Mechanisms of tolerance induction after rat liver transplantation: intrahepatic CD4(+) T cells produce different cytokines during rejection and tolerance in response to stimulation.
Increasing evidence supports the existence of regulatory T cells that may inhibit the allogeneic immune response after transplantation by secreting regulatory cytokines. To determine whether rat liver tolerance is associated with intrahepatic regulatory T cells secreting a characteristic cytokine profile, we analyzed the cytokine production of freshly isolated intragraft CD4(+) T cells at different times postoperatively by semiquantitative reverse transcription-polymerase chain reaction and by enzyme-linked immunosorbent assay before and after in vitro stimulation. Orthotopic arterialized liver transplantation was performed in two allogeneic rat strain combinations, one with fatal acute rejection (DA-to-LEW) and one with long-lasting tolerance (LEW-to-DA) without immunosuppression despite a complete major histocompatibility complex mismatch (spontaneous liver tolerance). Liver allografts of both groups showed continuously increasing cellular infiltration between day 3 and day 7 after transplantation. In this inflammatory situation, very low levels of interleukin-13 were detectable directly after cell isolation, as well as after in vitro stimulation. However, after 30 days, intrahepatic CD4(+)T cells in the tolerance group were then able to express elevated messenger RNA levels of the anti-inflammatory cytokine interleukin-13 in response to stimulation. This result indicates the presence of an intragraft Th2-like CD4(+) T cell population, which may have a regulatory function in the induction of liver tolerance.
Otto
Christoph
C
Experimental Transplantation Immunology Unit, Department of Surgery, University of Würzburg, Würzburg, Germany. chotto@chirurgie.uni-wuerzburg.de
Kauczok
Jens
J
Martens
Natascha
N
Steger
Ulrich
U
Möller
Ingo
I
Meyer
Detlef
D
Timmermann
Wolfgang
W
Ulrichs
Karin
K
Gassel
Heinz-Jochen
HJ
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D006084:Graft Rejection / Q000276:immunology*; D007108:Immune Tolerance / Q000502:physiology*; D018189:Immunomagnetic Separation; D016031:Liver Transplantation / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014184:Transplantation, Homologous
D016207:Cytokines