Rapamycin inhibits transplant vasculopathy in long-surviving rat heart allografts.
We have examined the effects of rapamycin (RPM) on transplant vasculopathy in long-surviving F344 rat heart allografts transplanted heterotopically into Lewis recipients. RPM was administered intraperitoneally for the first 14 days in groups 1 and 2 (0.5 and 2 mg/kg/day), and daily throughout the follow-up period in groups 3 (0.5 mg/kg/day) and 4 (5 mg/kg for 14 days, followed by a maintenance dose of 2.5 mg/kg/day). Treatment with low dose cyclosporine (CsA; 1.5 mg/kg/day) in combination with RPM (0.5 mg/kg/day for 14 days) (group 5) and immunosuppression with CsA only (5 mg/kg for 14 days, followed by 1.5 mg/kg/day) (group 6) were also examined. F344 isograft recipients treated with RPM (0.5 mg/kg/day for 14 days) (group 7), those that were untreated (group 8), and hearts in naive F344 animals (group 9) served as controls. Grafts of group 1 were removed at 50, 75, 100, 150, and 200 days and infiltrating cell populations and surface molecules were compared with those of the other groups at 100 days. All allografts in treated hosts functioned > 100 days; in contrast, grafts in untreated recipients were rejected acutely by 8 +/- 1 days (MST +/- SD). The incidence of transplant vasculopathy in group 1 increased progressively (MST +/- SD = 10 +/- 2%, 59 +/- 7%, 85 +/- 15%, and 80 +/- 12% at 50, 100, 150, and 200 days, respectively), as manifested by myointimal proliferation with dense mononuclear infiltration (predominantly ED1+ macrophages). Numbers of MHC class II+ infiltrating cells were prominent, as was expression of adhesion molecules and cytokines. The incidence of graft disease and extent of cellular infiltration at 100 days was significantly lower in animals receiving increased maintenance doses of RPM (for groups 2, 3, and 4: 25 +/- 15%, 22 +/- 11%, and 10 +/- 3%, respectively; P < 0.005). CsA treatment either in combination with RPM or alone (groups 5 and 6) failed to improve transplant vasculopathy, but reduced mononuclear cell infiltration. Isografts (groups 7 and 8) and naive hearts (group 9) developed no structural abnormalities throughout the follow-up period, regardless of RPM treatment. We conclude that the extent of transplant vasculopathy can be reduced markedly in this rat cardiac transplant model with maintenance RPM. Addition of CsA modifies the morphological picture but does not improve myointimal proliferation.
Schmid
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C
Surgical Research Laboratory, Harvard Medical School, Boston, Massachusetts, USA.
Heemann
U
U
Azuma
H
H
Tilney
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NL
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D016572:Cyclosporine / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D016027:Heart Transplantation / Q000009:adverse effects*; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D011090:Polyenes / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D020123:Sirolimus; D013997:Time Factors; D017539:Tunica Intima / Q000166:cytology / Q000187:drug effects; D014652:Vascular Diseases / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D016276:Ventricular Function / Q000187:drug effects
D007166:Immunosuppressive Agents; D011090:Polyenes; D016572:Cyclosporine; D020123:Sirolimus