Aim: Clinical lung Tx recipients do not have sustained long-term survival outcomes comparable to that of other recipients of solid organ allografts, despite generally comparable immunosuppression. As a first step towards analyzing potential contributory factors, we undertook the laborious but key task of actually assessing, for the first time, the effects of immunosuppressive therapy on Treg function of lung allograft recipients compared to their pre-Tx activity.

Methods: We compared Treg suppressive function, number and viability in patients listed for lung Tx with corresponding results obtained at 3 months post-Tx.

Results: Of the 77 patients enrolled in our study (mean age 57.2±1.2 years, 52% males), 18 patients received lung allografts. Induction therapy consisted of CD52 mAb (78.6%) or CD25 mAb (21.4%), and therapy at 3 months post-Tx included prednisone (93.3%), CNI (87%), MMF (80%) and azathioprine (7%). Patients receiving allografts during the follow-up period had no significant differences with patients who did not, in terms of demographic and clinical parameters analyzed, including primary lung diagnoses. However, compared to pre-Tx samples (50.7±3.8 units), Tregs from post-Tx patients demonstrated significantly impaired Treg suppressive function (24.1±4.4 units, p=0.0002, T-test), determined by area-under-curve analysis using healthy CD4+ responder T cells. Moreover, post-Tx Tregs demonstrated decreased viability (12.5±1.6% of dead Tregs in pre-Tx vs. 30.2±6.3% post-Tx, p=0.0003, T-test). At 3 months post-Tx, 43% of patients had leukopenia, and all had lymphopenia, but relative Treg numbers, calculated as % of Treg isolated from CD4+ cells, did not change (4.4±0.3% pre-Tx vs. 6.1±1.4% post-Tx).

Conclusion: Current conventional immunosuppressive therapy has a significant detrimental effect on Treg suppressive function and viability, which may have the important effect of preventing the achievement of long-term host hyporesponsiveness to a lung allograft. Inhibitory effects on Treg function may also contribute to acute rejection and various co-morbidities post-lung Tx. Our ongoing studies are directed at furthering such understanding in lung Tx recipients.

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