title: Iron chelation suppresses mononuclear cell activation, modifies lymphocyte migration patterns, and prolongs rat cardiac allograft survival in rats.
abstract: Iron influences host immunity, in part by affecting the function and migration patterns of T cell subpopulations. Removal of iron stores from the body by chelation decreases proliferation and differentiation of T cells, as shown in models of autoimmunity and pancreatic islet transplantation. We have examined the influence of iron chelation on rejection of vascularized heart allografts in rats. Two protocols were investigated: "treated" recipients received desferrithiocin (30 mg/kg/day) orally for 10 days beginning the day of transplantation; "pretreated" hosts received a similar dose of the drug for 10 days before engraftment. Graft survival increased from about 7 days in untreated animals to 14-16 days in both treatment groups (P < 0.001). Histological and immunoperoxidase studies of allografts at day 7 showed that iron chelation resulted in only a mild reduction in cell infiltration, but in a marked decrease in graft edema and interstitial hemorrhage and essentially complete suppression of mononuclear cell activation and cytokine production. Chelation therapy was also found to inhibit profoundly cytokine (TNF-alpha) production in rats treated with LPS, consistent with the effects observed in situ in the allografts. In vitro studies showed that pretreatment significantly inhibited the mixed lymphocyte reaction. Chelation also influenced migration of T lymphocyte subsets: treatment stimulated migration of CD4+ lymphocytes to peripheral lymph nodes; pretreatment strikingly and selectively increased CD8+ cell migration into parathymic lymph nodes draining the graft, with the opposite effect on nondraining node groups. We conclude that treatment with iron-chelating agents has several effects on host alloresponsiveness in a rat heart graft model secondary to inhibition of immune activation; these include prolongation of graft survival, inhibition of the mixed lymphocyte reaction (pretreatment), marked depression of cytokine production, and alteration in recirculation patterns of lymphocyte subpopulations.
authors.affiliation: Surgical Research Laboratory, Harvard Medical School, Boston, Massachusetts.
authors.forename: W D
authors.initials: WD
authors.lastname: Whitley
authors.forename: W W
authors.initials: WW
authors.lastname: Hancock
authors.forename: J W
authors.initials: JW
authors.lastname: Kupiec-Weglinski
authors.forename: M
authors.initials: M
authors.lastname: DeSousa
authors.forename: N L
authors.initials: NL
authors.lastname: Tilney
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D004095:Dihydropyridines / Q000494:pharmacology*; D006085:Graft Survival; D016027:Heart Transplantation; D007501:Iron / Q000502:physiology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D017262:Siderophores / Q000494:pharmacology*; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000502:physiology; D013844:Thiazoles / Q000494:pharmacology*; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D004095:Dihydropyridines; D017262:Siderophores; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; D007501:Iron; C050223:desferrithiocin