Viral delivery of the indoleamine 2,3-dioxygenase (IDO) transgene results in transprotein synthesis and mitigates rejection in rodent kidney transplants (J Gene Med 13:373); but in patients with allograft rejection there is a paradoxical increase in circulating IDO activity (KI:71:60), raising questions about the benefit of increased IDO. At issue is the source of IDO in acute rejection and what cytokine triggers, if any, can be identified. To address this question, we directly measured tissue IDO gene and protein expression, and 3 IDO-inducing cytokines from rejecting kidney transplants in a pig model.

Methods: Pigs underwent allogeneic (Allo) (n=9) or auto renal transplants (Auto) (n=10). For Allo, pairs of mismatched pigs were operated simultaneously with left kidneys exchanged and orthotopically transplanted. All pigs had right nephrectomy (Nx) prior to closure, and left Nx at sacrifice 72hrs postop. No immunosuppression was used. In all kidneys, rejection was assessed using Banff criteria; tissue cytokine (IL-1β, IFN-γ, and TNF-α) and IDO gene expression quantitated (PCR); and tissue IDO activity measured (HPLC).

Results: Postop creatinine was higher in Allo vs Auto (8.12±1.50 vs 2.83±0.60 mg/dL respectively, P=0.006). Auto had mild tubular injury, and no changes in IDO mRNA, IDO activity, or cytokine gene expression when compared to Allo and control right Nx (n=16). Allo showed acute rejection (Banff 1 to 3), with a 6 fold increase in allograft IDO mRNA and 19.5 fold increase in tissue IDO activity. Fold (X) increases in allograft cytokines included: 10X IL-1β; 4X IFN-γ; and 2X TNF-α vs Auto and control right Nx.

Conclusions: Allograft expression of IDO is greatly increased in acute rejection and is associated with increases in IL-1β, IFN-γ, and TNF-α mRNA. Increased circulating IDO activity in rejection likely emanates from the allograft, and may be associated with rejection-driven cytokine induction. Using an IDO transprotein to prevent rejection may still be of benefit if introduced prior to rejection-driven stimuli to IDO activation.

CITATION INFORMATION: Merchen T, Wang Y, Lassiter R, Kleven D, Jajosky R, Winn M, Ho C.-S, Nahman N. Allograft Cytokine Activation and Elevated Tissue Indoleamine 2,3-Dioxygenase Gene and Protein Expression in Rejecting Pig Transplants. Am J Transplant. 2017;17 (suppl 3).

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