The impact of induction therapy on the homeostasis and function of regulatory T cells in kidney transplant patients

Bouvy, Anne P.; Klepper, Mariska; Kho, Marcia M. L.; Boer, Karin; Betjes, Michiel G. H.; Weimar, Willem; Baan, Carla C.

doi:10.1093/ndt/gfu079

Cited by 51 publications

(42 citation statements)

References 58 publications

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“…Gurkan et al have described a natural Treg expansion earlier after lymphocyte depletion whereas peripheral Treg expansion occurred six months after transplantation (14). Conversely, Bouvy et al have recently shown that the repopulation of Treg after rATG and basiliximab therapy was the result of homeostatic proliferation and not thymopoiesis (20). This is consistent with our own results: the increase in Treg is rather dependent on ATG-induced peripheral expansion, since CD31…”

Section: Discussionsupporting

confidence: 90%

“…This phenomenon could favor the protective role of ATG against acute rejection, although Treg function after transplantation has not been studied in vivo. Bouvy et al demonstrated an in vitro suppressive function of Treg whatever the induction therapy but no difference in the occurrence of biopsyproven acute rejection between ATG and basiliximab in 33 consecutive transplanted patients (20). This Treg expansion could also be interpreted as a compensatory mechanism against the expansion of late stage differentiated T cells.…”

Section: Discussionmentioning

confidence: 98%

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ATG-Induced Accelerated Immune Senescence: Clinical Implications in Renal Transplant Recipients

Crépin

Carron

Roubiou

et al. 2015

American Journal of Transplantation

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y These authors contributed equally to this work. Persistent ATG-induced CD4þ T cell lymphopenia is associated with serious clinical complications. We tested the hypothesis that ATG induces accelerated immune senescence in renal transplant recipients (RTR). Immune senescence biomarkers were analyzed at transplant and one-year later in 97 incident RTR À62 patients receiving ATG and 35 receiving anti-CD25 mAb (a-CD25). This consisted in: (i) thymic output; (ii) bone marrow renewal of CD34 þ hematopoietic progenitor cells (CD34 þ HPC) and lymphoid (l-HPC) and myeloid (m-HPC) progenitor ratio; (iii) T cell phenotype; and (iv) measurement of T cell relative telomere length (RTL) and telomerase activity (RTA). Clinical correlates were analyzed with a 3 year follow-up. Thymic output significantly decreased oneyear posttransplant in ATG-treated patients. ATG was associated with a significant decrease in l-HPC/m-HPC ratio. Late stage differentiated CD57 þ /CD28 À T cells increased in ATG-treated patients. One-year posttransplant T cell RTL and RTA were consequently lower in ATG-treated patients. ATG is associated with accelerated immune senescence. Increased frequency of late differentiated CD4 þ T cell frequency at transplantation tended to be predictive of a higher risk of subsequent opportunistic infections and of acute rejection only in ATG-treated patients but this needs confirmation. Considering pretransplant immune profile may help to select those patients who may benefit from ATG to prevent severe infections and acute rejection.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 98%

ATG-Induced Accelerated Immune Senescence: Clinical Implications in Renal Transplant Recipients

Crépin

Carron

Roubiou

et al. 2015

American Journal of Transplantation

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“…Thus, induction therapy with either rabbit antithymocyte globulin or basiliximab (IL-2 receptor antagonist) has shown to favor the repopulation of functional Tregs through homeostatic proliferation and not of thymopoiesis. 69 Campath-1H (an anti-CD52 monoclonal antibody) generates an expansion of Tregs when it is administered with rapamycin in patients with kidney transplantation. 70 This effect could be related with homeostatic proliferation upon lymphopenia, as demonstrated in mice.…”

Section: Modulation Of Regulatory T Cells By Pharmacological Immunosumentioning

confidence: 99%

Regulatory T Cells as Biomarkers for Rejection and Immunosuppression Tailoring in Solid Organ Transplantation

López-Hoyos

Segundo

Brunet³

2016

Therapeutic Drug Monitoring

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The use of biomarkers to tailor immunosuppression and to predict graft and patient outcomes using biological samples obtained by non-invasive tests is one of the main objectives in solid organ transplantation. Although biopsies give the most accurate information, they are clearly invasive and are associated with potentially adverse effects. To date, regulatory T cells have been shown to play a role in allograft protection; for this reason, extensive research has been performed to define them as biomarkers. However, studies of the measurement of these cells in peripheral blood as biomarkers in solid organ transplantation have been very limited and still not validated in prospective randomized large cohorts with the use of standardized methodology. Such poor evidence has been almost exclusively obtained in renal transplantation. Available data summarized here point for their use as biomarkers in different clinical settings with discordant data in many cases.

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“…While the mTOR inhibitors sirolimus and everolimus were able to be linked to the development of tolerance, calcineurin inhibitors led to a smaller number of Tregs [80] . In a recent study, Bouvy et al demonstrated the different effect of induction therapy with anti-thymocyte globulin (ATG) and the IL-2 receptor antibody basiliximab on the repopulation of Tregs, which was better under ATG [81] .…”

Section: Biomarkers For the Development Of Tolerancementioning

confidence: 99%

Biomarkers in blood for individualization of the pharmacotherapy with immunosuppressive drugs after transplantation of solid organs

Wieland

Shipkova

2015

LaboratoriumsMedizin

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Abstract:The success of transplantation medicine is closely associated with the introduction of potent immunosuppressive drugs. Therapy guidance of the calcineurin inhibitors cyclosporine and tacrolimus as well as the mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus is achieved by therapeutic drug monitoring (TDM). For other immunosuppressive drugs such as mycophenolic acid, TDM is not established. It has been suggested that a better individualization of pharmacotherapy could be helpful in avoiding over-and underimmunosuppression, which have been associated with poor long-term outcome of grafts and patients. Therefore, a search for biomarkers that could complement TDM, thereby allowing a better individualization of therapy, is ongoing worldwide. Pharmacodynamic biomarkers in transplantation medicine can be either non-drug-specific, aiming at assessing the global effect on the immune system, or drug-specific, aiming at recording the pharmacologic effect on a drug target. Non-specific pharmacodynamic biomarkers can reflect the degree of immune activation by measuring T-or B-cell activation, the development of operational tolerance by monitoring, e.g., regulatory T-cells, or the graft damage by measuring cell-free DNA released by the graft in response to injury. Drug-specific pharmacodynamic biomarkers have been published for mycophenolic acid, calcineurin, and mTOR inhibitors. The field of biomarker research to complement TDM for a better individualization of immunosuppression is still in its infancy, and controlled prospective clinical trials are needed to unravel or dismiss the potential of particular biomarkers or biomarker combinations in various patient cohorts with different grafts.

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The impact of induction therapy on the homeostasis and function of regulatory T cells in kidney transplant patients

Cited by 51 publications

References 58 publications

ATG-Induced Accelerated Immune Senescence: Clinical Implications in Renal Transplant Recipients

ATG-Induced Accelerated Immune Senescence: Clinical Implications in Renal Transplant Recipients

Regulatory T Cells as Biomarkers for Rejection and Immunosuppression Tailoring in Solid Organ Transplantation

Biomarkers in blood for individualization of the pharmacotherapy with immunosuppressive drugs after transplantation of solid organs

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