Effects of Cyclosporin A, Antilymphocyte Serum and Donor-Specific Transfusions on Murine Delayed-Type Hypersensitivity and Skin Graft Survival

Abstract

The effect of immunosuppressive reagents cyclosporin A (CsA) and rabbit anti-mouse antilymphocyte serum (ALS) on the response to alloantigens was studied in inbred mouse strains. Alloantigen was given either as a cell suspension which induced a delayed-type hypersensitivity reaction (DTH), or as a full-thickness skin graft. Dose-response studies showed that DTH reactions in CBA mice sensitised to BALB/c cells were reduced to background levels when recipient mice were treated with 100 mg/kg CsA on days 0, 4 and 6 after primary alloantigenic challenge. The response to a second challenge was significantly decreased by CsA treatment during primary or secondary exposure to alloantigen and CsA was as effective as ALS in abrogating both primary and secondary DTH reactions. Survival of full-thickness grafts of BALB/c skin on CBA mice was increased from 9 to 23 days by ALS treatment on days ––1 and +2, with grafts given on day 0. Long-term treatment with CsA, from day ––14 to +12, also prolonged graft survival from 9 to 18 days but donor-specific transfusions, with or without concomitant ALS or CsA treatment, decreased graft survival and often sensitised the recipients. This occurred with transfusions administered from ––63 to ––7 days and on the day of grafting. Thus, in H-2 mismatched mice, both CsA and ALS treatments produced a state of tolerance when administered during short-term exposure to alloantigen. With a stronger antigenic stimulus, in the form of a skin graft, ALS was only partially effective in overcoming the sensitising effects of donor-specific transfusions given prior to grafting and CsA could not prevent sensitisation of the recipient, but the continued presence of the drug delayed the onset of rejection in unsensitised recipients.