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Peyer's patch is the essential site in initiating murine acute and lethal graft-versus-host reaction


  • A Corrigendum to this article was published on 01 May 2003


Acute graft-versus-host disease (a-GVHD) is initiated primarily by immunologically competent cytotoxic T cells (CTLs) that express anti-host specificities. However, the host lymphoid compartment in which these precursor CTLs are initially stimulated remains unclear. Here we show that gut Peyer's patches (PPs) are required to activate anti-host CTL responses in a well characterized murine acute graft-versus-host reaction (a-GVHR) model, involving transfer of parent lymphocytes into F1 hybrid recipients. The a-GVHR was prevented when recruitment of donor T cells into PP was interrupted either by disrupting the gene encoding chemokine receptor CCR5 or by blocking integrin α4β7–MAdCAM-1 (mucosal vascular addressin) interactions. Mice deficient for PPs failed to develop a-GVHD in two models of disease induction. Thus, blockade of CTL generation in PPs might offer new strategies for circumventing a-GVHD.

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  1. 1

    Appelbaum, F.R. Haematopoietic cell transplantation as immunotherapy. Nature 411, 385–389 (2001).

  2. 2

    Ho, V.T. & Soiffer, R.J. The history and future of T-cell depletion as graft-versus-host disease prophylaxis for allogeneic hematopoietic stem cell transplantation. Blood 98, 3192–3204 (2001).

  3. 3

    Mowat, A.M. & Felstein, M.V. Experimental studies of immunologically mediated enteropathy. V. Destructive enteropathy during an acute graft-versus-host reaction in adult BDF1 mice. Clin. Exp. Immunol. 79, 279–284 (1990).

  4. 4

    Sprent, J. & Korngold, R. Murine models for graft-versus-host disease. in Bone Marrow Transplantation (eds. Forman, S.J., Blume, K.J. & Thomas, E.D.) 220–230 (Blackwell Scientific Publications, Boston, 1994).

  5. 5

    Baker, B.M.B., Altman, N., Podack, E. & Levy, R.B. The role of cell-mediated cytotoxicity in acute GVHD after MHC-matched allogeneic bone marrow transplantation in mice. J. Exp. Med. 183, 2645–2656 (1996).

  6. 6

    Tamada, K. et al. Modulation of T-cell-mediated immunity in tumor and graft-versus-host disease models through the LIGHT co-stimulatory pathway. Nat. Med. 6, 283–289 (2000).

  7. 7

    Antin, J.H. Acute graft-versus-host disease: inflammation run amok? J. Clin. Invest. 107, 1497–1498 (2001).

  8. 8

    Shlomchik, W.D. et al. Prevention of graft-versus-host disease by inactivation of host antigen-presenting cells. Science 285, 412–415 (1999).

  9. 9

    Ferrara, J.L.M. & Deeg, H.J. Graft-versus-host disease. N. Eng. J. Med. 324, 667–674 (1991).

  10. 10

    Shustov, A., Nguyen, P., Finkelman, F., Elkeon, K.B. & Via, C.S. Differential expression of Fas and Fas ligand in acute and chronic graft-versus-host disease: up-regulation of Fas and Fas ligand requires CD8+ T cell activation and IFN-γ production. J. Immunol. 161, 2848–2855 (1998).

  11. 11

    Lin, T. et al. Fas ligand-mediated killing by intestinal intraepithelial lymphocytes. J. Clin. Invest. 101, 570–577 (1998).

  12. 12

    Mackay, C.R. Dual personality of memory T cells. Nature 401, 659–660 (1999).

  13. 13

    Sallusto, F., Lenig, D., Forster, R., Lipp, M. & Lanzavecchia, A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401, 708–712 (1999).

  14. 14

    Kunkel, E.J. & Butcher, E.C. Chemokines and the tissue-specific migration of lymphocytes. Immunity 16, 1–4 (2002).

  15. 15

    Campbell, D.J. & Butcher, E.C. Rapid acquisition of tissue-specific homing phenotypes by CD4+ T cells activated in cutaneous or mucosal lymphoid tissues. J. Exp. Med. 195, 135–141 (2002).

  16. 16

    Murai, M. et al. Active participation of CCR5+CD8+ T lymphocytes in the pathogenesis of liver injury in graft-versus-host disease. J. Clin. Invest. 104, 49–57 (1999).

  17. 17

    Serody, J.S. et al. T-lymphocyte production of macrophage inflammatory protein-1a is critical to the recruitment of CD8+ T cells to the liver, lung, and spleen during graft-versus-host disease. Blood 96, 2973–2980 (2000).

