mTOR Inhibitor Therapy Diminishes Circulating CD8+ CD28- Effector Memory T Cells and Improves Allograft Inflammation in Belatacept-refractory Renal Allograft Rejection.
Abatacept
/ pharmacology
Biopsy
CD28 Antigens
/ immunology
CD8-Positive T-Lymphocytes
/ immunology
Female
Graft Rejection
/ drug therapy
Graft Survival
Humans
Immunologic Memory
/ drug effects
Immunosuppression Therapy
/ methods
Immunosuppressive Agents
/ pharmacology
Kidney
/ pathology
Kidney Transplantation
Male
Middle Aged
Sirolimus
/ pharmacology
T-Lymphocytes, Regulatory
/ drug effects
TOR Serine-Threonine Kinases
/ antagonists & inhibitors
Tacrolimus
/ pharmacology
Transplantation, Homologous
Treatment Outcome
Journal
Transplantation
ISSN: 1534-6080
Titre abrégé: Transplantation
Pays: United States
ID NLM: 0132144
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
pubmed:
16
8
2019
medline:
8
10
2020
entrez:
16
8
2019
Statut:
ppublish
Résumé
Renal allograft rejection is more frequent under belatacept-based, compared with tacrolimus-based, immunosuppression. We studied kidney transplant recipients experiencing rejection under belatacept-based early corticosteroid withdrawal following T-cell-depleting induction in a recent randomized trial (Belatacept-based Early Steroid Withdrawal Trial, clinicaltrials.gov NCT01729494) to determine mechanisms of rejection and treatment. Peripheral mononuclear cells, serum creatinine levels, and renal biopsies were collected from 8 patients undergoing belatacept-refractory rejection (BRR). We used flow cytometry, histology, and immunofluorescence to characterize CD8 effector memory T cell (TEM) populations in the periphery and graft before and after mammalian target of rapamycin (mTOR) inhibition. Here, we found that patients with BRR did not respond to standard antirejection therapy and had a substantial increase in alloreactive CD8 T cells with a CD28/DR/CD38/CD45RO TEM. These cells had increased activation of the mTOR pathway, as assessed by phosphorylated ribosomal protein S6 expression. Notably, everolimus (an mTOR inhibitor) treatment of patients with BRR halted the in vivo proliferation of TEM cells and their ex vivo alloreactivity and resulted in their significant reduction in the peripheral blood. The frequency of circulating FoxP3 regulatory T cells was not altered. Importantly, everolimus led to rapid resolution of rejection as confirmed by histology. Thus, while prior work has shown that concomitant belatacept + mTOR inhibitor therapy is effective for maintenance immunosuppression, our preliminary data suggest that everolimus may provide an available means for effecting "rescue" therapy for rejections occurring under belatacept that are refractory to traditional antirejection therapy with corticosteroids and polyclonal antilymphocyte globulin.
Sections du résumé
BACKGROUND
Renal allograft rejection is more frequent under belatacept-based, compared with tacrolimus-based, immunosuppression. We studied kidney transplant recipients experiencing rejection under belatacept-based early corticosteroid withdrawal following T-cell-depleting induction in a recent randomized trial (Belatacept-based Early Steroid Withdrawal Trial, clinicaltrials.gov NCT01729494) to determine mechanisms of rejection and treatment.
METHODS
Peripheral mononuclear cells, serum creatinine levels, and renal biopsies were collected from 8 patients undergoing belatacept-refractory rejection (BRR). We used flow cytometry, histology, and immunofluorescence to characterize CD8 effector memory T cell (TEM) populations in the periphery and graft before and after mammalian target of rapamycin (mTOR) inhibition.
RESULTS
Here, we found that patients with BRR did not respond to standard antirejection therapy and had a substantial increase in alloreactive CD8 T cells with a CD28/DR/CD38/CD45RO TEM. These cells had increased activation of the mTOR pathway, as assessed by phosphorylated ribosomal protein S6 expression. Notably, everolimus (an mTOR inhibitor) treatment of patients with BRR halted the in vivo proliferation of TEM cells and their ex vivo alloreactivity and resulted in their significant reduction in the peripheral blood. The frequency of circulating FoxP3 regulatory T cells was not altered. Importantly, everolimus led to rapid resolution of rejection as confirmed by histology.
CONCLUSIONS
Thus, while prior work has shown that concomitant belatacept + mTOR inhibitor therapy is effective for maintenance immunosuppression, our preliminary data suggest that everolimus may provide an available means for effecting "rescue" therapy for rejections occurring under belatacept that are refractory to traditional antirejection therapy with corticosteroids and polyclonal antilymphocyte globulin.
