PREVENTION OF LETHAL GRAFT-VERSUS-HOST DISEASE IN MICE BY MONOCLONAL-ANTIBODIES DIRECTED AGAINST T-CELLS OR THEIR SUBSETS .1. EVIDENCE FOR THE INDUCTION OF A STATE OF TOLERANCE BASED ON SUPPRESSION

Lethal GVHD in the fully allogeneic BALB/c (donor)(C57BL X CBA)F-1 (re cipient) mouse strain combination could be prevented by a single dose of IgG2b monoclonal antibodies moAb) directed to T cells. The influenc e of the time of administration of this moAb after GVHD induction and the effect of anti-T cell subset moAb on the development of GVHD was i nvestigated in this study. Moreover, the state of tolerance in the mic e that had become long-term chimeras was examined. Anti-Thy-1 treatmen t of the recipients 1 day before, 2 h before or 1 day after reconstitu tion almost completely prevented lethal GVHD. A single dose of 100 mu g of anti-Thy-1 was as effective as four daily doses of 25 mu g each. Treatment with a single dose of 25 mu g or with intervals of 4 days be tween doses of 25 mu g was statistically significantly less effective. We injected the recipients with moAb directed to the CD4(+) or CD8(+) T cells subsets. Using a dose of 100 mu g moAb, anti-CD4 treatment ap peared to be less effective than anti-Thy-1 treatment whereas anti-CD8 treatment was not effective at all. A double dose of anti-CD4 was equ ally effective as anti-Thy-1 treatment. All mice that became long term survivors remained free of signs of GVHD and were > 99% repopulated w ith donor type cells. Injection of spleen cells from these BALB/c into (C57BL X CBA)F-1 chimeric mice was used to reconstitute lethally irra diated BALB/c, BALB.K and (C57BL X CBA)F-1 recipients. Lethal GVHD dev eloped in the BALB.K and (C57BL x CBA)F-1 recipients but not in the BA LB/c recipients. A graft-versus-host (GVH) reaction could only be indu ced in these stable chimeras when they were subjected to a second leth al irradiation and subsequently reconstituted with naive BALB/c spleen cells. Injection of the recipient with moAb directed to T cells or CD 4(+) T cells can effectively prevent lethal GVHD and leads to a state of complete chimerism and tolerance which is probably not due to clona l deletion of alloreactive T cells but to active suppression.