Letter | Published:

Donor APCs are required for maximal GVHD but not for GVL

Nature Medicine volume 10, pages 987992 (2004) | Download Citation

Subjects

Abstract

Graft-versus-host disease (GVHD) is a major source of morbidity in allogenic stem cell transplantation1. We previously showed that recipient antigen-presenting cells (APCs) are required for CD8-dependent GVHD in a mouse model across only minor histocompatibility antigens (minor H antigens)2. However, these studies did not address the function of donor-derived APCs after GVHD is initiated. Here we show that GVHD develops in recipients of donor major histocompatibility complex class I–deficient (MHC I) bone marrow. Thus, after initial priming, CD8 cells caused GVHD without a further requirement for hematopoietic APCs, indicating that host APCs are necessary and sufficient for GHVD. Nonetheless, GVHD was less severe in recipients of MHC I bone marrow. Therefore, once initiated, GVHD is intensified by donor-derived cells, most probably donor APCs cross-priming alloreactive CD8 cells. Nevertheless, donor APCs were not required for CD8-mediated graft-versus-leukemia (GVL) against a mouse model of chronic-phase chronic myelogenous leukemia. These studies identify donor APCs as a new target for treating GVHD, which may preserve GVL.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , & Acute graft-vs-host disease: Pathobiology and management. Exp. Hematol. 29, 259–277 (2001).

  2. 2.

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

  3. 3.

    & Induction of MHC class II gene products in rat intestinal epithelium during graft-versus-host disease and effects on the immune function of the epithelium. Immunology 75, 366–371 (1992).

  4. 4.

    et al. Graft-versus-leukemia in a retrovirally induced murine CML model: mechanisms of T-cell killing. Blood 103, 4353–4361 (2004).

  5. 5.

    et al. Efficient and rapid induction of a chronic myelogenous leukemia-like myeloproliferative disease in mice receiving P210 bcr/abl-transduced bone marrow. Blood 92, 3780–3792 (1998).

  6. 6.

    , & Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 247, 824–830 (1990).

  7. 7.

    & Memory CD8+ T cell differentiation: initial antigen encounter triggers a developmental program in naive cells. Nat. Immunol. 2, 415–422 (2001).

  8. 8.

    , & Naive CTLs require a single brief period of antigenic stimulation for clonal expansion and differentiation. Nat. Immunol. 2, 423–429 (2001).

  9. 9.

    et al. Cutting edge: precursor frequency affects the helper dependence of cytotoxic T cells. J. Immunol. 168, 977–980 (2002).

  10. 10.

    , & The duration of antigenic stimulation determines the fate of naive and effector T cells. Immunity 8, 89–95 (1998).

  11. 11.

    , & Naive versus memory CD4 T cell response to antigen. Memory cells are less dependent on accessory cell costimulation and can respond to many antigen-presenting cell types including resting B cells. J. Immunol. 152, 2675–2685 (1994).

  12. 12.

    & Qualitative differences between naive and memory T cells make a major contribution to the more rapid and efficient memory CD8+ T cell response. J. Immunol. 161, 674–683 (1998).

  13. 13.

    , , & Kinetics of the response of naive and memory CD8 T cells to antigen: similarities and differences. Eur. J. Immunol. 29, 284–290 (1999).

  14. 14.

    , , , & Functional differences between memory and naive CD8 T cells. Proc. Natl. Acad. Sci. USA 96, 2976–2981 (1999).

  15. 15.

    , & Functional responses and costimulator dependence of memory CD4+ T cells. J. Immunol. 164, 265–72 (2000).

  16. 16.

    T memory cells: quality not quantity. Curr. Biol. 12, R174–R176 (2002).

  17. 17.

    et al. Cross-priming of CD8(+) T cells stimulated by virus-induced type I interferon. Nat. Immunol. 4, 1009–1015 (2003).

  18. 18.

    et al. The heat shock protein gp96 induces maturation of dendritic cells and down-regulation of its receptor. Eur. J. Immunol. 30, 2211–2215 (2000).

