The immune response to a vascularized allograft involves a complex series of events, including T cell activation. A critical marker of T cell activation is the acquisition of stereospecific membrane receptors for the lymphokine, interleukin 2 (IL-2) (1-4). While resting T cells lack IL-2 receptors, in vitro studies (5,6) indicate that essentially all lectin-or alloantigen-stimulated proliferating T cells express the IL-2 receptor. Moreover, the interaction of IL-2 with receptorbearing cells is required for the clonal expansion of activated T cells (1-13). Whereas engagement of the T cell receptor for antigen is the first step in T cell activation, the interaction of IL-2 with the newly expressed IL-2 receptor is a requisite step in the common pathway of activation of all T cells. The extension of these in vitro findings to the process of allograft rejection in vivo has not been extensively studied. IL-2 is necessary to reconstitute the acute rejection response in vivo in T cell-deprived rats (14). However, direct evidence in vivo that the IL-2 receptor is involved in allograft rejection has been lacking.The rat monoclonal antibody (mAb) M7/20 binds to the murine IL-2 receptor, as demonstrated by its capacity to bind activated but not resting T cells in flow cytometry experiments, to prevent IL-2-mediated DNA synthesis in an IL-2-dependent cytotoxic T lymphocyte cell line, to precipitate an N-glycosylated 58 kilodalton glycoprotein, and to competitively inhibit binding of radiolabelled IL-2 (15). As such, it offers an opportunity to direct immunosuppressive therapy selectively against IL-2 receptor-bearing cells during allograft rejection. In this report, we examine the effect of administration of M7/20 on survival of cardiac allografts in mice.
Materials and MethodsAnimals. Inbred male mice, weighing 20-25 gm, of strains C57BL/10, B10.BR, and B10.AKM (The Jackson Laboratory, Bar Harbor, ME) were used throughout. These strains are completely mismatched for the H-2 locus, but share the same genetic background.Operative Technique. Vascularized, heterotopic heart allografts were performed as
Monitoring human cardiac allograft rejection is currently accomplished by endomyocardial biopsy. Available noninvasive methods for identifying rejection have lacked the necessary sensitivity or specificity, or both, for routine clinical application. In vivo phosphorus-31 (P-31) nuclear magnetic resonance (NMR) spectroscopy has been used for monitoring phosphorus metabolism in both animal models and humans. In the present study this technique was employed as a noninvasive means to assess the bioenergetic processes that occur during cardiac allograft rejection in a rat model. Brown Norway rat hearts were transplanted subcutaneously into the anterior region of the neck of Lewis rat recipients (allografts). Control isografts employed Lewis donors and recipients. Phosphocreatine to inorganic phosphate (PCr/Pi), phosphocreatine to beta-adenosine triphosphate (PCr/ATP beta), beta-adenosine triphosphate to inorganic phosphate (ATP beta/Pi) ratios and pH of the transplanted hearts were monitored using surface coil P-31 NMR spectroscopy (at 4.7 tesla) daily for 7 days. To allow recovery from the compromise induced by the surgical procedure, the measurements obtained on day 2 were taken as a baseline. PCr/Pi was unchanged or increased in the isografts but decreased continually in allografts, with the difference becoming significant by day 4 when compared with levels in day 2 allografts (p less than 0.005) and by day 3 when compared with levels in the isograft group (p less than 0.05). PCr/ATP beta in isografts did not change throughout the study; however, allografts demonstrated a significant decrease as early as day 3 (p less than 0.01), although a significant difference between isografts and allografts did not become manifest until day 4 (p less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)
IL-2-PE40 is a chimeric protein composed of human interleukin 2 (IL-2) genetically fused to the amino terminus of a modified form of Pseudomonas exotoxin lacking its cell recognition domain. IL-2-PE40, which is extremely cytotoxic to IL-2 receptor-positive cells, was examined for its ability to prevent graft rejection in mice in which activation of T cells is prominent. We demonstrate that intraperitoneally administered IL-2-PE40 specifically and significantly prolongs the survival of vascularized heart allografts in mice. The chimeric toxin, IL-2-PE40, offers an alternative approach to the treatment of autoimmune diseases and transplant rejection in humans.
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