Analysis of retinoid-mediated immunosuppression in vivo. Effects of Ro23-6457 on cellular alloimmune responses.
We have investigated the immunosuppressive effects of a synthetic retinoid, Ro23-6457, on the in vivo development of cellular alloimmunity. We initially observed that treatment of C57B1/6 mice with 10 mg/kg/day Ro23-6457 drug could prolong the survival of DBA/2 cardiac allografts, thus verifying its immunosuppressive potential in murine experimental models. We next used the sponge matrix model of allograft rejection and limiting dilution analysis (LDA) of cytotoxic T lymphocyte (CTL) frequency to dissect this phenomenon further. In this experimental system we observed the following effects of Ro23-6457: (1) dose-dependent decrease in the number of LDA-detectable, donor-reactive CTL accumulating in sponge matrix allografts; (2) failure to interfere with in vitro assays of cellular alloimmunity, including LDA; and (3) antigen non-specific depression of LDA-detectable CTL in lymph nodes, spleen and especially in peripheral blood. For peripheral blood CTL, the drug eliminated LDA-detectable CTL, an effect that was reversible and could not be attributed to the activation of suppressor cells. Since Ro23-6457 has little effect on the number of peripheral blood Thy1.2+ cells, it appears that this drug does not physically eliminate CTL, but makes them temporarily hyporesponsive to antigen stimulation, and thus undetectable in functional assays like LDA.
Orosz
C G
CG
Department of Surgery, Ohio State University College of Medicine, Columbus 43210.
Zinn
N E
NE
Bishop
D K
DK
Leppink
D L
DL
Faherty
D
D
Ferguson
R M
RM
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D016027:Heart Transplantation; D007111:Immunity, Cellular / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects; D014184:Transplantation, Homologous / Q000276:immunology; D014212:Tretinoin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
D007166:Immunosuppressive Agents; C061340:Ro 23-6457; D014212:Tretinoin