Li and Strom reply

Dharnidharka and colleagues raise an important point. Co-stimulation blockade using anti-CD154 and CTLA4-Ig, albeit remarkably effective in many models, has not proven universally successful in producing permanent engraftment in allograft models. Although the cited work of Larsen and Pearson4 showed universal survival of skin allografts for 50 days, after further observation, only 50% of the recipients in that study experienced permanent engraftment (C. Larsen, personal communication). In skin graft models, subtle differences in the precise source of the skin graft, the source of CTLA4-Ig and differences in the C3H/He substrains are potentially very important in determining outcome. In fact, Larsen and Pearson have just shown in another strain combination that asialo GM1+ CD8+ T cells are essential in co-stimulation blockade-resistant mouse skin allograft rejection7. Several other groups have noted that CD8+ T cells are responsible for co-stimulation blockade resistant rejection in intestinal8 and skin9 allograft models. And our own unpublished observations show that co-stimulation blockade is ineffective in blocking islet allograft rejection in a CD8+ T-cell receptor transgenic model. We know of several other groups that have noted CD8+ T-cell-dependent, co-stimulation blockade resistant allograft rejection. Recall that the expression of the co-stimulatory proteins differs from CD4+ to CD8+ T cells.

Larsen and Pearson have also failed to produce permanent engraftment in essentially the same subhuman primate kidney allograft model used by Kirk et al. (C. Larsen, personal communication). Larsen and Pearson use older monkeys than Kirk, and suspect that age related differences in the presence of memory cells in the older host may be important (C. Larsen, personal communication), as secondary immune responses are not as amenable to co-stimulation blockade as primary responses. A similar difference in the ability to tolerize young and old allograft responses with co-stimulation blockade has been noted in a rat model (H-D Volk, personal communication). And in an as-yet unpublished work, we found that co-stimulation blockade, even with the addition of donor specific transfusion, does not materially prolong survival of islet allografts placed into autoimmune non-obese diabetic mice.

In short, we believe that co-stimulation blockade based therapies have great promise for clinical application. Adjunctive therapies may well be required in many circumstances as memory T cells and, in some circumstances, naive CD8+ T cells are not ready tolerized after co-stimulation blockade. Although we do not advocate the addition of rapamycin2 as the only possible solution, we are convinced that a means to diminish the clone size of the responding alloreactive T cells through apoptosis or other measures is crucial to the success of co-stimulation blockade based and other potentially tolerizing therapies.