Background: Cellular alloreactivity is prevalent in patients prior to transplantation. A previous retrospective study showed that high cellular alloreactivity to a panel of third party (3P) allostimulators (high PRT) correlated with acute cellular rejection (ACR). However, not all patients with high PRT developed ACR. In this study, we show that frequency of CD8⁺CD28^–NKG2D⁺ memory T cells can help predict ACR in these highly sensitized patients.

Method: We prospectively studied 63 kidney transplant recipients (Cohort#1). We tested PBMC against donor and a panel of 3P HLA allogeneic B cell stimulators by IFNΓ-ELISPOT assays (PRT assay)at the time of transplantation. The panel was then validated in a new seperate cohort (Cohort#2) and flow cytometry was also performed to quantitate CD8⁺CD28^–NKG2D⁺ and CD8⁺CD28⁺NKG2D^– T cells (n=33)

Results: For Cohort#1, mean age was 50.3±13.2, 41.3% female, 30.2% AA. We found a significant correlation between 3P alloreactivity and anti-donor alloreactivity (R2=0.46, P=0.006). Percent reactivity to the panel was higher in patients with subsequent ACR than in those without rejection (44±20% vs 19±23%, p=0.002) High PRT (defined as >33% reactivity to the panel) was significantly higher in patients with ACR than in those with no ACR (23.1% vs 2.8%, p<0.018). However, the majority of patients with high PRT (20/27, 71%) did not develop ACR. In cohort#2, we found that the pretransplant frequencies of CD8⁺CD28^–NKG2D⁺ memory T cells were significantly higher in rejectors with high PRT(4/10) vs non-rejectors with high PRT(6/10) further differentiating those at high risk for ACR (507±157 vs 106±68 Tcells/10⁴ PBMCs, p=0.04).

Conclusion: Pretransplant 3P cellular alloreactivity as measured by the IFNΓ-ELISPOTs associates with posttransplant ACR. Measuring the frequencies of pretransplant CD8⁺CD28^–NKG2D⁺ memory T cells can help to further predict risk of ACR in patients with high preformed cellular alloreactivity.

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