FTY720 prevents GVHD: the host perspective

In this issue of Blood, Taylor and colleagues report that FTY720 hinders the initiation of GVHD by reducing the number of host DCs in the spleen, rather than by trapping T cells in secondary lymphoid tissues.

Sphingosine 1-phosphate (S1P) is a biologically active lysophospholipid that controls cellular differentiation, survival, and migration of several cell types. S1P is produced by mast cells, platelets, and macrophages, and is secreted in the extracellular fluid.¹  S1P binds a family of G-protein–coupled receptors with a diverse pattern of expression on immune cells, thus mediating the emigration of thymocytes from the thymus and the trafficking of lymphocytes and dendritic cells (DCs) in secondary lymphoid organs.¹  S1P₁ is the most abundant S1P receptor on T cells and is also expressed on DCs. T cells from S1P₁-deficient mice or mice treated with S1P₁-downregulating drug FTY720 (FTY) rapidly leave the blood, are sequestered in the lymph nodes, and mount a diminished response to immune challenges in tissues. FTY also inhibits DC function, thereby preventing IgE secretion and asthma in experimental animals.²  In patients with multiple sclerosis, oral FTY reduces the number of lesions and the amount of clinical disease activity.³  In de novo renal transplantation, FTY is as effective as mycophenolate mofetil in preventing graft rejection when used in combination with cyclosporine. Therefore, FTY appears to be a very promising immune-modulating agent.

Graft-versus-host disease (GVHD) is mediated by donor T cells that recognize host allo-antigens, and is associated with beneficial graft-versus-tumor (GVT) effects in recipients of allogeneic hematopoietic cell transplantation. In murine bone marrow transplantation (BMT) models, administration of FTY inhibits GVHD without abrogating GVT. It has been accepted that FTY prevents GVHD by trapping T cells in secondary lymphoid organs.⁴ 

In this issue of Blood, Taylor and colleagues present an elegant approach to visualize donor GFP-expressing T cells migrating to various recipient organs after transplantation. In the early phase of GVHD development, greater numbers of donor effector T cells accumulated in Peyer patches and mesenteric lymph nodes in FTY-treated recipients, but such an accumulation quickly diminished. Consistent with these data is the concept that FTY facilitates activation-induced T-cell death in the lymph nodes.⁵  Taylor and colleagues found fewer donor effector T cells in spleen, inguinal, and axillary lymph nodes, and in the gut-associated lymphoid tissues in FTY-treated recipients. In contrast, FTY did not reduce donor effector T cells in the liver or lung, implying that FTY does not prevent effector T cells from reaching epithelial organs targeted by GVHD.

The other novel finding presented in the article is that FTY reduced host DCs in recipient spleen before transplantation, and that pretreatment of the host alone was sufficient to inhibit GVHD. After transplantation, expansion of donor CD4⁺ and CD8⁺ effector cells was blunted by the same magnitude as host DCs were depleted by FTY before transplantation. Because host DCs are also required for optimal GVT, it was no surprise that FTY therapy impaired GVT. FTY alone appeared modestly immune suppressive, and combination therapy was required to prevent GVHD. FTY was additive with adoptively transferred donor T regulatory cells (Tregs), providing the rationale for testing the combination for GVHD prevention in humans.