Repeated Injections of IL‐2 Break Renal Allograft Tolerance Induced via Mixed Hematopoietic Chimerism in Monkeys

Tolerance of allografts achieved in mice via stable mixed hematopoietic chimerism relies essentially on continuous elimination of developing alloreactive T cells in the thymus (central deletion). Conversely, while only transient mixed chimerism is observed in nonhuman primates and patients, it is su...

Full description

Saved in:
Bibliographic Details
Published in:American journal of transplantation 2015-12, Vol.15 (12), p.3055-3066
Main Authors: Yamada, Y., Nadazdin, O., Boskovic, S., Lee, S., Zorn, E., Smith, R. N., Colvin, R. B., Madsen, J. C., Cosimi, A. B., Kawai, T., Benichou, G.
Format: Article
Language:English
Subjects:
animal models: nonhuman primate
Animals
basic (laboratory) research/science
Bone Marrow Transplantation
bone marrow/hematopoietic stem cell transplantation
Chimerism
Glomerular Filtration Rate
Graft Rejection - drug therapy
Graft Rejection - etiology
Graft Survival
immunosuppression/immune modulation
Injections, Subcutaneous
Interleukin-2 - administration & dosage
kidney (allograft) function/dysfunction
Kidney Failure, Chronic - surgery
Kidney Function Tests
Kidney Transplantation
kidney transplantation/nephrology
Macaca fascicularis
Mice
Postoperative Complications
Risk Factors
tolerance: chimerism
tolerance: mechanisms
translational research/science
Transplantation Chimera - immunology
Transplantation Conditioning
Transplantation Tolerance - immunology
Transplantation, Homologous
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Tolerance of allografts achieved in mice via stable mixed hematopoietic chimerism relies essentially on continuous elimination of developing alloreactive T cells in the thymus (central deletion). Conversely, while only transient mixed chimerism is observed in nonhuman primates and patients, it is sufficient to ensure tolerance of kidney allografts. In this setting, it is likely that tolerance depends on peripheral regulatory mechanisms rather than thymic deletion. This implies that, in primates, upsetting the balance between inflammatory and regulatory alloimmunity could abolish tolerance and trigger the rejection of previously accepted renal allografts. In this study, six monkeys that were treated with a mixed chimerism protocol and had accepted a kidney allograft for periods of 1–10 years after withdrawal of immunosuppression received subcutaneous injections of IL‐2 cytokine (0.6–3 × 106 IU/m2). This resulted in rapid rejection of previously tolerated renal transplants and was associated with an expansion and reactivation of alloreactive pro‐inflammatory memory T cells in the host's lymphoid organs and in the graft. This phenomenon was prevented by anti‐CD8 antibody treatment. Finally, this process was reversible in that cessation of IL‐2 administration aborted the rejection process and restored normal kidney graft function. Low dose injections of IL‐2 break tolerance of kidney allografts induced via transient mixed hematopoietic chimerism in nonhuman primates.
ISSN:1600-6135
1600-6143
DOI:10.1111/ajt.13382