Depletion of host Langerhans cells before transplantation of donor alloreactive T cells prevents skin graft-versus-host disease

Nat Med. 2004 May;10(5):510-7.  Epub 2004 Apr 18.

Speaker : 盧 淑 君                     Time : 15:00-16:00, Oct. 27, 2004

Commentator: 謝 奇 璋 醫師            Place : Room 601

Abstract:

    Skin is the most commonly affected organ in graft-versus-host disease (GVHD) (2). When T cells were depleted from the bone-marrow transplant, host Langerhans cells persisted in the skin, even though the blood and spleen were repopulated with donor-derived dendritic cells. By contrast, when T cells were included in the transplant, host Langerhans cells were replaced by donor-derived cells. The authors show that this occurred by two donor-T-cell-mediated processes: Fas ligand-mediated depletion (3) of host Langerhans cells and the induction of expression of inflammatory chemokines in the skin, which recruit donor Langerhans-cell precursors. However, mice that received whole bone marrow still developed GVHD, because the depletion of host Langerhans cells occurred after donor T cells cause disease. So, the authors developed a strategy to eliminate host Langerhans cells before donor T-cell infusion. First, irradiated mice were reconstituted with T-cell-depleted bone marrow, allowing complete chimerism to be established in the blood but not the skin. These mice were then exposed to ultraviolet light, which caused host Langerhans cells to migrate out of the skin and allowed repopulation with donor-derived cells. After several weeks, the mice were then retransplanted with bone marrow containing T cells. No GVHD developed in these mice, indicating that Langerhans-cell replacement in the skin is required to prevent GVHD following transplantation of T cells. Future experiments will address whether exposing patients to ultraviolet light before transplantation might help prevent GVHD in human recipients.

References :

1.     Merad M, Hoffmann P, Ranheim E, Slaymaker S, Manz MG, Lira SA, Charo I, Cook DN, Weissman IL, Strober S, Engleman EG. Depletion of host Langerhans cells before transplantation of donor alloreactive T cells prevents skin graft-versus-host disease. Nat Med. 2004 May;10(5):510-7.

2.     Goker H, Haznedaroglu IC, Chao NJ. Acute graft-vs-host disease: pathobiology and management. Exp Hematol. 2001 Mar;29(3):259-77.

3.     Takahashi T, Tanaka M, Brannan CI, Jenkins NA, Copeland NG, Suda T, Nagata S. Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand. Cell 1994 Mar 25;76(6):969-76.