Prevention of lethal graft-versus-host disease in mice by monoclonal antibodies directed against T cells or their subsets. I. Evidence for the induction of a state of tolerance based on suppression

Lethal GVHD in the fully allogeneic BALB/c (donor)(C57BL x CBA)F₁ (recipient) mouse strain combination could be prevented by a single dose of IgG2b monoclonal antibodies (moAb) directed to T cells. The influence 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 investigated in this study. Moreover, the state of tolerance in the mice that had become long-term chimeras was examined. Anti-Thy-1 treatment of the recipients 1 day before, 2h before or 1 day after reconstitution almost completely prevented lethal GVHD. A single dose of 100 μg of anti-Thy-1 was as effective as four daily doses of 25 μg each. Treatment with a single dose of 25 μg or with intervals of 4 days between doses of 25 μg 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 μg moAb, anti-CD4 treatment appeared 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 equally effective as anti-Thy-1 treatment. All mice that became long term survivors remained free of signs of GVHD and were > 99% repopulated with donor type cells. Injection of spleen cells from these BALB/c into (C57BL X CBA)F₁ chimeric mice was used to reconstitute lethally irradiated BALB/c, BALB.K and (C57BL X CBA)F₁ recipients. Lethal GVHD developed in the BALB.K and (C57BL X CBA)F₁ recipients but not in the BALB/c recipients. A graft-versus-host (GVH) reaction could only be induced in these stable chimeras when they were subjected to a second lethal irradiation and subsequently reconstituted with naive BALB/c spleen cells. Injection of the recipient with moAb directed to T cells or CD4⁺ T cells can effectively prevent lethal GVHD and leads to a state of complete chimerism and tolerance which is probably not due to clonal deletion of alloreactive T cells but to active suppression.