Posttransplant interleukin-4 treatment converts rat liver allograft tolerance to rejection.
BACKGROUND
Previous studies showed that liver transplant rejection in the Piebald Virol Glaxo (PVG)-to-Lewis combination was associated with more intragraft interleukin (IL)-4 mRNA expression than in spontaneously tolerant grafts in the PVG-to-Dark Agouti (DA) combination. There was also immunoglobulin (Ig) G1 antibody deposition, suggesting an IL-4-induced IgG class switch in rejection. The aim of this study was to investigate whether IL-4 treatment converts PVG-->DA liver transplant tolerance to rejection.


METHODS
DA (RT1a) rats were recipients of orthotopic PVG (RT1c) liver transplants and DA liver transplants were syngeneic controls. Supernatant from IL-4-transfected Chinese hamster ovary cells (0.5 mL, 30,000 U) or from untransfected cells was injected intraperitoneally on days 3 through 7. Samples were taken for immunohistochemical staining of frozen tissue sections to analyze cellular infiltrate and antibody deposition.


RESULTS
IL-4 treatment significantly reduced survival of liver allografts from greater than 100 days in untreated animals to 9 days (P=0.004). Pathologic analysis of IL-4-treated animals showed that death was caused by liver transplant rejection, with a heavy infiltrate of mononuclear cells, disruption of portal tract areas, and infarction. Immunohistochemistry revealed an extensive infiltrate of T cells, CD25-expressing cells, and B cells that was similar to the level in PVG--> Lewis liver allograft recipients that reject the liver. There was also a more extensive monocyte-macrophage infiltrate and more major histocompatibility complex class II expression in IL-4-treated animals compared with untreated animals. There was moderate increase of IgM, little IgG1, and no IgE or IgG2a antibody deposition.


CONCLUSIONS
IL-4, a T-helper type 2 cytokine that has previously been shown to inhibit delayed-type hypersensitivity responses such as rejection, was found to promote rejection of liver allografts. There was only slight evidence of a graft-specific antibody response, showing that IL-4 induces liver allograft rejection in association with some, but not all, of the changes accompanying rejection in the PVG-->Lewis strain combination.
Wang
Chuanmin
C
Liver Laboratory, Centenary Institute, Sydney University, Camperdown, NSW, Australia.
Li
Jian
J
Cordoba
Shaun P
SP
McLeod
Duncan J
DJ
Tran
Giang T
GT
Hodgkinson
Suzanne J
SJ
Hall
Bruce M
BM
McCaughan
Geoffrey W
GW
Bishop
G Alex
GA
D000818:Animals; D000917:Antibody Formation; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D015847:Interleukin-4 / Q000494:pharmacology*; D007518:Isoantibodies / Q000032:analysis; D016031:Liver Transplantation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D023001:Transplantation Tolerance; D014184:Transplantation, Homologous / Q000276:immunology
D007518:Isoantibodies; D015847:Interleukin-4