Ratten-Cytomegalievirusinfektion interferiert mit anti-CD4-MoAb (RIB 5/2)-induzierter Toleranz und führt zu einer chronischen Allotransplantatschädigung

Background: The translation of experimentally established tolerance induction (TI) protocols into clinical practice is confounded by interfering problems and phenomena, e. g., increased frequency of alloreactive T-cells and total T-cell memory pool prior to transplantation, homeostatic proliferation after depleting tolerance induction regimens, and heterologous immunity. In the following, the im-pact of rat cytomegalovirus infection (RCMVI) on anti-CD4-mAb induced tolerance is presented. Methods: Orthotopic rat-KTX (Dark Agouty (DA) → Lewis (LEW)) was performed after TI with RIB 5/2 (10 mg/kg BW; day −1, 0, 1, 2, 3; s. c.) without further intervention (Group G3), with RCMVI (5 × 10 E5 Plaque forming units (PFU) i. p.) simultaneously to KTX (G4), 50 days after KTX (G5), and 14 days before and after KTX (G6). Controls: isogenous KTx (Lew → Lew) without TI (G1), isogenous KTX with TI and simultaneous RCMVI (G2); allogeneic NTX (DA-LEW) without TI: G7. (all groups n = 6; observation time: 120 days). Parameters: proteinuria, crea-clearance, histology, immunohistol-ogy, allo- and RCMV-reactive T-cells, RCMV-Plaque Assay and RCMV-PCR. Results: Except for the allogeneic control G7 without TI (Survival: 8, 9, 10 (n = 4) days; acute rejection; p < 0,05), all animals survived for 120 days. There were a significantly reduced allograft function as determined by protein-uria and crea-clearance and significantly enhanced morphological signs of chronic allograft damage (glomerulosclerosis, arteriosclerosis, fibrosis; p < 0.05) in groups G4,G5, G6 vs. G1, G2 und G3. Cellular infiltrates and MHC-expression were more pronounced (p < 0.05) in G4,G5 and G6. RCMVI induced a significant increase of the frequency of alloreactive T-cells in G4,G5,G6 vs. G3 (p < 0,05). There was no viral replication in salivary glands in the controls G2 und G3 (threshold: 1,0 × 10E5 PFU/ml. G2/G3: < = 1,0 × 10 E5 PFU/ml at days 10, 50, 120). G4, G5, and G6 showed significantly increased RCMV-replication after RCMVI (G4: 2,6 × 10E4 PFU/ml-day 10; G5: 2,8 × 10 E2 PFU/ml-day 120; G6: 7,3 × 10 E2 PFU/ml-day 10; p < 0,05). Conclusion: RCMVI inter-feres with anti-CD4 MoAb — induced tolerance and leads to chronic allograft damage. The presented data suggest a potentially important role of viral infections and their prophylaxis in clinical tolerance induction protocols.