Lymphocyte loss and immunosuppression following acetaminophen-induced hepatotoxicity in mice as a potential mechanism of tolerance.
Current evidence suggests that drug-induced liver disease can be caused by an allergic response (drug-induced allergic hepatitis, DIAH) induced by hepatic drug-protein adducts. The relatively low incidence of these reactions has led us to hypothesize that tolerogenic mechanisms prevent DIAH from occurring in most people. Here, we present evidence for the existence of one of these regulatory pathways. Following a hepatotoxic dose of acetaminophen in C57Bl/6 mice, lymphocyte loss that appeared to be due at least in part to apoptosis was noted in the spleen, thymus, and draining lymph nodes of the liver. There was no observable lymphocyte loss in the absence of hepatotoxicity. Acetaminophen-induced liver injury (AILI) also led to a functional suppression of the immune system as determined by the inhibition of a delayed-type hypersensitivity response to dinitrochlorobenzene. Further studies with adrenalectomized mice suggested a role for corticosterone in the depletion of lymphocytes following APAP-induced liver injury. In conclusion, these findings suggest that lymphocyte loss and immunosuppression following AILI may prevent subsequent occurrences of allergic hepatitis and possibly other forms of APAP-induced allergies induced by hepatic drug-protein adducts. Similar regulatory pathways may inhibit other hepatotoxic drugs from causing allergic reactions.
Masson
Mary Jane
MJ
Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA. massonm@nhlbi.nih.gov
Peterson
Richard A
RA
Chung
Christine J
CJ
Graf
Mary L
ML
Carpenter
Leah D
LD
Ambroso
Jeffrey L
JL
Krull
David L
DL
Sciarrotta
Janeice
J
Pohl
Lance R
LR
D000082:Acetaminophen / Q000633:toxicity*; D000222:Adaptation, Physiological; D000818:Animals; D003345:Corticosterone / Q000097:blood; D008099:Liver / Q000187:drug effects*; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
D000082:Acetaminophen; D003345:Corticosterone