ANTI-LFA-1 (CD11A) MONOCLONAL-ANTIBODY INTERFERES WITH NEONATAL INDUCTION OF TOLERANCE TO ALLOANTIGENS

The injection of(C57BL/6 x BALB/c)F1 spleen cells into newborn BALB/c mice results in the induction of a specific cytotoxic T lymphocyte (CT L) tolerance to the alloantigens. On the contrary, alloreactive CD4(+) T cells persist in the host and are still able to activate autoreacti ve F1 B cells to produce autoantibodies. This state of ''split toleran ce'' is closely associated with the development of a lupus-like autoim mune syndrome. The LFA-1 integrin plays a relevant role in homing, int ercellular adhesion and tranduction of co-stimulatory signals in leuko cytes. Because of the beneficial effects of anti-LFA-1 monoclonal anti bodies (mAb) treatment in various models of organ transplantation and autoimmune disease, we have investigated if such a treatment could int erfere with the induction of neonatal tolerance or the development of the autoimmune syndrome in F1 cell-injected newborn mice. For this pur pose, BALB/c mice neonatally injected with F1 cells were treated from day 1 up to day 15 with a non-cytotoxic anti-LFA-1 (CD11a) mAb. Anti-L FA-1 mAb treatment interfered with the persistence of a stable chimeri sm and with the establishment of CTL tolerance, as shown by rejection of allogeneic skin grafts and F1 B cells, and by a normal in vitro CTL activity against the corresponding alloantigens. As a consequence, th ese mice did not develop the characteristic autoimmune features seen i n close association with an effective induction of CTL tolerance to al loantigens. These results stress the importance of the interactions be tween LFA-1 and its ligands during the neonatal induction of tolerance to alloantigens.