Early administration of lenalidomide after allogeneic hematopoietic stem cell transplantation suppresses graft-versus-host disease by inhibiting T-cell migration to the gastrointestinal tract

Abstract

Introduction: Allogeneic hematopoietic stem cell transplantation (aHSCT) is a curative treatment for hematopoietic malignancies. Graft-versus-host disease (GVHD) is a major complication of aHSCT. After transplantation, the balance of immune conditions, such as proinflammatory cytokine level and T-cell subset count, influences GVHD magnitude. Lenalidomide (LEN) is an immunomodulatory drug used for treating several hematological malignancies such as multiple myeloma, adult T-cell lymphoma/leukemia, and follicular lymphoma. However, the impact of LEN on immune responses after aHSCT has not been elucidated.

Methods: We analyzed the lymphocyte composition in naïve mice treated with LEN. Subsequently, we treated host mice with LEN, soon after aHSCT, and analyzed GVHD severity as well as the composition and characteristics of lymphocytes associated with GVHD.

Results: Using a mouse model, we demonstrated the beneficial effects of LEN for treating acute GVHD. Although natural killer cells were slightly increased by LEN, it did not significantly change T-cell proliferation and the balance of the T-cell subset in naïve mice. LEN did not modulate the suppressive function of regulatory T cells (Tregs). Unexpectedly, LEN prevented severe GVHD in a mouse acute GVHD model. Donor-derived lymphocytes were more numerous in host mice treated with LEN than in host mice treated with vehicle. Lymphocyte infiltration of the gastrointestinal tract in host mice treated with LEN was less severe compared to that in host mice treated with vehicle. The percentage of LPAM-1 (α₄ β₇ -integrin)-expressing Foxp3^- CD4⁺ T cells was significantly lower in host mice treated with LEN than in host mice treated with vehicle, whereas that of LPAM-1-expressing Tregs was comparable.

Conclusions: LEN may be useful as a prophylactic agent for acute GVHD-induced mortality through the inhibition of lymphocyte migration to the gastrointestinal tract. Our data show the effect of LEN on immune responses early after aHSCT and suggest that cereblon, a molecular target of LEN, may be a therapeutic target for preventing acute GVHD-induced mortality.

Keywords: graft-versus-host disease; hematopoietic stem cell transplantation; lenalidomide; regulatory T cells.