Identifiants
pubmed: 31415033
doi: 10.1097/TP.0000000000002917
pmc: PMC7012662
mid: NIHMS1054078
pii: 00007890-202005000-00028
doi:
Substances chimiques
CD28 Antigens
0
Immunosuppressive Agents
0
Abatacept
7D0YB67S97
TOR Serine-Threonine Kinases
EC 2.7.11.1
Sirolimus
W36ZG6FT64
Tacrolimus
WM0HAQ4WNM
Banques de données
ClinicalTrials.gov
['NCT01729494']
Types de publication
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1058-1069Subventions
Organisme : NIAID NIH HHS
ID : R21 AI142264
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM063483
Pays : United States
Références
Larsen CP, Pearson TC, Adams AB, et al. Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties.Am J Transplant20055443–453
Talawila N, Pengel LH. Does belatacept improve outcomes for kidney transplant recipients? A systematic review.Transpl Int2015281251–1264
Heher E, Markmann JF. The clearer BENEFITS of belatacept.N Engl J Med2016374388–389
Vincenti F, Charpentier B, Vanrenterghem Y, et al. A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study).Am J Transplant201010535–546
Vincenti F, Rostaing L, Grinyo J, et al. Belatacept and long-term outcomes in kidney transplantation.N Engl J Med2016374333–343
de Graav GN, Baan CC, Clahsen-van Groningen MC, et al. A randomized controlled clinical trial comparing belatacept with tacrolimus after de novo kidney transplantation.Transplantation20171012571–2581
Newell KA, Mehta AK, Larsen CP, et al. Lessons learned: early termination of a randomized trial of calcineurin inhibitor and corticosteroid avoidance using belatacept.Am J Transplant2017172712–2719
Ferguson R, Grinyó J, Vincenti F, et al. Immunosuppression with belatacept-based, corticosteroid-avoiding regimens in de novo kidney transplant recipients.Am J Transplant20111166–76
Woodle E KD, Shields A, Leone J, et al. The BEST Trial: a prospective randomized multicenter trial of belatacept-based CNI- and corticosteroid-free immunosuppression [abstract].Available at https://atcmeetingabstracts.com/abstract/the-best-trial-a-prospective-randomized-multicenter-trial-of-belatacept-based-cni-and-corticosteroid-free-immunosuppression/2018. Accessed September 3, 2019
Xu H, Perez SD, Cheeseman J, et al. The allo- and viral-specific immunosuppressive effect of belatacept, but not tacrolimus, attenuates with progressive T cell maturation.Am J Transplant201414319–332
de Graav GN, Hesselink DA, Dieterich M, et al. Down-regulation of surface CD28 under belatacept treatment: an escape mechanism for antigen-reactive T-cells.PLOS One201611e0148604
Mathews DV, Wakwe WC, Kim SC, et al. Belatacept-resistant rejection is associated with CD28+ memory CD8 T cells.Am J Transplant2017172285–2299
Lo DJ, Weaver TA, Stempora L, et al. Selective targeting of human alloresponsive CD8+ effector memory T cells based on CD2 expression.Am J Transplant20111122–33
Weaver TA, Charafeddine AH, Agarwal A, et al. Alefacept promotes co-stimulation blockade based allograft survival in nonhuman primates.Nat Med200915746–749
Kirk AD, Guasch A, Xu H, et al. Renal transplantation using belatacept without maintenance steroids or calcineurin inhibitors.Am J Transplant2014141142–1151
Pollizzi KN, Patel CH, Sun IH, et al. mTORC1 and mTORC2 selectively regulate CD8+ T cell differentiation.J Clin Invest20151252090–2108
Woodle ES, Cronin D, Newell KA, et al. Tacrolimus therapy for refractory acute renal allograft rejection: definition of the histologic response by protocol biopsies.Transplantation199662906–910
Deepak A, Rao CCB, Arazi A, et al. A protocol for single-cell transcriptomics from cryopreserved renal tissue and urine for the Accelerating Medicine Partnership (AMP) RA/SLE network.bioRxiv2018doi: https://doi.org/10.1101/275859
doi: https://doi.org/10.1101/275859
Gaber AO, First MR, Tesi RJ, et al. Results of the double-blind, randomized, multicenter, phase III clinical trial of Thymoglobulin versus Atgam in the treatment of acute graft rejection episodes after renal transplantation.Transplantation19986629–37
Jones DL, Sacks SH, Wong W. Controlling the generation and function of human CD8+ memory T cells in vitro with immunosuppressants.Transplantation2006821352–1361
Lo DJ, Anderson DJ, Weaver TA, et al. Belatacept and sirolimus prolong nonhuman primate renal allograft survival without a requirement for memory T cell depletion.Am J Transplant201313320–328
Merino D, San Segundo D, Medina JM, et al. Different in vitro proliferation and cytokine-production inhibition of memory T-cell subsets after calcineurin and mammalian target of rapamycin inhibitors treatment.Immunology2016148206–215
Kumar D, LeCorchick S, Gupta G. Belatacept as an alternative to calcineurin inhibitors in patients with solid organ transplants.Front Med (Lausanne)2017460
Emamaullee J, Toso C, Merani S, et al. Costimulatory blockade with belatacept in clinical and experimental transplantation - a review.Expert Opin Biol Ther20099789–796
de Graav GN, Hesselink DA, Dieterich M, et al. An acute cellular rejection with detrimental outcome occurring under belatacept-based immunosuppressive therapy: an immunological analysis.Transplantation20161001111–1119
Mou D, Espinosa J, Lo DJ, et al. CD28 negative T cells: is their loss our gain?Am J Transplant2014142460–2466
Trzonkowski P, Zilvetti M, Chapman S, et al. Homeostatic repopulation by CD28-CD8+ T cells in alemtuzumab-depleted kidney transplant recipients treated with reduced immunosuppression.Am J Transplant20088338–347
Espinosa J, Herr F, Tharp G, et al. CD57(+) CD4 T cells underlie belatacept-resistant allograft rejection.Am J Transplant2016161102–1112
Jin YP, Valenzuela NM, Ziegler ME, et al. Everolimus inhibits anti-HLA I antibody-mediated endothelial cell signaling, migration and proliferation more potently than sirolimus.Am J Transplant201414806–819
Jindra PT, Jin YP, Rozengurt E, et al. HLA class I antibody-mediated endothelial cell proliferation via the mTOR pathway.J Immunol20081802357–2366
Levitsky J, Miller J, Huang X, et al. Immunoregulatory effects of everolimus on in vitro alloimmune responses.PLOS One201611e0156535
Gallon L, Traitanon O, Yu Y, et al. Differential effects of calcineurin and mammalian target of rapamycin inhibitors on alloreactive Th1, Th17, and regulatory T cells.Transplantation2015991774–1784
Tang Q, Vincenti F. Transplant trials with Tregs: perils and promises.J Clin Invest20171272505–2512