Effect of Cyclosporin A on the in Situ Inflammatory Response of Rat Renal Allograft Rejection

Abstract

The impact of cyclosporin A (CyA) on a normal kidney parenchyma and on the in situ inflammatory response of rejection was investigated in normal DA rats and after transplantation of DA renal allografts to Lewis recipients. In a normal, non-transplanted DA kidney more than 80 mg/kg/day of CyA induced light-microscopic changes in the distal tubular cells of the renal cortex and outer medulla. These changes were not accompanied by any visible inflammation and were directly proportional to the dose of the drug and to the duration of drug administration. Treatment of a transplant recipient with 40 mg/kg/day of CyA abolished or at least efficiently reduced the in situ inflammatory response of rejection both as analysed from tissue sections and as quantified from the recovery of inflammatory cells after enzymatic digestion. It also reduced efficiently not only the number of T and B blast cells of the inflammatory infiltrate but also the number of other inflammatory cells, such as in situ lymphocytes, monocytes, and macrophages, and abolished or at least reduced the generation of (T) killer cells in situ and in the recipient spleen. These effects were inversely proportional to the time elapsed between grafting and initiation of treatment: although a complete suppression of all three features was obtained if the drug treatment was initiated already on the day of transplantation, a significant reduction of these functions was still found if the treatment was initiated later when the blastogenic response was already underway.

The Inflammatory Mechanisms of Allograft Rejection

“…This is demonstrated in Table IX. The impact of CyA on the inflammatory response is directly proportional to how early the interference with this drug is made and to the degree of the suppression of the blastogenic response (Nemlander et al 1982c). In contrast, CyA has no direct effect on the inflammatory lymphocytes and macrophages.…”

Lymphocyte Migration Patterns in Organ Allograft Recipients

“…Alternatively, CsA may inactivate some lymphocyte surface receptors and prevent graft MHC antigens from sensitizing the cells passing through the transplant or diminish nonspecific accumulation of lymphocytes that would have been a consequence of such activation (Cox et al 1984). The lack of functional CTL in spleens of CsA-treated graft recipients (Nemlander et al 1982b) or in the graft itself (Mason & Morris 1984), despite infiltration of the latter with large number of lymphocytes, supports this idea. In the studies designed to recreate immune responsiveness in CsA-treated hosts, infusion of alloimmune lymphocytes failed to induce rejection ).…”

Cyclosporine in Treatment of Corticosteroid-Resistant Episodes of Rejection

“…4 However, no definitive conclusions can be drawn on the therapeutic value of cyclosporine in the treatment of rejec¬ tion until the results of a prerandomized clinical trial are available. It is possible that the early, blast cell-dominat¬ ed inflammatory episodes are more sensitive to cy¬ closporine than is an episode of chronic rejection that is devoid of a distinct blastogenic component.…”