1. Chemotherapy agent AZD80559, a competitive mTOR inhibitor, suppressed T cell proliferation in vitro more effectively than Rapamycin.
2. Like Rapamycin, AZD80559 increased cardiac allograft survival when compared with graft survival in mice having received no immunosuppressive therapy.
Evidence Rating Level: 2 (Good)
Study Rundown: Transplant rejection is mediated by a strong host immune response against the graft and immunosuppressive therapies have been shown to decrease acute rejection events. One such agent is Rapamycin (Rapa), which blocks T- and B-cell activation by inhibiting the pathway of the immune regulator mTOR through binding of the mTOR complex I. Recent studies have shown that Rapa inhibition of mTOR is somewhat incomplete, as mTOR complex 2, which is not blocked by Rapa, may also play a role in immune cell activation. Alternatively, ATP-competitive mTOR inhibitors block both mTOR complexes and thus may suppress Rapa-resistant immune responses against transplants.
This study investigated the role of AZ, an ATP-competitive mTOR inhibitor, in suppressing T cell proliferation in vitro and in improving murine cardiac allograft survival in vivo. The authors found that AZ treatment was more effective than Rapa at preventing CD4+ and CD8+ T cell proliferation when compared at concentrations greater than 200nM. In the cardiac allograft mouse model, a 10-day course of AZ promoted long-term (> 80 days) graft survival in 20% of recipients. This result was not significantly different when compared to Rapa results (50% long-term survival), but was significantly better than those for mice having received no immunosuppressive therapy (0% long-term survival). Both AZ and Rapa therapy led to increased populations of regulatory T cells (T-Regs) and decreased T cell cytokine production. This study highlights a potential future role for ATP-competitive mTOR inhibitor in increasing graft survival either through combination therapies or improved pharmacokinetics. Phase I trails AZ and AZD2014 (improved pharmacokinetics) to investigate inhibition of cancer progression are currently underway and may provide further insight into ATP-competitive mTOR inhibitors mechanisms of action.
In-Depth [animal study]: This study examined the effects of Rapa or AZ treatment on T cell proliferation in vitro and cardiac allograft survival in 8- to 12-week old C57BL/6 or BALB/c male mice. BALB/c to B6 heterotypic heart transplants were performed before a 10-day treatment of either Rapa (2mg/kg loading dose followed by 1 mg/kg delivered once daily intraperitoneally) or AZ (10 mg/kg delivered twice daily intraperitoneally). Plasma levels of AZ and whole blood levels of Rapa were collected. Graft rejection was determined by full cessation of cardiac contraction and confirmed with histology. Evaluation of immune cells and graft histology were performed for mice sacrificed at days 10-11, 20 or 80.
CD8+ and CD4+ T cell proliferation in vitro was evaluated under treatments of AZ or Rapa at concentrations ranging 1.95 to 1000 nM. At concentrations greater than 200nM, AZ was significantly more effective at suppressing T cell proliferation when compared to Rapa (n = 3-4 experiments, p < 0.05). In subsequent the in vivo studies, mouse plasma levels of AZ were measured at ≥ 200 nM. Both AZ and Rapa significantly increased allograft survival when compared to no immunosuppressive therapy (p < 0.001). Median graft survival time was 28 days following AZ therapy and 68 days following Rapa therapy, though this difference was not significant (p=0.26). Without immunosuppressive therapy no long-term (>80 days) graft survival was achieved, whereas 80% of Rapa recipients and 20% of AZ recipients achieved long-term survival.
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