PREVENTION OF FUNCTIONAL, STRUCTURAL, AND MOLECULAR-CHANGES OF CHRONIC REJECTION OF RAT RENAL-ALLOGRAFTS BY A SPECIFIC MACROPHAGE INHIBITOR

Chronic rejection is the primary cause of long-term allograft loss, Ma crophages and their products have been shown to be critical in the dev elopment of this process in an established kidney allograft rat model, A new synthetic agent, Gamma lactone, is a specific inhibitor of macr ophages and monocytes that inhibits the generation of these population s in vitro and their activities in the effector phase of host alloresp onsiveness. We tested its effects on the development of chronic change s in the model, Untreated control allograft recipients developed incre asing proteinuria after 12 weeks; progressive glomerulosclerosis, inte rstitial fibrosis, and arterial obliteration developed thereafter, Inf iltrating ED1+ macrophages as noted by immunohistology increased drama tically between 12 and 16 weeks, localizing preferentially in glomerul i and perivascular areas, The presence of these cells was associated w ith dense expression of their products, Reverse transcription polymera se chain reaction confirmed and expanded the immunohistological findin gs, showing significant gene expression of macrophage-derived mediator s, In contrast, recipients treated with G-Lac daily for 32 weeks never developed proteinuria; macrophage infiltration was dramatically reduc ed, and expression of their products was virtually absent. At 32 weeks , most glomeruli and arteries remained histologically normal. In anoth er group in which treatment was stopped at 24 weeks, however, proteinu ria began to develop by 32 weeks; macrophages infiltrated the organs a nd expression of their products became manifest. These results confirm the importance of macrophages and macrophage-derived factors in chron ic rejection and suggest that a specific inhibitor of macrophage activ ation may be useful in the prevention of the process over the long ter m.