  19. 19.

    et al. CD28, TNF receptor, and IL-12 are critical for CD4-independent cross-priming of therapeutic antitumor CD8+ T cells. J. Immunol. 169, 4897–4904 (2002).

  20. 20.

    , , , & Proinflammatory cytokines and CD40 ligand enhance cross-presentation and cross-priming capability of human dendritic cells internalizing apoptotic cancer cells. J. Immunother. 24, 162–171 (2001).

  21. 21.

    & Recognition of microbial infection by Toll-like receptors. Curr. Opin. Immunol. 15, 396–401 (2003).

  22. 22.

    et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood 75, 555–562 (1990).

  23. 23.

    et al. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. European Group for Blood and Marrow Transplantation Working Party Chronic Leukemia. Blood 86, 2041–2050 (1995).

  24. 24.

    et al. Use of leukemic dendritic cells for the generation of antileukemic cellular cytotoxicity against Philadelphia chromosome-positive chronic myelogenous leukemia. Blood 89, 1133–1142 (1997).

  25. 25.

    et al. High incidence of cytomegalovirus infection after nonmyeloablative stem cell transplantation: potential role of Campath-1H in delaying immune reconstitution. Blood 99, 4357–4363 (2002).

  26. 26.

    et al. A randomized trial comparing prednisone with antithymocyte globulin/prednisone as an initial systemic therapy for moderately severe acute graft-versus-host disease. Biol. Blood Marrow Transplant. 6, 441–447 (2000).

  27. 27.

    et al. Rejection of class I MHC-deficient haemopoietic cells by irradiated MHC-matched mice. Nature 349, 329–331 (1991).

  28. 28.

    et al. Memory CD4+ T cells do not induce graft-versus-host disease. J. Clin. Invest. 112, 101–108 (2003).

  29. 29.

    , , & Production of high-titer helper-free retroviruses by transient transfection. Proc. Natl. Acad. Sci. USA 90, 8392–8396 (1993).

Download references

Acknowledgements

We thank M. Shlomchik for discussions and reading of the manuscript. This work was supported by National Institutes of Health RO1 grants CA96943 and HL66279. W.D.S. was supported by National Institutes of Health grant K08 HL03979 and B.E.A. was supported by National Institutes of Health grant T32 AI071019-23-25.

Author information

Affiliations

  1. Section of Medical Oncology, Yale University School of Medicine, PO Box 208032, 333 Cedar Street, New Haven, Connecticut 06520, USA.

    • Catherine C Matte
    • , Jinli Liu
    • , Ioanna Athanasiadis
    •  & Warren D Shlomchik
  2. Department of Biochemistry and Molecular Biology, 913 Lederle Graduate Research Tower, 710 North Pleasant Street, University of Massachusetts, Amherst, Massachusetts 01003, USA.

    • James Cormier
  3. Department of Laboratory Medicine, PO Box 208035; Yale University School of Medicine, 333 Cedar St., New Haven, Connecticut 06520, USA.

    • Britt E Anderson
  4. Department of Pathology, PO Box 208023; Yale University School of Medicine, 333 Cedar St., New Haven, Connecticut 06520, USA.

    • Dhanpat Jain
  5. Department of Dermatology, PO Box 208059; Yale University School of Medicine, 333 Cedar St., New Haven, Connecticut 06520, USA.

    • Jennifer McNiff
  6. Section of Immunobiology, PO Box 208035; Yale University School of Medicine, 333 Cedar St., New Haven, Connecticut 06520, USA.

    • Warren D Shlomchik

Authors

  1. Search for Catherine C Matte in:

  2. Search for Jinli Liu in:

  3. Search for James Cormier in:

  4. Search for Britt E Anderson in:

  5. Search for Ioanna Athanasiadis in:

  6. Search for Dhanpat Jain in:

  7. Search for Jennifer McNiff in:

  8. Search for Warren D Shlomchik in:

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Warren D Shlomchik.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nm1089