n engl j med 349;23 www.nejm.org december 4, 2003 2183 PERSPECTIVE Hematopoietic stem-cell transplantation is an ef- fective but toxic therapy for a number of life-threat- ening diseases, especially hematologic cancers. The principal complication of allogeneic stem-cell trans- plantation (the transplantation of grafts from genet- ically different donors) is graft-versus-host disease (GVHD), which can occur despite aggressive immu- nosuppressive prophylaxis and even when the donor is a “perfectly” matched (HLA-identical) sibling. The complex pathophysiology of GVHD fundamentally depends on interactions between antigen-present- ing cells of the recipient and mature T cells of the donor (see Figure). A substantial body of research in animal models has uncovered the contribution of cytokines to the inflammation and tissue damage that characterize GVHD. Recent studies suggest that small variations in the genes that encode these pro- teins, called single-nucleotide polymorphisms, de- termine the relative levels of cytokines under condi- tions of stress and may therefore predict outcomes after hematopoietic stem-cell transplantation. In a study reported in this issue of the Journal, Lin and colleagues (pages 2201–2210) analyzed nearly 1000 recipients of allogeneic hematopoietic stem- cell transplants and their HLA-identical sibling do- nors for genetic variants of several cytokine genes. They show that a simple genetic test for a common variant in the promoter region of the interleukin- 10 gene (IL10) can identify patients who are homozy- gous at this locus (A/A genotype) and are therefore at low risk for GVHD after stem-cell transplanta- tion. Variations in other cytokine genes (in the donor or the recipient) did not have any prognostic sig- nificance. This favorable interleukin-10 genotype has been associated with increased production of interleu- kin-10 — a finding that underscores its role in the regulation of immune responses. Physiologically, interleukin-10 secreted by antigen-presenting cells promotes the development of immunologic toler- ance and suppresses the production of inflamma- tory cytokines. Although Lin et al. did not measure serum interleukin-10 levels, their data confirm and extend the results of several smaller studies from other institutions that correlate genetic variants in this region of the interleukin-10 promoter and high- er levels of interleukin-10 with protection against GVHD. The results of these studies support the hy- pothesis that the antigen-presenting cells of a recip- ient with a favorable (A/A) interleukin-10 genotype produce large amounts of interleukin-10, thereby inducing tolerance in donor T cells to foreign an- tigens (alloantigens) in the recipient. As a result, the activation of donor T cells is minimized, and the recipient has little or no GVHD and has improved long-term survival after transplantation (see Fig- ure). By contrast, antigen-presenting cells in pa- tients with an unfavorable interleukin-10 genotype produce insufficient interleukin-10 to promote tol- erance to donor T cells. Alloantigens on these anti- gen-presenting cells activate the donor T cells, with ensuing severe GVHD and decreased overall surviv- al (see Figure). These important findings are likely to change clinical practice. Although validation in additional patients is always desirable, we believe that the data already support the inclusion of the interleukin-10 genotype in the standard evaluation of a patient who is under consideration for transplantation of allo- geneic hematopoietic stem cells from an HLA-iden- tical sibling donor. Knowledge of the interleukin-10 genotype will help physicians to inform their pa- tients about the relative risks after stem-cell trans- plantation and will help to prioritize transplantation as a therapeutic option. For example, a patient with acute myelogenous leukemia and a favorable inter- leukin-10 genotype may wish to consider transplan- tation from an HLA-identical sibling during the first complete remission, rather than wait for a possible relapse with its attendant risks and complications. For young patients with a favorable interleukin-10 genotype and chronic myelogenous leukemia who have an incomplete response to imatinib and for patients with sickle cell anemia and severe neuro- logic complications, an argument could be made for early transplantation if an HLA-identical sibling donor were available. Moreover, the interleukin-10 genotype is likely to influence the choice of an A Protective Gene for Graft-versus-Host Disease Kenneth R. Cooke, M.D., and James L.M. Ferrara, M.D. The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF MICHIGAN on September 23, 2013. For personal use only. No other uses without permission. Copyright © 2003 Massachusetts Medical Society. All rights reserved.