Pretransplant treatment of donors with immunomodulators to control graft-versus-host disease (GVHD) in transplant recipients.

Abstract

OBJECTIVE: Prevention of graft-versus-host disease (GVHD) by pretransplant donor treatment with known immunomodulators like complete Freund's adjuvant (CFA) and synthetic oligo-deoxynucleotides expressing CpG motifs (CpG). METHODS: Induction of GVHD by inoculation of C57BL/6 (C57) splenocytes into sublethally irradiated (BALB/c x C57BL/6) F1 (F1) mice. Splenocytes were derived from either naive C57 mice or from C57 mice that were treated previously with the immunomodulators. RESULTS: Inoculation of CFA or CpG into C57 mice led to an increase in the total number of spleen cells and resulted in activation of immunoregulatory cells that significantly suppressed mixed allogeneic lymphocyte reaction in vitro. CFA-treated C57 splenocytes led to GVHD-related death in only 14 out of 61 F1 recipients while the remaining 47 mice survived without disease for more than 200 days. Pretransplant treatment of donor C57 mice with GpG emulsified in incomplete Freund's adjuvant resulted in 19/20 GVHD-free survivors of sublethally irradiated F1 mice for more than 200 days. In contrast, naive C57 splenocytes injected into sublethally irradiated F1 recipients induced severe GVHD, which resulted in the death of 77/78 recipient mice (median of survival was 16 days). CONCLUSION: Our results suggest that adjuvant-induced immunoregulation of donor cells prior to allogeneic cell therapy may augur a new strategy that will bring the benefits of safe cellular immunotherapy aiming to eradicate malignant and nonmalignant pathological cells while avoiding or minimizing the risk of GVHD.