Are stem cells and T cells best transplanted separately

In the prehistory of marrow transplantation in the 1950s, long before clinical stem cell transplantation became a routine procedure, it was already appreciated that donor lymphocytes conferred on the recipient both harmful (GvHD) and beneficial effects (GvL and immune function). However, it was not until the early 1980s, when methods of T-cell depletion with Ab became available, that it was possible to test the impact of T-cell depletion of BM in clinical transplants. It soon emerged that T-cell depletion was more of a great leap sideways than forward, introducing as it did a new set of problems (all predictable): increased relapse, infection and graft rejection. As emerging results of T-cell depletion showed inferior, or at best comparable, disease-free survivals between T-cell depleted vs. unmanipulated transplants, it was generally concluded that T-cell depletion of marrow was not worth the effort. Some investigators still persisted, however, notably Hale et al. [1] championing Campath MAb, those seeking selective T-cell depletion and those investigating T-cell depleted stem cell transplants followed by delayed T-cell add-back [2]. The experimental basis for this latter approach came from studies by Johnson et al. [3,4], who showed that spleen cells that induced fatal GvHD when given together with a marrow transplant could be safely transfused into recipient mice if the spleen cells were given 30 or more days after the marrow [3]. Interestingly this approach could also be used to conserve GvL reactions [4]. As delayed delivery of T cells to the recipient might get the best of both worlds, restoration of useful immunity without GvHD, several investigators, including ourselves, explored different ways to deliver T cells to recipients receiving T-cell depleted transplants [5 /9]. In humans, it is not possible to prevent GvHD completely, which occurs either immediately after transplant or after the T-cell addback. Even small doses of T cells given without immunosuppression at the time of transplant or add-back could induce GvHD, which could occasionally be severe [5]. Appropriately therefore, Kobbe et al. [10], published in this issue of Cytotherapy, elected to use CYA to mitigate the effects of GvHD from the transplant of T-depleted stem cells. They used the Isolex† system to deplete peripheral blood stem cell transplant (PBSCT) transplants profoundly of T cells, delivering around 5 /10 CD3 cells/kg at transplant, then reinfusing the T cells put aside at time of transplant, in logarithmically increased doses, on days 25 and 50 or days 50 and 100. Despite receiving CYA immunosuppression, in 29 evaluable patients 10% developed GvHD from lymphocytes given at transplant, and 67% developed GvHD after lymphocyte return, but only 4/24 patients got grade III /IVGvHD and none died of this complication. Chronic GvHD did not appear to be much diminished in frequency but only two patients developed extensive disease. Results for patients with myeloid malignancies were a respectable 74% survival, but patients with multiple myeloma (MM) and acute lymphoblastic leukemia (ALL) had only a 30% survival. Kobbe et al . [10] conclude that low-dose DLI given pre-emptively after SCT is safe and has low toxicity. Certainly the impression is that their approach resulted in minimal problems from GvHD. These findings are provocative, but tantalizingly raise more questions than they answer. First, without a properly randomized controlled prospective study, it is not possible to know how T-cell depletion, vs. T-cell depletion with