Immunosuppressive properties of CD95L-transduced "killer" hybrids created by fusing donor- and recipient-derived dendritic cells

Allogeneic immune responses, which are initiated by dendritic cells (DCs) o f both donor and host origins, remain a major obstacle in organ transplanta tion. Presentation of intact major histocompatibility complex (MHC) molecul es by allogeneic DCs and allogeneic peptides by syngeneic DCs leads to comp lex allogeneic immune responses. This study reports a novel strategy design ed to suppress both pathways. A stable DC line XS106 (A/J mouse origin) was transfected. with CD95L cDNA and fused with splenic DCs purified from allo geneic BALB/c mice. The resulting "killer" DC-DC hybrids: (1) expressed CD9 5L and MHC class I and class II molecules of both AM and BALB/c origins, wh ile maintaining otherwise characteristic surface phenotypes of mature DCs; (2) inhibited MHC class I- and class II-restricted mixed leukocyte reaction s between the parental strains by triggering apoptosis of alloreactive T ce lls; and (3) abolished delayed-type hypersensitivity responses of A/J (and BALB/c) mice to BALB/c-associated (and A/J-associated) alloantigens when in jected intravenously into A/J (and BALB/c) mice. The onset of graft-versus- host disease in (BALB/c x A/J) F1 hosts receiving A/J-derived hematopoietic cell transplantation was suppressed significantly (P <.001) by killer DC-D C hybrid treatment. These results form both technical and conceptual framew orks for clinical applications of CD95L-transduced killer hybrids created b etween donor DCs and recipient DCs in the prevention of allogeneic immune r esponses following organ transplantation. (Blood. 2001;98:3465-3472) (C) 20 01 by The American Society of Hematology.