Generation of donor-specific regulatory T-cell function in kidney transplant patients.
BACKGROUND
In the search for mechanisms that can induce and maintain transplant tolerance, donor-specific CD4CD25FoxP3 regulatory T cells have been frequently mentioned. However, it remains to be demonstrated, whether these cells are generated after clinical transplantation.


METHODS
We prospectively analyzed the phenotype and function of peripheral regulatory CD4CD25 T cells of 79 patients before, 3, 6, and 12 months after kidney transplantation. The immune regulatory capacities of CD4CD25 T cells were assessed by their depletion from peripheral blood mononuclear cells and in co-culture with CD25 responder T-cells in the mixed lymphocyte reactions.


RESULTS
In the first year after transplantation, the number and proportion of CD4CD25 T cells significantly decreased (P<0.05 and P<0.001, respectively). In the mixed lymphocyte reactions, we observed donor-specific hyporesponsiveness in the presence of significantly increased proliferation to third and fourth Party-Ag, (P<0.001 and P<0.05, respectively). Furthermore, functional analysis of CD25 cells showed that the effect of depletion of these cells from peripheral blood mononuclear cells, and their suppressive capacities in co-culture with donor-Ag stimulated CD25 responder T-cells (1:10 ratio) significantly improved (P<0.01 and P<0.001, respectively). Moreover, the difference between the stimulation with donor-Ag and third Party-Ag became apparent at 6 months after transplantation.


CONCLUSIONS
These findings demonstrate that donor-specific CD4CD25 regulatory T-cell function is generated in fully immunosuppressed renal recipients in the first year after transplantation.
Hendrikx
Thijs K
TK
Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
van Gurp
Evelien A F J
EA
Sewgobind
Varsha D K D
VD
Mol
Wendy M
WM
Schoordijk
Wenda
W
Klepper
Masriska
M
Velthuis
Jurjen H L
JH
Geel
Annemarie
A
Ijzermans
Jan N M
JN
Weimar
Willem
W
Baan
Carla C
CC
D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000032:analysis; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D007676:Kidney Failure, Chronic / Q000601:surgery* / Q000628:therapy; D016030:Kidney Transplantation / Q000276:immunology*; D018655:Lymphocyte Count; D008297:Male; D008775:Methylprednisolone / Q000627:therapeutic use; D008875:Middle Aged; D010530:Peritoneal Dialysis; D011446:Prospective Studies; D006435:Renal Dialysis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014019:Tissue Donors / Q000706:statistics & numerical data
D015703:Antigens, CD; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007166:Immunosuppressive Agents; D053645:Interleukin-2 Receptor alpha Subunit; D008775:Methylprednisolone