Low Dose Interleukin-7 Supplementation Increases Intrinsic Cord Blood T Cell Survival without Enhancing Proliferative Alloresponses

Umbilical cord blood (CB) transplantation is associated with delayed and defective immune reconstitution, in part because recent thymic emigrants, the most abundant subset among CB T cells, have limited intrinsic survival capacity. Interleukin-7 has been reported to increase the initial recovery of the graft-derived T cell compartment. The aim of this in vitro study was to define the optimal supplementation with recombinant human IL-7 (rhIL-7) than can promote the survival of CB T cells without enhancing allogeneic reactions, so as to limit the risk of eliciting an uncontrolled acute GVHD in vivo.

Twenty-six CB were obtained immediately after normal-term delivery, using the same procedure as for CB banking, and a freeze-thawing step in order to recapitulate the clinical procedure. CB T cells were cultured for one week alone or with HLA-mismatched monocytes from healthy adults (MLR conditions), in medium supplemented or not with rhIL-7. Cell viability was assessed by flow cytometry by scatter analysis and 3,3'-dihexyloxacarbocyanine iodide [DiOC6(3)] and propidium iodide staining. CB T cell proliferation was assessed by CFSE dilution.

Under basic culture conditions, a unique high dose of rhIL-7 (1 ng/mL) added on day 0 improved CB T cell survival but also triggered their proliferation. A daily addition of a low dose of rhIL-7 (final concentration of 100 pg/mL) reduced CB T cell apoptosis and increased significantly cell survival after 1 week of culture (p <0.001), without inducing any cell proliferation.

After one week of culture in allogeneic condition, small and large CB T cells were individualized on the cytogramm. Small cells corresponded to nonresponder CB T cells (CFSE dilution < 6,3%), while large CB T cells were allogeneic responder cells which underwent cell division. When allogeneic cultures were run with daily addition of rhIL-7 (100 pg/mL), the number of viable quiescent small CB T cells rose markedly (median 59,279 versus 36,726 without IL-7 supplementation, p=0.01), but the number of dividing cells among the large CB T cells did not increase significantly (median 29, 437 versus 24,471, p=0.19).

These experimental data show that repeated exposition to low-doses of rhIL-7 can preserve a viable CB T cell compartment, potentially useful in CB transplantation both for T cell reconstitution and T cell recruitment after primary infections. In these IL-7 exposition conditions, recent thymic emigrants could survive better without undergoing an uncontrolled expansion that would be deleterious in increasing the risk of acute GVHD.

These results indicate that clinical low dose IL-7 administration in umbilical cord blood transplanted patients, could improve post-transplant immune reconstitution, without potentiating risk of acute GVHD.

No relevant conflicts of interest to declare.