Exploitation of the continuum between early ischemia/reperfusion injury and host alloresponsiveness: indefinite kidney allograft survival by treatment with a soluble P-selectin ligand and low-dose cyclosporine in combination.
BACKGROUND
We have shown previously that sPSGL, a soluble glycoprotein ligand for P and E selectins, reduces the events associated with ischemia/reperfusion injury of the kidney. In the present study, we have attempted to modulate differentially early inflammatory influences and later host alloresponsiveness in an LBNF1-Lewis renal graft model by treatment with sPSGL in combination with a marginally effective dose of cyclosporine (CsA).


METHODS
Four experimental groups were studied: group 1=control animals receiving vehicle only; group 2=sPSGL monotherapy alone; group 3=low-dose CsA; group 4=sPSGL plus low-dose CsA. Grafts were removed at 1, 3, 5, and 7 days (n=3/time point) and assessed by histology, immunohistology, and reverse transcriptase-polymerase chain reaction. Long-surviving grafts in recipients of groups 3 and 4 were followed functionally for more than 28 weeks.


RESULTS
Graft function was prolonged indefinitely in recipients in group 4, all of which survived for more than 200 days. In contrast, survival of animals in groups 1 and 2 was not increased substantially, whereas only 4 of 17 animals in group 3 (23.5%) survived more than 24 days (P<0.01). Five days after engraftment, necrosis was relatively minimal in group 4 organs but pronounced in those of the other groups. By immunohistology, numbers of infiltrating CD4+ and CD8+ T cells and ED1+ macrophages were significantly diminished in group 4 allografts compared with those of the other groups. Serial assessment of chemokine and cytokine mRNA expression confirmed these findings. The long-term effects of CsA treatment alone were compared with those of sPSGL in combination with CsA. Proteinuria remained virtually absent in group 4 recipients. Morphologically, the few long-surviving grafts in group 3 showed signs of chronic rejection; those in group 4 remained relatively normal.


CONCLUSIONS
Although treatment with sPSGL alone showed no apparent influence on the acutely rejecting transplants, at least by the parameters examined in this study, it produced indefinite survival of kidney grafts when used in combination with low-dose CsA. The data support the influence of early nonspecific injury on later immunological rejection.
Kusaka
M
M
Harvard Medical School, Department of Surgery, Brigham Women's Hospital, Boston, Massachusetts 02115, USA.
Zandi-Nejad
K
K
Kato
S
S
Beato
F
F
Nagano
H
H
Shaw
G D
GD
Tilney
N L
NL
D000818:Animals; D018932:Chemokine CCL2 / Q000096:biosynthesis; D016572:Cyclosporine / Q000494:pharmacology*; D004306:Dose-Response Relationship, Immunologic; D004359:Drug Therapy, Combination; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology*; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007511:Ischemia / Q000276:immunology*; D007518:Isoantibodies / Q000096:biosynthesis* / Q000276:immunology; D007668:Kidney / Q000098:blood supply* / Q000276:immunology / Q000378:metabolism; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000276:immunology* / Q000378:metabolism
D018932:Chemokine CCL2; D007166:Immunosuppressive Agents; D007518:Isoantibodies; D008562:Membrane Glycoproteins; C084882:P-selectin ligand protein; D012333:RNA, Messenger; D018799:Intercellular Adhesion Molecule-1; D016572:Cyclosporine