Transforming growth factor-beta 1 gene transfer ameliorates acute long allograft rejection

Background: The aim of the current work was to study the feasibility of fun ctional gene transfer using the gene encoding for transforming growth facto r-beta 1, a known immunosuppressive cytokine, on rat lung allograft functio n in the setting of acute rejection. Methods: The rat left lung transplant technique was used in all experiments , with Brown Norway donor rats and Fischer recipient rats. After harvest, l eft lungs were transfected ex vivo with either sense or antisense transform ing growth factor-beta 1 constructs complexed to cationic lipids, then impl anted into recipients. On postoperative days 2, 5, and 7, animals were put to death, arterial oxygenation measured, and acute rejection graded histolo gically. Results: On postoperative day 2, there were no differences in acute rejecti on or lung function between animals treated with transforming growth factor -beta 1 and control animals. On postoperative day 5, oxygenation was signif icantly improved in grafts transfected with the transforming growth factor- beta 1 sense construct compared with antisense controls (arterial oxygen te nsion = 411 +/- 198 vs 103 +/- 85 mm Hg, respectively; P = .002). Acute rej ection scores from lung allografts were also significantly improved, corres ponding to decreases in both vascular and airway rejection (vascular reject ion scores: 2.0 +/- 0.5 vs 2.8 +/- 0.6; P = .04; airway rejection scores: 1 .3 +/- 0.7 vs 2.3 +/- 0.8, respectively; P = .02), The amelioration of acut e rejection was temporary and decreased by postoperative day 7. Conclusions: The feasibility of using gene transfer techniques to introduce novel functional genes in the setting of lung transplantation is demonstra ted. In this model of rat lung allograft rejection, gene transfer of transf orming growth factor-beta 1 resulted in temporary but significant improveme nts in lung allograft function and acute rejection pathology.