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The development of long-term allograft survival and understanding the mechanism(s) by which it is induced are major goals of experimental transplantation. Studies by several different investigators have provided conflicting evidence for the role of interleukin (IL)-4 in the process of allograft rejection or long-term allograft survival. These studies examine the role of IL-4 in experimental cardiac allograft rejection and in inducing long-term allograft survival. A possible mechanism for long-term allograft maintenance via alternative allosensitization is discussed.Adult IL-4-intact or IL-4-deficient (knock-out, KO) C57BL/6 (B6) mice were transplanted with heterotopic DBA/2 cardiac allografts and immunosuppressed either with gallium nitrate (GN), or the anti-CD4 monoclonal antibody, GK1.5. Cellular allosensitization was assessed by testing the allograft recipients for donor-reactive delayed-type hypersensitivity (DTH) responses. The presence of antigen-driven suppressive mechanisms was assessed using a linked unresponsiveness (bystander suppression) DTH assay.In general, the results were the same with either GN or GK1.5. We observed that (1) IL-4 is not required for acute allograft rejection or allogeneic DTH responses in nonsuppressed mice, (2) IL-4 is required for long-term allograft survival in immunosuppressed mice, (3) immunosuppression creates a requirement for IL-4 in major histocompatibility complex self-restricted, but not allorestricted, DTH responses, and (4) the development of alloantigen-dependent linked DTH unresponsiveness (bystander suppression) in allograft recipients requires IL-4.In summary, these studies demonstrate a common requirement for IL-4 during the development of long-term allograft survival and the concurrent development of alloantigen-dependent DTH down-regulation in cardiac allograft recipients after immunosuppression.