Gramicidin as a potential immunosuppressant for organ transplantation: suppression of human lymphocyte blastogenesis in vitro and prolongation of heart allograft survival in the rat.
Linear polypeptide antibiotic gramicidin is known to interact with the cell membrane and deregulate cation exchange. Because perturbation of cell membrane function may suppress the immune cell network, the authors investigated the effects of gramicidin on lymphocyte blastogenesis in vitro and allograft survival in vivo. Gramicidin blocked blastogenesis of human peripheral blood lymphocytes that responded to mitogens (IC50 = 0.2-10.1 ng/ml) or allogeneic lymphocytes (IC50 = 4.9 ng/ml). The extent of these suppressive effects was equal to or superior to that of cyclosporine or prednisolone. The antibiotic caused no apparent cytotoxicity at a dose of 10,000 ng/ml. The suppression of lymphocyte blastogenesis in vitro by cyclosporine or prednisolone was restored by addition of interleukin (IL)-1, IL-2, IL-4, IL-5 or IL-6. In contrast, none of these cytokines affected the suppressive activity of gramicidin on lymphocyte blastogenesis. The immunosuppressive efficacy of gramicidin was further examined in vivo in heterotopically heart-transplanted rats. A heart graft from (Lewis x BN) F1 donor was implanted in the neck of allogeneic Lewis rats. In this model, beating of the graft in control recipients (placebo group) stopped as a result of acute allograft rejection at 5.4 +/- 0.4 days after transplantation (n = 38), whereas beating of the graft in recipients that received 2.0 or 4.0 mg kg-1 day-1 of gramicidin i.p. for 6 days was significantly prolonged to 15.4 +/- 4.3 (n = 5) or 18.4 +/- 3.9 (n = 5) days after transplantation, respectively (P < .001).(ABSTRACT TRUNCATED AT 250 WORDS)
Hirano
T
T
Department of Clinical Pharmacology, Tokyo College of Pharmacy, Japan.
Oka
K
K
Tamaki
T
T
D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006085:Graft Survival / Q000187:drug effects*; D006096:Gramicidin / Q000494:pharmacology*; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007378:Interleukins / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D008969:Molecular Sequence Data; D051381:Rats; D011917:Rats, Inbred Lew; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous
D007166:Immunosuppressive Agents; D007378:Interleukins; D006096:Gramicidin