Prevention of graft-versus-host disease by induction of immune tolerance with ultraviolet B-irradiated leukocytes in H-2 disparate bone marrow donor

Transfusions (Tx) of Ultraviolet B (UVB)-irradiated peripheral blood mononu clear leukocytes (MNL) have been shown to induce humoral immune tolerance t o major histocompatability complex (MHC) antigens (Blood 88:4375, 1996), To determine whether cellular immune tolerance to MHC antigens can be induced by the same approach, transplantation of bone marrow and spleen cells from tolerant donors across the H-2 barrier was conducted to study its effect o n prevention of graft-versus-host disease (GVHD). After immune tolerance in duction by four weekly Tx of UVB-irradiated BALB/c (H-2(d)) peripheral bloo d MNL into CBA/HT6 (H-2(k)) mice, hone marrow cells (BMC) and spleen MNL fr om tolerant or naive CBA mice were transplanted into lethally irradiated BA LB/c mice, The transplanted mice were followed by measuring body weight, pe ripheral leukocyte counts, GVHD, survival, and cytokine response, All BALB/ c recipient mice were fully engrafted with H-2(k) CBA donor cells after tra nsplantation. The severity of GVHD was significantly attenuated in BALB/c m ice transplanted with BMC and spleen MNL from tolerant CBA donor mice, The recovery of peripheral leukocyte and lymphocyte counts were faster and more complete in mice transplanted with cells from the tolerant donors. The ser um cytokine profile after transplantation with tolerant donor cells showed increased interleukin-4 and reduced gamma interferon that are consistent wi th a polarized Th2 response. The results pooled from three separate experim ents showed that BALB/c mice transplanted with 5 x 10(6) BMC and 4 x 10(5) spleen MNL from tolerant CBA donors had better overall survival than the co ntrol group (72% v 17%, P =.018). The findings show that transplantation wi th bone marrow and spleen cells from tolerant H-2 disparate donor mice is a ssociated with significant attenuation of GVHD and better outcomes. The res ults also support that transfusions of UVB-irradiated leukocytes may induce cellular immune tolerance, (C) 1999 by The American Society of Hematology.