Good-bye to GVHD

Bone marrow transplantation would be even more widely used if the complications of graftversus-host disease (GVHD) could be routinely and simply avoided. GVHD is induced by T cells in the bone marrow (BM) graft recognizing and reacting against the host. The disease tends to be much more severe when host and donor differ at the major histocompatibility complex (MHC) but can also occur for MHC-identical transplants. The simple solution of removing all T cells from the graft prevents GVHD induction but then the graft, for reasons that are not totally clear, often fails. Residual T cells not only promote engraftment but also may provide some immune (particularly anti-tumor) protection. A solution to this problem might be a procedure that specifically removes only those T cells in the graft that can recognize and react against the host. Bachar-Lustig and colleagues (page 1943) describe such a protocol using “veto cells” for the successful transplantation of fully allogeneic BM containing large numbers of allogeneic T cells. They have worked with a mouse model but the design is such that the protocol should be readily transferable to the clinic. More important, they also show that when the immunosuppressive drug rapamycin is included in the protocol, it synergizes with rather than blocks the action of the veto cells.

Veto cells have been defined as cells that can delete T cells that recognize them.¹  As reviewed by Bachar-Lustig and colleagues, a number of different cells appear to have this ability, among them being CD8⁺ cytotoxic T-lymphocyte (CTL) lines. Let A, B, C, and D represent 4 MHC-different inbred mouse strains. When an A anti-B mixed-lymphocyte reaction (MLR) is set up, strain-A origin CTLs reactive against strain B are generated. If CD8⁺ CTLs syngeneic to the strain-B stimulator but not reactive against the A-strain responder (eg, from a B anti-D MLR) are included in the culture, they act as veto cells.²  A anti-B CTL precursors in the culture that recognize strain-B antigens on the added CTLs are now known to undergo apoptosis in a process involving both CD8 and Fas-L on the veto cell (Figure 1 in Bachar-Lustig et al). When the same B anti-D CTLs are added to an A anti-C MLR they do not affect the response because the A anti-C–activated CTL precursors cannot recognize them. Bachar-Lustig et al have effectively done the same series of experiments in vivo. Lethally irradiated strain-B mice received strain-A BM transplants containing large numbers of strain-A T cells. Rapid death ensued unless cells from a B anti-D CTL line were also included. Addition of rapamycin could make these cells more effective. In principle, the problem of GVHD has been solved!