Conversion from calcineurin inhibitor to mycophenolate mofetil-based immunosuppression changes the frequency and phenotype of CD4+FOXP3+ regulatory T cells.
BACKGROUND
CD4+FOXP3+ regulatory T cells (Treg) depend on interleukin (IL)-2 for their function and survival. By interfering with the IL-2 production, calcineurin inhibitors (CNI) may negatively affect Treg. Here, we describe the effects of conversion from CNI to mycophenolate mofetil (MMF) monotherapy on renal function, and on Treg frequency and phenotype in liver transplant recipients.


METHODS
Patients (n=16) with renal impairment on CNI were converted to MMF and received a single dose of IL-2-receptor blocking antibody (Daclizumab). Control patients (n=8) continued CNI treatment.


RESULTS
Renal function rapidly and significantly improved after conversion. Daclizumab treatment resulted in a 75% blocking of CD25 at 1 month causing a significant reduction in the percentage of CD4+CD25+ cells but not affecting the percentage of CD4+CD25+Foxp3+ cells. Six months after conversion to MMF, the percentage of CD4+CD25+Foxp3+ cells increased significantly by 125%. FOXP3 mRNA analysis of mononuclear cells confirmed the enrichment of Foxp3 in peripheral blood. Interestingly, the CD25 expression level on CD4+Foxp3+, but not CD4+Foxp3-, cells significantly increased compared with preconversion.


CONCLUSIONS
Conversion to MMF increases the percentage and CD25 expression of CD4+FOXP3+ cells indicating that MMF therapy can overturn the repressive effect of CNI on circulating Treg levels and therefore may promote Treg-mediated suppression of alloreactivity.
Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
Ahmet
A
Demirkiran
Varsha D K D
VD
Sewgobind
Joyce
J
van der Weijde
Alice
A
Kok
Carla C
CC
Baan
Jaap
J
Kwekkeboom
Hugo W
HW
Tilanus
Herold J
HJ
Metselaar
Luc J W
LJ
van der Laan
D000368:Aged; D015703:Antigens, CD / Q000276:immunology; D001806:Blood Urea Nitrogen; D015704:CD4 Antigens / Q000276:immunology*; D019703:Calcineurin / Q000276:immunology*; D003404:Creatinine / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D051858:Forkhead Transcription Factors / Q000276:immunology*; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods* / Q000639:trends*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D007677:Kidney Function Tests; D008107:Liver Diseases / Q000145:classification / Q000601:surgery; D008111:Liver Function Tests; D016031:Liver Transplantation / Q000276:immunology* / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D015703:Antigens, CD; D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007166:Immunosuppressive Agents; D053645:Interleukin-2 Receptor alpha Subunit; D003404:Creatinine; D019703:Calcineurin; D009173:Mycophenolic Acid