The role of chemokines in mediating graft versus host disease: opportunities for novel therapeutics

Abstract

Bone marrow transplantation (BMT) is the current therapy of choice for several malignancies and severe autoimmune diseases. Graft versus host disease (GVHD) is the major complication associated with BMT. T lymphocytes and other leukocytes migrate into target organs during GVHD, become activated and mediate tissue damage. Chemokines are well known inducers of leukocyte trafficking and activation and contribute to the pathogenesis of GVHD. Here, we review the major animal models used to study GVHD and the role of chemokines in mediating tissue damage in these models. The role of these molecules in promoting potential beneficial effects of the graft, especially graft versus leukemia, is also discussed. Finally, the various pharmacological strategies to block the chemokine system or downstream signaling events in the context of GVHD are discussed.

Keywords: GVHD; chemokines; inflammation; therapy.

Figure 1

Overview of chemokine and chemokine receptor expression in the major organs targeted by GVHD. Shown are the major target organs that are affected by GVHD, the intestine, liver, lung, and skin, and the major chemokines and chemokine receptors that are expressed during the course of the disease.

Figure 2

Depicts of downstream signaling of chemoattractant receptors in GVHD. Signaling by chemokine receptors is mediated by heterotrimeric G-proteins. Activation of G-proteins leads to activation of PI₃K, JAK, STAT, and MAPK. In GVHD, activation of PI₃Kγ, JAK, STAT-1/3 leads to pro-inflammatory events that crucial to development of GVHD. STAT-3/STAT-1 activation preceded the activation of NF-κB and MAP kinases with the subsequent expression of IRF-1, SOCS-1, and IL-17. NF-κB has a dual role in development of GVHD, depending of phase of it expression. STAT-3 phosphorylation acts as a promoter of GVHD inflammation and is regulated by SOCS-3.