Increased interleukin-10 production without expansion of CD4+CD25+ T-regulatory cells in early stable renal transplant patients on calcineurin inhibitors.
BACKGROUND
Increasing long-term allograft survival is the main challenge in organ transplantation, and allograft loss due to chronic rejection has been found to correlate with episodes of early acute rejection. It is important to understand the mechanisms that maintain the donor-specific hyporesponsive state. This study prospectively evaluates immune events related to donor-specific hyporesponsiveness in the stable transplant patients on calcineurin inhibitors (CNIs).


METHODS
Peripheral blood mononuclear cells of transplant recipients on CNI (n=19) were tested in mixed lymphocyte reaction (MLR) against donor and third-party peripheral blood mononuclear cells pretransplant and at 6 to 8 weeks, 14 to 18 weeks, and 6 to 8 months posttransplant. Interleukin (IL)-10 and transforming growth factor-beta were quantitated in cultures supernatants by enzyme-linked immunosorbent assay. CD4CD25 T-regulatory cells (Tregs) were enumerated using flow cytometry.


RESULTS
All patients showed sharp decline in anti-donor and third-party MLR response at 6 to 8 weeks posttransplant with progressive decline up to 6 to 8 months. This was accompanied by increased IL-10 levels in the supernatant at all the follow-ups. Transforming growth factor-beta level in the supernatant was significantly lower at 14 to 18 weeks. Frequency of CD4CD25 Tregs showed a significant decrease at 6 to 8 weeks posttransplant, which was sustained up to 6 to 8 months.


CONCLUSIONS
The study shows that the maintenance of good graft function in early posttransplant period in recipients on CNI is associated with a decrease in donor-specific and third-party MLRs. There is a decline in Treg numbers along with increased IL-10 levels. High IL-10, probably from a non-Tregs source, may have an important role in maintaining hyporesponsiveness and good graft function.
Mittal
Sharad K
SK
Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.
Sharma
Raj Kumar
RK
Gupta
Amit
A
Naik
Sita
S
D000328:Adult; D065095:Calcineurin Inhibitors; D049109:Cell Proliferation; D002478:Cells, Cultured; D016572:Cyclosporine / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000097:blood / Q000627:therapeutic use*; D000068338:Everolimus; D005260:Female; D006085:Graft Survival / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000627:therapeutic use*; D016753:Interleukin-10 / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis*; D007676:Kidney Failure, Chronic / Q000601:surgery; D016030:Kidney Transplantation; D018655:Lymphocyte Count; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D011239:Prednisolone / Q000627:therapeutic use; D011446:Prospective Studies; D020123:Sirolimus / Q000031:analogs & derivatives / Q000627:therapeutic use; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D016559:Tacrolimus / Q000627:therapeutic use; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D023001:Transplantation Tolerance / Q000187:drug effects*; D015854:Up-Regulation; D055815:Young Adult
D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; C508609:IL10 protein, human; C508017:IL2RA protein, human; D007166:Immunosuppressive Agents; D053645:Interleukin-2 Receptor alpha Subunit; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D016572:Cyclosporine; D000068338:Everolimus; D011239:Prednisolone; D009173:Mycophenolic Acid; D020123:Sirolimus; D016559:Tacrolimus