title: Selectin blockade plus therapy with low-dose sirolimus and cyclosporin a prevent brain death-induced renal allograft dysfunction.
abstract: Both antigen-dependent and -independent factors influence long-term organ allograft function and survival. Brain death (BD), a significant antigen-independent, donor-related injury upregulates a variety of inflammatory mediators in peripheral organs. One of the earliest responses to such an insult is the expression of selectins by endothelial cells of the transplanted tissues; these in turn trigger a cascade of nonspecific events, that enhance host alloresponses and which may be worsened by toxic effects of long-term immunosuppression. Using a rat model in which donor BD accentuates subsequent renal allograft injury, we have tested the effects of therapy with recombinant P-selectin glycoprotein ligand (rPSGL-Ig) alone, or in combination with sirolimus (SRL) and cyclosporin A. We found that in contrast to the effects of standard doses of SRL or cyclosporine, rPSGL-Ig decreased inflammation in the early posttransplant period such that lower doses of maintenance immunosuppression were sufficient to maintain long-term graft function.
authors.affiliation: Surgical Research Laboratory, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Gasser
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Waaga-Gasser
authors.forename: Michael W
authors.initials: MW
authors.lastname: Grimm
authors.forename: Martin R
authors.initials: MR
authors.lastname: Grimm
authors.forename: Miriam S
authors.initials: MS
authors.lastname: Lenhard
authors.forename: Joana E
authors.initials: JE
authors.lastname: Kist-van Holthe
authors.forename: Igor
authors.initials: I
authors.lastname: Laskowski
authors.forename: Gray D
authors.initials: GD
authors.lastname: Shaw
authors.forename: Arnulf
authors.initials: A
authors.lastname: Thiede
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Hancock
authors.forename: Nicholas L
authors.initials: NL
authors.lastname: Tilney
mesh_terms: D000818:Animals; D001926:Brain Death; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016030:Kidney Transplantation; D011507:Proteinuria; D051381:Rats; D011916:Rats, Inbred F344; D051437:Renal Insufficiency / Q000517:prevention & control*; D019087:Selectins / Q000494:pharmacology*; D020123:Sirolimus / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; D019087:Selectins; D016572:Cyclosporine; D003404:Creatinine; D020123:Sirolimus