  18. 18

    Pals, S.T., Radaszkiewicz, T. & Gleichmann, E. Allosuppressor- and allohelper-T cells in acute and chronic graft-versus-host disease IV. Activation of donor allosuppressor cells is confined to acute GVHD. J. Immunol. 132, 1669–1678 (1984).

  19. 19

    Sakai, T., Ohara-Inagaki, K., Tsuzuki, T. & Yoshikai, Y. Host intestinal intraepithelial gd T lymphocytes present during acute graft-versus-host disease in mice may contribute to the development of enteropathy. Eur. J. Immunol. 25, 87–91 (1995).

  20. 20

    Okabe, M., Ikawa, M., Kominami, K., Nakanishi, T. and Nishimune, Y. 'Green mice' as a source of ubiquitous green cells. FEBS Lett. 407, 313–319 (1997).

  21. 21

    Kelsall, B.L. & Strober, W. Distinct populations of dendritic cells are present in the subepithelial dome and T cell regions of the murine Peyer's patch. J. Exp. Med. 183, 237–247 (1996).

  22. 22

    Banchereau, J. & Steinman, R.M. Dendritic cells and the control of immunity. Nature 392, 245–252 (1998).

  23. 23

    Iwasaki, A. & Kelsall, B.L. Freshly isolated Peyer's patch, but not spleen, dendritic cells produce interleukin 10 and induce the differentiation of T helper type 2 cells. J. Exp. Med. 190, 229–239 (1999).

  24. 24

    Yasmineh, W.G., Filipovich, A.H. & Killeen, A.A. Serum 5′ nucleotidase and alkaline phosphatase—highly predictive liver function tests for the diagnosis of graft-versus-host disease in bone marrow transplantation recipients. Transplantation 48, 809–814 (1989).

  25. 25

    Butcher, E.C., Williams, M., Youngman, K., Rott, L. & Briskin, M. Lymphocyte trafficking and regional immunity Adv. Immunol. 72, 209–253 (1999).

  26. 26

    Yoshida, H. et al. IL-7 receptor α+ CD3 cells in the embryonic intestine induces the organizing center of Peyer's patches. Int. Immunol. 11, 643–655 (1999).

  27. 27

    Hamada, H. et al. Identification of multiple isolated lymphoid follicles on the antimesenteric wall of the mouse small intestine. J. Immunol. 168, 57–64 (2002).

  28. 28

    Korngold, R. & Sprent, J. T-cell subsets in graft-versus-host disease. in Graft- versus-Host Disease: Immunology, Pathophysiology and Treatment (eds. Burakoff, S.J., Deeg, H.J., Ferrara, J.L.M. & Atkinson, K.) 31–50 (Marcel Dekker, New York, 1990).

  29. 29

    Tamada, K. et al. Blockade of LIGHT/LTβ and CD40 signaling induces allospecific T cell anergy, preventing graft-versus-host disease. J. Clin. Invest. 109, 549–557 (2002).

  30. 30

    Sprent, J. Fate of H2-activated T lymphocytes in syngeneic hosts I. Fate in lymphoid tissues and intestines traced with 3H-Thymidine, 125I-Deoxyuridine and 51Chromium. Cell. Immunol. 21, 278–302 (1976).

  31. 31

    Sprent, J. & Miller, J.F.A.P. Interaction of thymus lymphocytes with histocompatible cells. II. Recirculating lymphocytes derived from antigen-activated thymus cells. Cell. Immunol. 3, 385–404 (1972).

  32. 32

    Sprent, J. & Miller, J.F.A.P. Interaction of thymus lymphocytes with histocompatible cells. I. Quantitation of the proliferative response of thymus cells. Cell. Immunol. 3, 361–384 (1972).

  33. 33

    Gebert, A., Rothkotter, H.J. & Pabst, R. M cells in Peyer's patches of the intestine. Int. Rev. Cytol. 167, 91–159 (1996).

  34. 34

    Neutra, M.R., Mantis, N.J. & Kraehenbuhl, J.-P. Collaboration of epithelial cells with organized mucosal lymphoid tissues. Nat. Immunol. 2, 1004–1009 (2001).

  35. 35

    Hurst, S.D., Sitterding, S.M., Ji, S. & Barrett, T.A. Functional differentiation of T cells in the intestine of T cell receptor transgenic mice. Proc. Natl. Acad. Sci. USA 94, 3920–3925 (1997).

