Anti-rejection prophylaxis by blocking selectin dependent cell adhesion after rat allogeneic and xenogeneic lung transplantation.

Abstract

Adhesion molecules regulate the infiltration of leukocytes into the graft during rejection after lung transplantation. The first step of the adhesion cascade is mediated by selectins. Sialyl-LewisX is a ligand of P-selectin. The purpose of the study was to evaluate SLX, a synthetic oligosaccharide analog of Sialyl-LewisX, for anti-rejection prophylaxis after allogeneic and xenogeneic left lateral, orthotopic rat lung transplantation. In groups A and B, allogeneic lung transplantation was performed using fully incompatible rat strains (donors: Dark-Agouti (RT1a); recipients: Lewis (RT11)). In group A (n = 10), recipients recieved 200 microg/d SLX i.v. on day 0-4. Group B rats (n = 10) served as untreated controls. The animals were sacrificed on days 5 and 10, respectively. In groups C and D, xenogenic lung transplantation was performed using Gold Syrian hamsters as donors and Lewis rats as recipients. In group C (n = 10), recipients received 200 microg/d SLX i.v. on day 0-4. Group D rats (n = 10) served as untreated controls. The animals were sacrificed on days 2 and 5, respectively. Rejection was graded by histology from 0 (no rejection) to 5 (necrosis). By immunhistology, alveolar, interstitial CD11a, CD18 and VLA-4 positive leukocytes were counted. Histologically, there were a lower grade of rejection (A: 2.7 +/- 0.6; B: 4.0 +/- 0.0; P < 0.05) and fewer CD11a positive leukocytes (A: 66 +/- 27; B: 186 +/- 73; P < 0.05) on day 5 in the SLX-treated allograft group compared to the untreated group. In xenotransplantation, SLX also reduced the grade of rejection (C: 3.3 +/- 0.5; D: 4.7 +/- 0.5; P < 0.05) and the number of CD11a positive leukocytes (C: 145 +/- 22; D: 176 +/- 20; P < 0.05) on day 2. It is concluded, that the administration of SLX significantly reduces allograft rejection. After discontinuation treatment with SLX unmodified rejection appeared. SLX also modifies xenograft rejection, but to a lesser extent, and xenograft necrosis appeared during treatment in this model.