Blocking LFA-1 Activation with Lovastatin Prevents Graft-versus-Host Disease in Mouse Bone Marrow Transplantation

Yang Wang, Dan Li, Dan Jones, Roland Bassett, George E. Sale, Jahan Khalili, Krishna V Komanduri, Daniel R. Couriel, Richard E. Champlin, Jeffrey J. Molldrem, Qing Ma

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Graft-versus-host disease (GVHD) following bone marrow transplantation (BMT) is mediated by alloreactive donor T lymphocytes. Migration and activation of donor-derived T lymphocytes play critical roles in the development of GVHD. Leukocyte function-associated antigen-1 (LFA-1) regulates T cell adhesion and activation. We previously demonstrated that the I-domain, the ligand-binding site of LFA-1, changes from the low-affinity state to the high-affinity state on LFA-1 activation. Therapeutic antagonists, such as statins, inhibit LFA-1 activation and immune responses by modulating the affinity state of the LFA-1 I-domain. In the present study, we report that lovastatin blocked mouse T cell adhesion, proliferation, and cytokine production in vitro. Furthermore, blocking LFA-1 in the low-affinity state with lovastatin reduced the mortality and morbidity associated with GVHD in a murine BMT model. Specifically, lovastatin prevented T lymphocytes from homing to lymph nodes and Peyer's patches during the GVHD initiation phase and after donor lymphocyte infusion (DLI) after the establishment of GVHD. In addition, treatment with lovastatin impaired donor-derived T cell proliferation in vivo. Taken together, these results indicate the important role of lovastatin in the treatment of GVHD.

Original languageEnglish
Pages (from-to)1513-1522
Number of pages10
JournalBiology of Blood and Marrow Transplantation
Volume15
Issue number12
DOIs
StatePublished - Dec 1 2009
Externally publishedYes

Fingerprint

Lovastatin
Lymphocyte Function-Associated Antigen-1
Graft vs Host Disease
Bone Marrow Transplantation
T-Lymphocytes
Cell Adhesion
Cell Proliferation
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Peyer's Patches
Therapeutics
Lymph Nodes
Binding Sites
Lymphocytes
Cytokines
Ligands
Morbidity
Mortality

Keywords

  • GVHD
  • LFA-1
  • Statin

ASJC Scopus subject areas

  • Transplantation
  • Hematology

Cite this

Blocking LFA-1 Activation with Lovastatin Prevents Graft-versus-Host Disease in Mouse Bone Marrow Transplantation. / Wang, Yang; Li, Dan; Jones, Dan; Bassett, Roland; Sale, George E.; Khalili, Jahan; Komanduri, Krishna V; Couriel, Daniel R.; Champlin, Richard E.; Molldrem, Jeffrey J.; Ma, Qing.

In: Biology of Blood and Marrow Transplantation, Vol. 15, No. 12, 01.12.2009, p. 1513-1522.

Research output: Contribution to journalArticle

Wang, Y, Li, D, Jones, D, Bassett, R, Sale, GE, Khalili, J, Komanduri, KV, Couriel, DR, Champlin, RE, Molldrem, JJ & Ma, Q 2009, 'Blocking LFA-1 Activation with Lovastatin Prevents Graft-versus-Host Disease in Mouse Bone Marrow Transplantation', Biology of Blood and Marrow Transplantation, vol. 15, no. 12, pp. 1513-1522. https://doi.org/10.1016/j.bbmt.2009.08.013
Wang, Yang ; Li, Dan ; Jones, Dan ; Bassett, Roland ; Sale, George E. ; Khalili, Jahan ; Komanduri, Krishna V ; Couriel, Daniel R. ; Champlin, Richard E. ; Molldrem, Jeffrey J. ; Ma, Qing. / Blocking LFA-1 Activation with Lovastatin Prevents Graft-versus-Host Disease in Mouse Bone Marrow Transplantation. In: Biology of Blood and Marrow Transplantation. 2009 ; Vol. 15, No. 12. pp. 1513-1522.
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