells) . This results in a decrease of circulating Tregs after LT and lower FOXP3 mRNA expression in non‐inflamed tissues from LT recipients on triple therapy compared to healthy patients . Although we did not measure Tregs and FOXP3 mRNA expression, appropriate immunosuppression was ensured by monitoring drug levels.…”

Section: Discussionmentioning

confidence: 99%

Anti‐platelet factor 4/heparin antibodies in patients with impaired graft function after liver transplantation

Bakchoul¹,

Aßfalg

H³

et al. 2014

Journal of Thrombosis and Haemostasis

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A, H€ user N. Anti-platelet factor 4/heparin antibodies in patients with impaired graft function after liver transplantation. J Thromb Haemost 2014; 12: 871-8.Summary. Background: Heparin, the standard perioperative anticoagulant for the prevention of graft vessel thrombosis in patients undergoing liver transplantation (LT), binds to the chemokine platelet factor 4 (PF4). Antibodies that are formed against the resulting PF4/heparin complexes can induce heparin-induced thrombocytopenia. LT is a clinical situation that allows the study of T-cell dependency of immune responses because T-cell function is largely suppressed pharmacologically in these patients to prevent graft rejection. Objectives: To investigate the immune response against PF4/heparin complexes in patients undergoing LT. Patients and Methods: In this prospective cohort study, 38 consecutive patients undergoing LT were systematically screened for anti-PF4/ heparin antibodies (enzyme immunoassay and heparininduced platelet aggregation assay), platelet count, liver function, and engraftment. Results: At baseline, 5 (13%) of 38 patients tested positive for anti-PF4/heparin IgG (non-platelet-activating) antibodies. By day 20, an additional 5 (15%) of 33 patients seroconverted for immunoglobulin G (two platelet-activating) antibodies. No patient developed clinical heparin-induced thrombocytopenia. Two of six patients with graft function failure had anti-PF4/heparin IgG antibodies at the time of graft function failure. Graft liver biopsy samples from these patients showed thrombotic occlusions of the microcirculation. Conclusions: Anti-PF4/heparin IgG antibodies are generated despite strong pharmacologic suppression of T cells, indicating that T cells likely have a limited role in the immune response to PF4/heparin complexes in humans.

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“…Previously, we demonstrated an imbalance between Th17 and Treg cells in peripheral blood mononuclear cells (PBMCs) from LT recipients ( 21 ); immunosuppressive treatment had no significant effect on Th17 cells, but significantly reduced the frequency of Treg cells. Therefore, we designed this study to undertake long-term monitoring of LT recipients.…”

Section: Introductionmentioning

confidence: 99%

Serial Monitoring of Immune Markers Being Represented Regulatory T Cell/T Helper 17 Cell Ratio: Indicating Tolerance for Tapering Immunosuppression after Liver Transplantation

Jhun¹,

Lee

et al. 2018

Front. Immunol.

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Recipients of liver transplantation (LT) require long-term immunosuppressive drug treatment, but lifelong immunosuppressive treatment has severe side effects. It is known that some LT recipients develop immune tolerance, and although the development of such operational tolerance should allow a decrease in the burden of immunosuppressive drug treatment, the factors that indicate operational tolerance are not clear. This study aimed to monitor immunological markers over time in LT recipients to identify those markers indicating the development of operational tolerance. We performed a prospective pilot study measuring immune markers, including the ratio of regulatory T (Treg) and T helper (Th) 17 cells in peripheral blood in the 14 most immunologically stable patients among 70 clinically stable LT recipients. The doses of immunosuppressive drugs given to these 14 LT recipients were tapered over time and they were monitored for immunological markers related to the development of immune tolerance. As the doses of immunosuppressive drugs were reduced, the Treg/Th17, Th1/Th17, and CD8/Th17 ratio in tolerant recipients was significantly increased compared with that of nontolerant recipients. These results suggest that monitoring of changes in the immune makers, including Treg/Th17 ratio during tapering of immunosuppression may allow prediction of the development of tolerance.

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The imbalance of T helper 17/regulatory T cells and memory B cells during the early post‐transplantation period in peripheral blood of living donor liver transplantation recipients under calcineurin inhibitor‐based immunosuppression

Cited by 22 publications

References 30 publications

Behavioral Conditioning of Immune Responses with Cyclosporine A in a Murine Model of Experimental Autoimmune Uveitis

Behavioral Conditioning of Immune Responses with Cyclosporine A in a Murine Model of Experimental Autoimmune Uveitis

Anti‐platelet factor 4/heparin antibodies in patients with impaired graft function after liver transplantation

Serial Monitoring of Immune Markers Being Represented Regulatory T Cell/T Helper 17 Cell Ratio: Indicating Tolerance for Tapering Immunosuppression after Liver Transplantation

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