Effect of immunosuppressants on the expansion and function of naturally occurring regulatory T cells.
The induction of immune tolerance is one of the final therapeutic goals in clinical transplantation. Regulatory T lymphocytes are important for the induction and maintenance of immune tolerance to grafts. If immunosuppressive drugs used clinically to prevent immune rejection also inhibit regulatory T lymphocytes, tolerance would not be achieved. We therefore tested the effect of several immunosuppressants with different mechanisms of action on the proliferation and suppressive activity of CD4(+)CD25(+) regulatory T cells. Highly purified CD4(+)CD25h(+) T cells from C57BL/6 (H-2(b)) mice were stimulated with allogeneic T-depleted splenocytes (BALB/c; H-2(d)) in the presence of various immunosuppressants. After one week in culture, viable T cells were recovered, their regulatory capacity was assessed by their ability to inhibit responder T cell proliferation in MLR, and their cytokine production profile was measured by ELISA. The immunosuppressants rapamycin, cyclosporine A, and methylprednisolone significantly inhibited the expansion of regulatory T cells upon stimulation with alloantigen, whereas mycophenolic acid and the costimulatory blockers, anti-CD40L and CTLA4Ig, did not. None of these immunosuppressants, however, reduced the suppressive capacity of regulatory T cells. Pretreatment with immunosuppressants did not induce significant changes in the cytokine production profile of regulatory T cells. Our results suggest that costimulatory blockers and mycophenolate mofetil can be utilized therapeutically in the induction of immune tolerance. In contrast, the use of rapamycin, cyclosporine A, and methylprednisolone should be reconsidered, due to their deleterious effects on the expansion of naturally occurring regulatory T cells.
Lim
Dong-Gyun
DG
Department of Surgery and Asan Institute for Life Sciences, Ulsan University College of Medicine and Asan Medical Center, Seoul 138-736, Republic of Korea.
Joe
In-Yi
IY
Park
Youn-Hee
YH
Chang
Sung-Ho
SH
Wee
Yu-Mee
YM
Han
Duck-Jong
DJ
Kim
Song-Cheol
SC
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D007108:Immune Tolerance / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D023001:Transplantation Tolerance / Q000187:drug effects
D016207:Cytokines; D007166:Immunosuppressive Agents; D053645:Interleukin-2 Receptor alpha Subunit