COBLOCKADE OF THE LFA1-ICAM AND CD28 CTLA4-B7 PATHWAYS IS A HIGHLY EFFECTIVE MEANS OF PREVENTING ACUTE LETHAL GRAFT-VERSUS-HOST DISEASE INDUCED BY FULLY MAJOR HISTOCOMPATIBILITY COMPLEX-DISPARATE DONOR GRAFTS/

We have developed an in vitro system in which C57BL/6 donor splenocyte s are exposed to B10.BR host alloantigens in the context of deficient CD28:B7 signaling as a means of preventing graft-versus-host disease ( GVHD). Although 54% to 82% of MLR alloresponse was inhibited by cytoto xic T-lymphocyte antigen 4 (CTLA4)-lg treatment of host stimulator cel ls, treated splenocytes were still capable of causing GVHD when infuse d in vivo. By adding anti-leukocyte function antigen 1 (anti-LFA1) ant ibody to hCTLA4-lg in vitro to coblock the LFA1:intercellular adhesion molecule (ICAM) signaling, splenic alloresponse was inhibited by grea ter than or equal to 89%, yet GVHD induction capabilities were retaine d. Because antigen-primed cells might be more susceptible to CD28:B7 b lockade, we investigated whether hCTLA4-lg alone, anti-LFA1 antibody a lone, or the combination of both added to donor-antihost in vitro prim ed cells could reduce GVHD. To facilitate hyporesponsiveness induction and to block B7 and ICAM ligands that are upregulated during GVHD, th ese reagents were also administered to recipients post-BMT. We have sh own that hCTLA4-lg plus anti-LFA1 antibody is highly effective in prev enting GVHD-induced lethality (88% to 100% of treated mice surviving v ersus 0% to 28% of controls surviving), For optimal prevention, both h CTLA4-lg and anti-LFA1 must be used in vitro in the context of donor-a ntihost primed splenocytes and continued in vivo. This in vitro-in viv o combined approach was associated with donor engraftment, and recipie nts were not globally immunosuppressed, We conclude that blocking both the CD28/B7 and the LFA1:ICAM pathways are critical to effective GVHD prevention and may offer advantages to in vitro donor T-cell removal. (C) 1995 by The American Society of Hematology.