Successful induction of donor-specific unresponsiveness by intrathymic inoculation of alloantigen in several experimental acute rejection models has led us to hypothesize that similar immune manipulations can prevent chronic rejection and development of graft arteriosclerosis in the Lewis-to-F344 rat chronic cardiac allograft rejection model. Recipient F344 rats were treated with donor (Lewis) splenocytes by intrathymic injection (i.t.) alone (10×106 cells/lobe); with donor splenocytes i.t. plus a one-time dose of ALS (1 mg) by intraperitoneal injection (i.p.); or with ALS i.p. (1 mg) alone 2 and 6 weeks prior to heterotopic Lewis heart transplantation. Control F344 recipients received saline i.t. Allografts were monitored by daily palpation, and long-term surviving grafts were harvested on day 90 for histopathologic analysis. Control allografts had 28.6% long-term survival (>90 days) with mean graft survival of 46.7±12.2 days. At day 90 the surviving control allografts were enlarged and fibrotic with barely palpable heartbeat (mean heartbeat grade 0.29±0.18), and histologically showed diffuse moderate mononuclear cell infiltrates and advanced graft arteriosclerosis (mean vessel score 3.57±0.10 and 89±1% vessels diseased). Recipient treatment with intrathymic donor splenocytes alone significantly prolonged graft survival (89% long-term survival; mean 83.8±6.2 days, P<0.04), but did not significantly inhibit the development of graft arteriosclerosis (score 2.98±0.53 and 79±8% diseased, P=NS). By contrast, treatment with i.t. donor splenocytes plus ALS 2 weeks prior to transplantation prolonged graft survival (100% long-term; mean 90.0±0.0 days, P<0.04), and markedly inhibited graft arteriosclerosis (score 0.80±0.14, P<0.05; 27±4% diseased, P<0.05). ALS alone given two weeks prior to transplantation also prolonged graft survival (100% long-term; mean 90.0±0.0 days, P<0.04), and inhibited graft arteriosclerosis(score 0.89±0.31, P<0.05; 25±7% diseased, P<0.05). Howerver, when ALS was given 6 weeks prior to heart transplantaion the beneficial effect of ALS alone was abolished, suggested that lymphocyte depletion may have been responsible for the observed effects when ALS was administered at 2 weeks. Interestingly, intrathymic donor splenocytes plus ALS given 6 weeks prior to transplantation, on the other hand, showed significant prolongation of allograft survival (100% long-term, mean 90.0±0.0 days, P<0.04), and inhibited graft arteriosclerosis (score 0.41±0.02, P<0.05; 16±12% diseased, P<0.05). Our results indicate the importance of the cell-mediated immune response in initiating and mediating development of chronic rejection and graft ateriosclerosis, and suggest that strategies aimed at induction of tolerance may be effective in their prevention.
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