To the editor—We read with interest the articles by Li et al. 1 and Wells et al. 2 in the November 1999 issue of Nature Medicine. They have made an impressive case for the fundamental role of activated T-cell apoptosis in the induction of long-term transplant tolerance. However, we were concerned about the lack of efficacy of combined co-stimulatory blockade (cytotoxic T-lymphocyte antigen 4 immunoglobulin (CTLA4-Ig) and mouse antibody against CD40 ligand (anti-CD40L)) in preventing rejection of skin allografts in the fully major histocompatibility complex-mismatched mice, as reported by Li et al.

The most remarkable aspect about combined co-stimulatory blockade has been its universal success in inducing longterm graft acceptance in a variety of animal models3–6. Indeed Larsen and Pearson’s original paper documented indefinite graft survival in skin grafts in the same strain combination (Balb/c to C3H/He), using the same protocol4. Other studies have documented similar results in primate kidney grafts3, in bone marrow transplants6 and in xenotransplantation5. Thus, combined co-stimulatory blockade, rather than blockade of one co-stimulatory path alone, seems to work in even the most stringent transplant models. Yet Li et al. described the mean survival time for skin grafts that received both CTLA4-Ig and the mouse anti-CD40L as only 15 days (range, 8–19), and not significantly different from that seen in controls. To our knowledge, this is the first report of a failure of this protocol to induce longterm skin graft survival. It is not clear why the protocol failed, as a strain dependency or a difference in dosing regime does not seem to be the issue. The mechanisms for the failure need to be investigated. This may have considerable importance for upcoming human trials.