INITIAL T-CELL ACTIVATION REQUIRED FOR TRANSPLANT VASCULOPATHY IN RETRANSPLANTED RAT CARDIAC ALLOGRAFTS1

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Abstract
A precise understanding of immunological mechanisms is needed to prevent transplant vasculopathy. The developing process of transplant vasculopathy was investigated by retransplanting rat cardiac allografts and measuring the expressions of 21 different genes inside the retransplanted allografts under nonimmunosuppressive conditions. Significant transplant vasculopathy developed if WKY hearts were grafted to LEW and retransplanted to WKY 5 days after the initial grafting, but it did not in allografts retransplanted 3 days after the initial grafting. The disease did not progress in retransplanted isografts or if nude rats were used as the initial recipients. However, the development of transplant vasculopathy was not affected by changing the second recipients to the F1 progeny of donor × recipient or to nude animals. Among the expressions of 21 different genes observed in allografts at 1, 14, 30, or 60 days after retransplantation, those of T-cell activation-related genes, such as interferon-γ and Fas ligand, showed the earliest and the most dramatic difference between 3- and 5-day-retransplanted allografts whereas macrophage/monocyte activation-related genes showed little difference. Furthermore, reverse transcription-polymerase chain reaction analyses of allografts retransplanted to nude animal indicated that T cells of the initial recipient origin survive and remain activated even 60 days after retransplantation. The T-cell response occurring between 3 and 5 days after grafting was identified as the critical parameter to the disease progression. Once alloreactive T cells enter a graft, they may be able to survive a long period and promote chronic rejection.