Suppressor function of umbilical cord blood-derived CD4+CD25+ T-regulatory cells exposed to graft-versus-host disease drugs

Abstract

Background: This study examines the effects of the most commonly used graft-versus-host disease (GVHD) prophylactic drugs on inducing apoptosis and suppressor cell function of human umbilical cord blood (UCB) CD4+25+ Treg and CD4+25- cells.

Methods: Cyclosporin A (CSA), methylprednisolone (MP), methotrexate (MTX), and mycophenolic acid (MPA) were added to the final 6 days of expansion cultures of Treg or CD4+25- T-cells isolated from the same donor and each concurrently cultured under the same conditions. Cell viability was measured for CD4+25+ as compared to CD4+25- T-cells and Treg function was assessed. The effects of these immunosuppressive drugs, Treg cells, or both also were tested in a primary allogeneic mixed lymphocyte response (MLR) response.

Results: The cell viability percentages were lower for CD4+25- cells than for Treg cells when MP, MTX, or MPA was added for the last 6 days of an expansion culture. Under these interleukin (IL)-2 based expansion conditions, CSA had no effect. The addition of any of the four GVHD prophylactic agents to the expansion phase of culture did not reduce the MLR suppressive capacity of Treg cells. Overall MLR suppression was increased when Treg cells were added along with CSA and MP to a primary MLR culture, whereas MTX modestly reduced Treg suppression.

Conclusion: These data indicate a general resistance of expanded UCB Treg cells to GVHD immune suppressive agents and support trials to test UCB Treg infusions under the cover of GVHD prophylactic drugs in hematopoietic cell transplantation.