The effect of sirolimus- or cyclosporine-based immunosuppression effects on T-cell subsets in vivo.
While sirolimus (SRL) is thought to be a non-nephrotoxic agent, cyclosporine A (CsA) toxicity is a serious problem in kidney transplantation. We compared the effects of the two drugs on T-helper (Th) subsets in kidney transplant patients. We examined 24 first cadaver kidney recipients equally randomized to receive SRL/mycophenolate mofetil (MMF)/methylprednisolone (MP), or cyclosporine with either MMF or MP. The Th1 and Th2 subsets in peripheral blood were separated based on their production of interferon-gamma (INFgamma) or interleukin (IL)-4/IL-5. The lymphocytes were stimulated with phytohemoagglutinin or with allogenic CD3-depeted and irradiated antigen-presenting cells. Furthermore, the conversion potential of Th0 to Th1 was determined by measuring IL-12 and IL-18 levels after lipopolysaccharide challenge. When peripheral blood lymphocytes taken from SRL-treated patients were stimulated by phytohemoagglutinin, there were significantly lower INFgamma-producing cells compared with the lymphocytes taken from patients treated with CsA. The number of IL-4/IL-5-producing cells did not differ among the patient groups. Release of IL-12 but not IL-18 from peripheral lymphocytes following treatment with lipopolysaccharide was significantly lower in the SRL-treated patients. These results show that compared with CsA, SRL caused a significant decrease in the Th1 lymphocyte subset associated with a significant reduction of IL-12 release.
Libetta
C
C
Unit of Nephrology, Fondazione IRCCS Policlinico San Matteo, and University of Pavia, Italy. carmelo.libetta@unipv.it
Sepe
V
V
Zucchi
M
M
Portalupi
V
V
Meloni
F
F
Rampino
T
T
Dal Canton
A
A
D000328:Adult; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D015848:Interleukin-5 / Q000235:genetics / Q000378:metabolism; D016030:Kidney Transplantation; D008297:Male; D008775:Methylprednisolone / Q000494:pharmacology / Q000627:therapeutic use; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use*; D018417:Th1 Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018418:Th2 Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents; D020382:Interleukin-18; D015848:Interleukin-5; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; D016572:Cyclosporine; D009173:Mycophenolic Acid; D020123:Sirolimus; D008775:Methylprednisolone