Suppression of cytolytic function in murine lymphocytes exposed to 1,4-bis[(2-aminoethyl)amino]-5,8-dihydroxy-9,10-anthracenedione dihydrochloride (AEAD): inhibition of proliferation by cytotoxic T-lymphocyte precursors.
Previous reports have shown that exposure of murine splenic lymphocytes to the substituted anthraquinone 1,4-bis[(2-aminoethyl)amino]-5,8-dihydroxy-9,10-anthracenedione dihydrochloride (AEAD) results in a persistent, strong immunosuppression which is limited to induction of cytotoxic T-lymphocytes (CTL). In the present study the cellular mechanism of this specificity was examined in detail. Proliferation of T-lymphocytes is inhibited by in vitro exposure to AEAD, with suggestive evidence that this inhibition may be selective for the CTL precursor cells. Activation and differentiation of CTL precursors into functional CTL, as well as the function of T-helper lymphocytes, was unaffected by AEAD exposure. Rather, the committed CTL precursor cells are prevented from clonal proliferation, resulting in a much smaller population of antigen-induced CTL effectors. Finally, it was shown that AEAD is unable to prevent the anamnestic response of CTL memory cells to eliciting antigen. Taken together these data provide strong evidence that AEAD-induced CTL suppression results from its antiproliferative effect, directed primarily toward the CTL precursor subpopulation. This effect is manifested as decreased CTL function due to lower absolute number of specific CTL, since AEAD has no significant direct effect on expression of either specific or polyclonal cytolysis by T-lymphocytes.
House
R V
RV
Department of Cellular and Molecular Toxicology, Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709.
Pallardy
M J
MJ
Cornacoff
J B
JB
Thurmond
L M
LM
Dean
J H
JH
D000818:Animals; D002478:Cells, Cultured; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D015848:Interleukin-5; D007378:Interleukins / Q000378:metabolism; D007700:Kinetics; D008213:Lymphocyte Activation; D051379:Mice; D008942:Mitoxantrone / Q000031:analogs & derivatives* / Q000276:immunology / Q000494:pharmacology; D012313:RNA / Q000096:biosynthesis / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*
D015848:Interleukin-5; D007378:Interleukins; D012313:RNA; C043485:CL 232468; D008942:Mitoxantrone