Levels of anti-Gal IgG2 negatively correlate with the survival of porcine islet graft in non-human primates under immunosuppression of anti-CD154

Abstract

Abstract Background Anti-CD154, the most successful immunosupppression (IS) regimen in porcine islet transplantation (PITx) is prohibited for clinical use. Anti-CD40, an alternative to anti-CD154, is not as effective as anti-CD154. To understand the reason, the relationship between anti-Gal responses and the graft survival was investigated in rhesus monkeys of PITx. Methods Intraportal PITx was performed in 18 diabetic monkeys: 3 received various IS without CD40 pathway blockade (Tx-control); 12, IS with anti-CD154 (Tx-anti-CD154); and 3, IS with anti-CD40 (Tx-anti-CD40). Blood samples were weekly obtained from the monkeys after PITx until the graft ceased to function, and additionally from 3 monkeys without transplantation (non-Tx-control) for 6 months. Levels of anti-Gal IgG, IgG1, IgG2 and IgM in the samples were analyzed by in-house ELISA, and levels of D-dimer and high-sensitive CRP by turbidimetry. Results Intraportal PITx led to strong induction of anti-Gal IgG1 response, not IgG2, in Tx-control, which was suppressed in both Tx-anti-CD154 and Tx-anti-CD40. The level of anti-Gal IgG2 revealed negative association with the levels of CRP and D-dimer in Tx-anti-CD40 and non-Tx-control, not in Tx-anti-CD154. The time-weighted average levels of anti-Gal IgG2 in Tx-anti-CD154 were significantly lower than in non-Tx-control. Additionally, the levels of anti-Gal IgG2 and D-dimer negatively correlated with the graft survival in Tx-anti-CD154. Conclusions The strong correlation between the suppression of anti-Gal IgG2 response and the graft survival in Tx-anti-CD154 suggests that IgG2 response is implicated with the effector mechanism mediating rejection, possibly NK cell activation which is known to promote IgG2 response.