Effect of interleukin (IL)-12 and IL-15 on apoptosis and proliferation of umbilical cord blood mononuclear cells

Decreased graft-versus-host disease (GVHD) in cord blood (CB) transplantation may be attributed to the immunological immaturity and susceptibility to apoptosis of CB mononuclear cells (MNCs). Cytokines like interleukin (IL)-12 and IL-15 may be used for in vivo administration or ex vivo expansion of lymphoid cells for more rapid recovery following stem cell transplant, and for providing a graft-versus-leukemia (GVL) effect. We investigated the effects of IL-12 and IL-15, alone or in combination on apoptosis and proliferation of both CB and adult peripheral blood (APB) MNCs, with particular emphasis on CB CD4⁺, CD8⁺ and CD56⁺ lymphocyte subpopulations. The results of our study indicated that: (1) the combination of IL-12+IL-15 resulted in a greater degree of CB and APB apoptosis than either cytokine alone; (2) the level of both spontaneous and cytokine-induced apoptosis by IL-12 and/or IL-15 are greater in CB MNCs than in APB MNCs using TUNEL assays; (3) IL-15 is superior to IL-12 in enhancing the proliferative response in CB and APB MNCs; (4) the combination of IL-12+IL-15, but not either cytokine alone, significantly enhanced apoptosis in CD8⁺ and CD56⁺ CB subsets, but not in CD4⁺ CB subsets; (5) IL-12 or IL-15 alone resulted in increased proliferation in CD4⁺, CD8⁺ and CD56⁺ CB subsets, with IL-12+IL-15 producing the greatest increase of proliferation in all three CB subsets; and (6) IL-15 and/or IL-12 significantly upregulate Fas (CD95) expression on CB T and NK cells. These findings may have therapeutic implications when designing cytokine therapy in patients receiving CB transplant.