Activity of nuclear factor of activated T cells is independent of the number of peripheral lymphocytes in FTY720-treated patients.
We studied the inhibition of nuclear factor of activated T-cell (NFAT)-regulated gene expression (interleukin-2 [IL-2], interferon-gamma [IFN-gamma], granulocyte-macrophage colony-stimulating factor [GMCSF]) in cyclosporine (CsA)-treated de novo patients with and without lymphopenia due to FTY720.


METHODS
Sixteen CsA-treated de novo renal transplant recipients received either FTY720 (n = 8) or mycophenolic acid (MPA; n = 8) in combination with low-dose steroids. Expressions of IL-2, INF-gamma, and GMCSF were measured at 1 (visit 1), 2 (visit 2), and 14 (visit 3) months postoperatively using peripheral lymphocytes obtained at 0 hour versus 2 hours after CsA intake. Gene expression was assessed by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR).


RESULTS
CsA 0- and 2-hour levels were comparable in both groups. Absolute NFAT-regulated gene expression was significantly lower among FTY720-treated patients at visits 1 and 2. Median residual NFAT-regulated gene expression was 5.9% in the FTY720 group and 4.2% in the MPA-treated group at visit 1, increasing to 7.2% and 7.0%, respectively, at visit 3. One borderline rejection occurred in the MPA group. Median serum creatinine was 1.5 mg/dL among FTY720 and 1.8 mg/dL among MPA patients.


CONCLUSIONS
Despite significantly lower expression of NFAT-regulated genes, the relative reduction in NFAT gene expression was comparable in both groups. The absolute number of lymphocytes was not relevant for this immune response. In addition, gene expression increased to comparable levels after FTY720 was switched to MPA. The relative residual gene expression increased with reduction in CsA dose.
Sommerer
C
C
Department of Nephrology, University of Heidelberg, Heidelberg, Germany.
Morath
C
C
Giese
T
T
Meuer
S
S
Zeier
M
M
D016572:Cyclosporine / Q000627:therapeutic use; D000068876:Fingolimod Hydrochloride; D005786:Gene Expression Regulation / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000235:genetics; D007376:Interleukin-2 / Q000235:genetics; D016030:Kidney Transplantation / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D008231:Lymphopenia / Q000139:chemically induced; D008775:Methylprednisolone / Q000627:therapeutic use; D050778:NFATC Transcription Factors / Q000378:metabolism*; D011409:Propylene Glycols / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D007166:Immunosuppressive Agents; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D011409:Propylene Glycols; D012333:RNA, Messenger; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D016572:Cyclosporine; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine; D008775:Methylprednisolone