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The impact of acute rejection on the development of intimal hyperplasia associated with chronic rejection
D A Hullett1, J G Geraghty, R L Stoltenberg
1Division of Transplantation, Department of Surgery, University of Wisconsin-Madison, USA.
Abstract:
The rat aortic model of chronic rejection was used to study the effect of acute rejection on the development of intimal hyperplasia (IH). Two model systems were studied. In the first, continuous monotherapy with mycophenolate mofetil (MM) (40 mg/dx14 d followed by 30 mg/kg/d) was initiated 2 or 4 weeks posttransplant. Digital computer image analysis was used to quantify IH. While the development of IH was delayed, it was not prevented. In allografts where MM treatment was delayed for 2 wk, a 35.5% reduction in the amount of IH was observed. Delaying drug treatment for 4 wk resulted in a 42.2% reduction of IH. In contrast, continuous therapy from the time of transplant resulted in a 76.3% reduction in the amount of IH in comparison with untreated allograft controls. To further define the role of acute rejection in the development of IH, aortic allografts, ACI or (ACIxLewis)F1 (F1), were orthotopically transplanted to Lewis recipients and then retransplanted to donor strain secondary recipients after 2 or 4 wk. Grafts were harvested at 12 weeks posttransplant. When the retransplant was performed at 2 wk, intimal hyperplasia was decreased by 55.9% in ACI and by 66.7% in F1 allografts in comparison to conventional (ACI-->Lewis) allograft controls. When retransplantation was delayed until 4 wk, IH was not decreased in ACI allografts (105.9%) and was only marginally decreased in F1 allografts (26.2%). Syngeneic control F1 grafts (F1-->F1-->F1) did not develop significant IH at 12 or 20 wk when retransplanted at 2 wk (10% and 12%, respectively) or when retransplanted at 4 wk and harvested at 12 wk (18.6%). A common feature of IH is the development of medial acellularity. Unlike conventional allograft recipients (ACI-->Lewis; no retransplantation), F1 retransplanted grafts did not develop significant medial myocyte dropout. In contrast, delayed MM immunosuppressive therapy or retransplantation of ACI allografts at 4 weeks to ACI secondary recipients resulted in significant loss of medial myocytes. Our results show that acute rejection, which occurs during the first 4 wk posttransplant, is sufficient to mediate the development of IH associated with CR. However the lack of a continued allogenic environment slows the process.
Insights
Acute rejection within the first 4 weeks post-transplant drives chronic rejection and intimal hyperplasia (IH) development. However, removing the allogeneic stimulus can slow IH progression, suggesting a key role for ongoing immune response.
Area of Science:
- Transplantation immunology
- Vascular biology
- Chronic rejection mechanisms
Background:
- Chronic rejection (CR) is a major cause of graft failure.
- Intimal hyperplasia (IH) is a hallmark of chronic vascular rejection.
- The precise role of acute rejection in initiating IH is not fully understood.
Purpose of the Study:
- To investigate the impact of acute rejection on the development of intimal hyperplasia in a rat aortic allograft model.
- To determine if early immunosuppression or removal of the allogeneic stimulus affects IH progression.
Main Methods:
- A rat aortic allograft model was used.
- Two experimental systems were employed: delayed immunosuppression with mycophenolate mofetil (MM) and graft retransplantation at 2 or 4 weeks post-transplant.
- Digital computer image analysis quantified intimal hyperplasia and medial acellularity.
Main Results:
- Delayed MM treatment reduced IH by 35.5% (2 wk delay) and 42.2% (4 wk delay), while continuous therapy reduced IH by 76.3%.
- Retransplantation at 2 weeks significantly decreased IH (55.9% in ACI, 66.7% in F1 allografts).
- Delayed retransplantation (4 wk) showed minimal reduction in IH for ACI allografts (105.9%) and marginal reduction for F1 allografts (26.2%), with significant medial myocyte loss in some groups.
Conclusions:
- Acute rejection within the first 4 weeks post-transplant is sufficient to initiate IH development in chronic rejection.
- The absence of a continued allogeneic environment significantly slows the progression of IH.
- Medial myocyte dropout is associated with IH development and is influenced by the duration of the allogeneic stimulus.