Selectin blockade plus therapy with low-dose sirolimus and cyclosporin a prevent brain death-induced renal allograft dysfunction.
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.
Gasser
Martin
M
Surgical Research Laboratory, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Waaga-Gasser
Ana Maria
AM
Grimm
Michael W
MW
Grimm
Martin R
MR
Lenhard
Miriam S
MS
Kist-van Holthe
Joana E
JE
Laskowski
Igor
I
Shaw
Gray D
GD
Thiede
Arnulf
A
Hancock
Wayne W
WW
Tilney
Nicholas L
NL
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
D016207:Cytokines; D007166:Immunosuppressive Agents; D019087:Selectins; D016572:Cyclosporine; D003404:Creatinine; D020123:Sirolimus