CP-690,550 is the first reported JAK3 inhibitor combining efficacy and good tolerability in a preclinical model of allotransplantation in nonhuman primates and thus has interesting potential for immunosuppression in humans.

HAR of hDAF solid organs could be ascribed to high levels of anti-pig antibodies. It is hypothesized that the hDAF transgene shows a threshold in efficacy, above which an overwhelming attack by antibodies and complement activation cannot be modulated to prevent HAR. HAR does not occur when animals with lower levels are used, or when antibodies are effectively depleted from the circulation by GAS914 treatment.

The inclusion of TP10 in the immunosuppressive protocol does not clearly lead to improved xenograft survival. Despite effective neutralization of anti-Gal antibodies and effective inhibition of systemic complement activity, AHXR was apparent in four of six animals under chronic TP10 treatment, including deposits of complement activation products in the graft. Apparently, effective systemic complement inhibition by TP10 in combination with local complement regulation by the hDAF transgene product does not necessarily result in effective inhibition of complement activation at locations in the xenograft upon binding of anti-porcine antibodies to the grafted endothelium.

Summary Janus kinase 3 (JAK3) mediates signal transduction from cytokine receptors using the common γ chain. The rationally designed inhibitor of JAK3, CP‐690,550, prevents acute allograft rejection in rodents and in nonhuman primates. Here we investigated the ability of CP‐690,550, to prevent allograft vasculopathy in a rodent model of aorta transplantation. Aortas from AxC Irish (RT1a) or Lewis (RT1l) rats were heterotopically transplanted into the infra‐renal aorta of Lewis recipients and harvested at 28 or 56 days. Treated recipients received CP‐690,550 by osmotic pumps (mean drug exposure of 110 ± 38 ng/ml). Significant intimal hyperplasia was demonstrated in untreated allografts when compared with isografts at 28 days (2.08 ± 0.85% vs. 0.43 ± 0.2% luminal obliteration, respectively, P = 0.001) and 56 days (5.3 ± 2.4% vs. 0.38 ± 0.3%, P = 0.002). Treatment caused a 51% reduction in intimal hyperplasia at day 56. CP‐690,550‐treated animals also had a significant reduction of donor‐specific IgG production and of the gene expression for suppressor of cytokine signaling‐3 and with unchanged levels of expression of RANTES, IP‐10 and transforming growth factor‐β1. These results are the first to show that JAK3 blockade by CP‐690,550 effectively prevents allograft vasculopathy in this rat model of aorta transplantation.

Natural antibody levels show a significant variation between various groups of non-human primates, with levels in some groups well above those in a human serum standard.