  36. 36

    MacDonald, T. Introduction. Semin. Immunol. 13, 159–161 (2001).

  37. 37

    Elson, C.O., Cong, Y., Iqbal, N. & Weaver, C.T. Immuno-bacterial homeostasis in the gut: new insight into an old enigma. Semin. Immunol. 13, 187–194 (2001).

  38. 38

    Simmons, C.P., Clare, S. & Dougan, G. Understanding mucosal responsiveness: lessons from enteric bacterial pathogens. Semin. Immunol. 13, 201–209 (2001).

  39. 39

    Weinstein, P.D. & Cebra, J.J. The preference for switching to IgA expression by Peyer's patch germinal center B cells is likely due to the intrinsic influence of their microenvironment. J. Immunol. 147, 4126–4135 (1991).

  40. 40

    Sudo, N. et al. The requirement of intestinal bacterial flora for the development of an IgE production system fully susceptible to oral tolerance induction. J. Immunol. 159, 1739–1745 (1997).

  41. 41

    Singh, B. et al. Control of intestinal inflammation by regulatory T cells. Immunol. Rev. 182, 190–200 (2001).

  42. 42

    Vossen, J.M. & Heidt, P.J. Gnotobiotic measures for the prevention of acute graft-versus-host disease. in Graft-versus-Host Disease: Immunology, Pathophysiology and Treatment (eds. Burakoff, S.J., Deeg, H.J., Ferrara, J.L.M. & Atkinson, K.) 403–413 (New York, Marcel Dekker, 1990).

  43. 43

    Nestle, F.P., Price, K.S., Seemayer, T.A. and Lapp, W.S. Macrophage priming and lipopolysaccharide-triggered release of tumor necrosis factor α during graft-versus-host disease. J. Exp. Med. 175, 405–413 (1992).

  44. 44

    Cooke, K.R. et al. Tumor necrosis factor-α production to lipopolysaccharide stimulation by donor cells predicts the severity of experimental acute graft-versus-host disease. J. Clin. Invest. 102, 1882–1891 (1998).

  45. 45

    Cooke, K.R. et al. LPS antagonism reduces graft-versus-host disease and preserves graft-versus-leukemia activity after experimental bone marrow transplantation. J. Clin. Invest. 107, 1581–1589 (2001).

  46. 46

    Dazzi, F., Simpson, E. & Goldman, J.M. Minor antigen solves major problem. Nat. Med. 7, 769–770 (2001).

  47. 47

    Garside, P. & Mowat, A.M. Oral tolerance. Semin. Immunol. 13, 177–185 (2001).

  48. 48

    Decker, T. & Lohmann-Matthes, M.L. A quick and simple method for the quantitation of lactate dehydrogenese release in mesasurements of cellular cytotoxicity and tumor necrosis factor (TNF) activity. J. Immunol. Methods 115, 61–69 (1988).

  49. 49

    Yoneyama, H. et al. Regulation by chemokines of circulating dendritic cell precursors, and the formation of portal tract-associated lymphoid tissue, in a granulamatous liver disease. J. Exp. Med. 193, 35–49 (2001).

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We thank J.J. Oppenheim, K. Matsuno, S. Ishikawa, M. Haino and C. Vestergaard for helpful discussions and S. Fujita for assistance in animal surgery. This work was supported by Research Fellowships of the Japan Society for the Promotion of Science for Young Scientists (M.M.), by Grant-in-Aid for Creative Scientific Research, the Japan Society for the Promotion of Science (13GS0015) and Special Coordination Fund for Promoting Science and Technology, Ministry of Education, Culture, Sport, Science and Technology (H.I.) and by a grant from Solution Oriented Research for Science and Technology (SORST), Japan Science and Technology Corporation (K.M.).

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The authors declare no competing financial interests.

Correspondence to Kouji Matsushima.

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Figure 1: Early and prominent infiltration of donor CD8+ T cells into SED regions of host PPs.
Figure 2: Characterization of donor CD8+ T cells that infiltrate into SED regions of host PPs.
Figure 3: Production of CCR5−/− mice and analysis of CCR5−/− lymphocytes.
Figure 4: CCR5–CCL5 and α4β7–MAdCAM-1 interactions are implicated in the induction of a-GVHR.
Figure 5: Flow cytometric and immunohistochemical analyses of lymphocytes that reside in BDF1 mice with and without PPs.
Figure 6: Induction of acute and lethal GVHR is abolished in hosts that lack PPs.