Objectives. Chronic rejection of transplanted organs is a major obstacle in human organ transplantation. Although the mechanisms of chronic rejection are poorly understood it is known that chronic rejection is caused by the immune cells, such as T cells and macrophages, accumulating within the graft. The immune cell movement is regulated by actin cytoskeleton and small GTPase RhoA pathway. We showed recently that the blockade of early T cell response in conjunction with the genetic or pharmacologic interference with the small GTPase RhoA pathway, by RhoA-deletion or Y27632 inhibition of RhoA/ROCK kinase, inhibits macrophage movement into the graft and abrogates chronic rejection of cardiac allografts in rodent model. Although besides the Y27632 inhibitor, there are other RhoA/ROCK inhibitors available commercially, their efficacy in inhibition of chronic rejection remains unknown. Methods. Heart allografts from BALB/c (H-2d) donors were heterotopically transplanted into C57BL/6 (H-2b) recipients (each experimental group consisted of 3-5 animals), which received CTLA4-Ig (0.25 mg i.p. day 2 and day 4 post- transplantation) alone or in conjunction with RhoA/ROCK inhibitors. We screened six RhoA/ROCK inhibitors: Azaindole-1, Fasudil (HA-1077) HCl, GSK 269962A, SAR-407899, SB 772077B dihydrochloride and SLX-2119 for their ability to inhibit chronic rejection of heterotopically transplanted mouse cardiac allografts. We also tested macrophage infiltration using macrophage markers and immunostaining. Results. We found that out of six tested compounds, the Fasudil and Azaindole, inhibited macrophage infiltration, vessel occlusion and tissue fibrosis and abrogated chronic rejection of mouse cardiac allografts. The remaining inhibitors decreased only tissue fibrosis, and were ineffective in inhibiting chronic rejection. Conclusions. The results of this study might help in development of anti-chronic rejection therapy for clinical use.

CITATION INFORMATION: Chen W., Chen W., Li X., Ghobrial R., Kloc M. Screening of RhoA/ROCK Inhibitors for the Ability to Prevent Chronic Rejection of Mouse Cardiac Allografts Am J Transplant. 2017;17 (suppl 3).

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