In Vivo Mechanisms of Alloreactivity - IV. Cyclosporine Differentially Impairs Accumulation of Donor-Reactive CTL but Not Donor-Reactive Alloantibody in Murine Sponge Matrix Allografts

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We have studied the influence of Cyclosporine on accumulation of donor-reactive CTL, donor-reactive cytotoxic alloantibody and as an immunosuppressive drug in individual murine sponge matrix allografts. During these studies, we observed that: (1) levels of CsA in sponge matrix allografts rapidly reach levels that are immunosuppressive in vitro, i.e. >100 ng/ml, following daily i.m. or subsponge CsA injections of 30 mg/kg; (2) donor-reactive CTL continue to accumulate and develop cytolytic activity in sponge allografts from mice treated i.m., but not subsponge with CsA; (3) delay or interruption of subsponge CsA therapy decreases the ability of CsA to block CTL accumulation in sponge matrix allografts; (4) relatively high local concentrations of CsA appeared to be necessary to influence CTL behavior in sponge matrix allografts; (5) CsA therapy had a different effect on the development of donor-reactive cytotoxic alloantibody. Intramuscular CsA therapy potentiated alloantibody production whereas subsponge CsA therapy temporarily delayed alloantibody production. These studies demonstrate that CsA can differentially impair the accumulation of donor-reactive CTL, but not donor-reactive alloantibody in sponge matrix allografts. These results have several theoretical and clinical implications. They also illustrate the utility of sponge matrix allografts from concomitant in vivo immunologic and pharmacologic studies at the site of a localized immune response.