In a recent issue of PNAS, Lewis et al. (1) demonstrated that treatment with human α1-antitrypsin, the major serum serine-protease inhibitor whose substrates include many proinflammatory and prothrombotic molecules, serves to protect murine insulin-producing pancreatic islet transplants placed into insulin-deficient recipients grossly mismatched for major histocompatibility complex (MHC) genes from early rejection. This observation is interesting, very relevant to troublesome clinical practice issues, and somewhat counterintuitive. Although rejection of islet allografts is a T cell-dependent immune response (reviewed in ref. 2), α1-antitrypsin, an apparently safe agent approved by the Federal Drug Administration for use in other circumstances, is known as an antiinflammatory agent, not as an immunosuppressive agent. Nonetheless, until mouse anti-human α1-antitrypsin antibodies are generated, the islet allografts are protected from rejection. Although it is not certain whether α1-antitrypsin can completely protect or (more likely) delay graft rejection, the respite from T cell-dependent rejection afforded by α1-antitrypsin is a delightful surprise. The marked susceptibility of islets to injurious effects of activated macrophages (3) and proinflammatory cytokines (4), cytokines that are often expressed as the product of activated macrophages, are well known. Moreover, islet transplants are subjected to ischemia and anoxia as a consequence of the transplant procedures. During the harvesting of donor islets, the islets are literally stripped from their blood vessels. After transplantation, perfusion of the graft is drastically compromised for days until neovascularization of the islet allograft is established (2). Once blood flow is established, the islets obviously become an inviting target for ischemia–reperfusion type injury. In addition to the inherent ischemia and anoxia during the period of compromised blood flow, coagulation and thrombosis also contribute to the multiple insults suffered by the islet allografts during the peritransplant and early posttransplant period (5). Ischemia–reperfusion and coagulation–thrombosis lead to inflammation, and the islets, as noted above, are very …