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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

Abstract

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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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.

References

  1. 1

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

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  7. 7

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

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  9. 9

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

    CAS  Article  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  11. 11

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

    CAS  Article  Google Scholar 

  12. 12

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

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  14. 14

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

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  22. 22

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

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  25. 25

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

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  36. 36

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

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  38. 38

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

    CAS  Article  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  41. 41

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

    CAS  Article  Google Scholar 

  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).

    Google Scholar 

  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).

    Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  46. 46

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

    CAS  Article  Google Scholar 

  47. 47

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

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

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Acknowledgements

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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Correspondence to Kouji Matsushima.

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Murai, M., Yoneyama, H., Ezaki, T. et al. Peyer's patch is the essential site in initiating murine acute and lethal graft-versus-host reaction. Nat Immunol 4, 154–160 (2003). https://doi.org/10.1038/ni879

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