The impact of induction therapy on the homeostasis and function of regulatory T cells in kidney transplant patients.
BACKGROUND
To evaluate the influence of induction therapy on Tregs we investigated their origin, kinetics and function in kidney transplant patients after treatment with T-cell depleting rabbit antithymocyte globulin (rATG) or IL-2 receptor antagonist basiliximab.


METHODS
Flow cytometry was used to study thymopoiesis by CD31+ naïve Tregs, homeostatic proliferation by Ki-67+ Tregs and Treg origin by the expression of Helios (nTreg-marker). FACSsorted Tregs were analysed for the demethylation status of the Treg-specific demethylated region (TSDR) of the FoxP3 gene, and Treg-suppressive function.


RESULTS
Differential effects of rATG and basiliximab induction therapies were measured on the repopulation kinetics of Tregs. While decreased absolute numbers of Tregs were found in both study arms, increased percentages of Tregs were found in rATG treated patients and decreased percentages in basiliximab treated patients. In both groups, Treg repopulation was the result of homeostatic proliferation and not of thymopoiesis. At 1 month after rATG and 6 months after basiliximab therapy, high percentages of Ki-67+ Treg were measured, which in the rATG group, was accompanied by low percentages of Ki-67+Helios+ Treg, and by cells with a demethylated TSDR in the FoxP3 gene. After both rATG and basiliximab therapy, repopulated Tregs inhibited proliferation of allo-antigen activated T effector cells (Teff).


CONCLUSIONS
In kidney transplant patients, repopulation of Treg after rATG and basiliximab therapy is the result of homeostatic proliferation and not of thymopoiesis. These repopulated Treg were functional after both induction strategies; however only after rATG therapy, were increased proportions of Helios(-) methylated FoxP3 Treg found.
Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Anne P
AP
Bouvy
Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Mariska
M
Klepper
Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Marcia M L
MM
Kho
Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Karin
K
Boer
Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Michiel G H
MG
Betjes
Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Willem
W
Weimar
Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Carla C
CC
Baan
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000077552:Basiliximab; D005260:Female; D005434:Flow Cytometry; D006084:Graft Rejection / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016030:Kidney Transplantation; D008212:Lymphocyte Depletion / Q000379:methods; D008297:Male; D008875:Middle Aged; D011817:Rabbits; D015375:Receptors, Interleukin-2 / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D016896:Treatment Outcome; D055815:Young Adult
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D000077552:Basiliximab
homeostatic proliferation; induction therapy; kidney transplantation; regulatory T cells; thymopoiesis