Functional responses of T cells blocked by anti-CD25 antibody therapy during cardiac rejection

Background. Despite anti-CD25 (interleukin [IL]-2 receptor-a chain) monoclo nal antibody (mAb) therapy, rejection can still occur. T-cell activation th rough the IL-2 receptor beta and gamma chains by IL-2 or other growth facto rs may contribute to this rejection. Recently, we have demonstrated that th e T-cell growth factor IL-15 was abundantly present in rejecting cardiac gr afts during anti-CD25 mAb treatment. Methods. To test whether IL-2- and IL-15-responsive T cells play an active role in rejection during anti-CD25 mAb therapy, we measured the frequency o f IL-2- and IL-15-proliferative T cells in peripheral blood from treated pa tients during rejection (n = 12). Measurements were made by limiting diluti on analysis in the absence and presence of extra in vitro-added mouse anti- human CD25 mAb. Results. In the absence of anti-CD25 mAb, the frequencies of peripheral T c ells responding to recombinant human (rh)IL-a and rhIL-15 from patients wer e lower than those measured in samples of healthy controls (n = 7): median of IL-S-responding T cells 78 per 10(6) (range 31-210 per 10(6)) vs. 154 pe r 10(6) (122-484 per 10(6), P = 0.008) and median of IL-15-responding T cel ls 62 per 10(6) (range 19-207 per 10(6)) vs. 129 per 10(6) (range 79-192 pe r 10(6), P = 0.02), respectively. In the presence of extra in vitro-added a nti-CD25 mAb, frequencies of IL-2-responding T cells from patients signific antly decreased, although a considerable number of T cells still proliferat ed on rhIL-2 (median 85%, range 46-100%). In:contrast, the frequencies of I L-15 T cells still responding remained stable (median 2%, range 0-50%, P < 0.001). Conclusions. Treatment with anti-CD25 mAbs cannot provide complete suppress ion of T-cell function because significant numbers of IL-2- and IL-15-respo nsive:T cells remain present in the peripheral blood of allograft recipient s during anti-CD25 mAb treatment.