Selectin Blockade Plus Therapy with Low-Dose Sirolimus and Cyclosporin A Prevent Brain Death-Induced Renal Allograft Dysfunction |
| |
Authors: | Martin Gasser Ana Maria Waaga-Gasser Michael W. Grimm Martin R. Grimm Miriam S. Lenhard Joana E. Kist-van Holthe Igor Laskowski Gray D. Shaw Arnulf Thiede Wayne W. Hancock Nicholas L. Tilney |
| |
Affiliation: | Surgical Research Laboratory, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA;Department of Surgery, Molecular Oncology and Immunology, University of Wuerzburg, Germany;Laboratory of Immunogenetics and Transplantation, Brigham and Women's Hospital, Harvard Medical School, Boston, MA;Genetics Institute/Wyeth Research, Cambridge, MA;Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, and the University of Pennsylvania School of Medicine, Philadelphia, PA |
| |
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. |
| |
Keywords: | Brain death chronic rejection ischemia/reperfusion injury P-selectin glycoprotein ligand-1 |
|
|