Editors' ChoiceMEDICINE

The Inflammasome and Transplantation

Sci. Signal.  08 Oct 2013:
Vol. 6, Issue 296, pp. ec240
DOI: 10.1126/scisignal.2004791

Allogeneic hematopoietic cell transplantation (allo-HCT) is used to treat patients with malignancies such as leukemias and lymphoproliferative disorders. In successful cases, the donor T cells lead to reconstitution of the recipient’s immune system, but they can also target the recipient’s tissues in graft-versus-host disease (GvHD), a serious complication that can kill the patient. As part of pretransplant conditioning, recipients are treated by irradiation and cytotoxic drugs; however, this treatment causes tissue damage, particularly in the skin and intestine, enabling microbial products to infiltrate other tissues, which results in the production of proinflammatory cytokines that can activate T cells subsequently derived from the donor. Jankovic et al. performed allo-HCT experiments in mice preconditioned with irradiation or cytotoxic drugs and found that early inhibition of the proinflammatory cytokine interleukin-1β (IL-1β) reduced the severity of GvHD. IL-1β is produced in a two-step process. First, microbial products stimulate the nuclear factor κB–dependent production of pro–IL-1β, which is then processed by caspase-1 in response to activation of a multiprotein complex known as the inflammasome. The authors found that deletion of NLRP3 inflammasome components in recipient, but not donor, mice alleviated GvHD. Treatment of recipient mice with antibiotics reduced the amount of IL-1β produced. Host dendritic cells were identified as the major source of IL-1β, and the numbers of proinflammatory interleukin-17 (IL-17)–producing T cells were greater in wild-type recipient mice than in NRLP3-deficient mice. Finally, active caspase-1 (a hallmark of inflammasome activation) was more abundant in the peripheral blood cells from transplant patients with GvHD than in the same cells from transplant patients without GvHD, and GvHD patients had more IL-1β in the intestine and skin than did patients without GvHD. Together, these data suggest that activation of the NRLP3 inflammasome promotes an IL-1β– and IL-17–dependent inflammatory response that results in GvHD and suggest that targeting of NLRP3 inflammasome components or microbiota may provide therapies for the treatment of GvHD.

D. Jankovic, J. Ganesan, M. Bscheider, N. Stickel, F. C. Weber, G. Guarda, M. Follo, D. Pfeifer, A. Tardivel, K. Ludigs, A. Bouazzaoui, K. Kerl, J. C. Fischer, T. Haas, A. Schmitt-Gräff, A. Manoharan, L. Müller, J. Finke, S. F. Martin, O. Gorka, C. Peschel, J. Ruland, M. Idzko, J. Duyster, E. Holler, L. E. French, H. Poeck, E. Contassot, R. Zeiser, The Nlrp3 inflammasome regulates acute graft-versus-host disease. J. Exp. Med. 210, 1899–1910 (2013). [Abstract][Full Text]