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MECHANISMS OF GRAFT REJECTION AND ADAPTATION IN PEDIATRIC LIVER TRANSPLANTATION.
Rakesh Sindhi MD , Amy Magill BS , Mary Yost BS , Carol Bentlejewski BS and Adriana Zeevi PhD . Pittsburgh PA, University of Pittsburgh, 15261, Children
s Hospital and Pathology .
Pretransplant use of rabbit anti-human-thymocyte globulin (rATG) in pediatric liver transplant (LTx) recipients is associated with early rejection in one third of cases, while the remainder experience clinical graft adaptation.
Aims/Methods: To identify potential mechanisms, 31 LTx, with median follow-up 8 months, were analyzed for: inter-dose changes in mitogen-stimulated T- and B-cell responses (sLR); peripheral blood mononuclear cell subsets; dendritic cell (DC); CD8+28- suppressor effect on donor antigen-presenting cells (APC).
Results: All measurements were performed at a median interval of 47 days after LTx. The frequency of T-cells expressing the cytokines IFN-γ, TNF-α, and IL-2 decreased with increasing total exposure (AUC) to TAC in historical controls (n=6). This relationship was markedly dampened in rATG patients (n=15). Significant decrease in CD4 absolute counts were seen at 1 week after LTx and partial reconstitution at 2 months while monocytes and B-cells remained stable. DC2 remained unchanged, while DC1 frequency increased from 0.15 to 0.23, (p=0.05). Purified CD8+28- subpopulations from two recipients down regulated CD86 expression on donor APC, but increased its expression in HLA-mismatched APC. Eleven of 31 subjects experienced rejection, while 18 subjects are being maintained on daily (n=13) or every other day doses of TAC or sirolimus.
Conclusions: Despite lymphocyte depletion, rejection in the setting of T-cell anergy can be explained by relative sparing of APC, via recruitment of alternative effector mediators. The appearance of donor-specific CD8 suppressor cells in LTx recipeints on low immunosuppression suggests that these conditions may also foster a favorable immunomodulatory response toward the liver allograft