PATTERN OF ALLOIMMUNE RESPONSE IN SECOND SAME DONOR ALLOGRAFTS AFTER INDUCTION OF TOLERANCE USING CTLA4Ig1

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Abstract
The pattern of allograft acceptance in the presence of costimulatory blockade is manifested by the sequential appearance of Th1 cells, followed by Th2 cells. The aim of this study was to examine whether this phenomenon repeats itself after second same donor allotransplantation, hoping to determine whether acceptance in this setting provokes a predominance of the Th2 response. Tolerance was achieved by transplantation of CTLA4Ig-transduced ACI liver allografts in Lewis recipients. Recipient long-term survivors received a second transplant, consisting of a cervical heterotopic heart from the same ACI donor strain. Animals were sacrificed at predetermined intervals following the second transplant and the heart and liver were processed for histology and cytokine mRNA expression. Recipients of CTLA4Ig-transduced livers survived indefinitely. Rechallenge with same donor strain second allograft was manifested by an anergic immune response in the second cardiac allograft, and a very mild transient infiltrate within the first accepted liver graft. Cardiac function was maintained with resolution of all infiltrates. The cytokine cascade was activated within the allografts; however, the pattern of acceptance was not associated with predominance of a specific Th subtype. The pattern of acceptance of an allograft following CTLA4Ig-mediated costimulatory blockade is not related to long-term predominance of Th2 cells, a phenomenon that may be unique to the setting of a tolerant liver. It may be likely that the infiltrating lymphocytes that are dominant in the second graft are suppressed by other memory mechanisms.