CC Chemokine Receptor 2 Expression in Donor Cells Serves an Essential Role in Graft-versus-Host-Disease

Arun R. Rao, Marlon P. Quinones, Edgar Garavito, Yogeshwar Kalkonde, Fabio Jimenez, Caroline Gibbons, Jennifer Perez, Peter Melby, William Kuziel, Robert L. Reddick, Sunil K. Ahuja, Seema S. Ahuja

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

The complete repertoire of cellular and molecular determinants that influence graft-vs-host disease (GVHD) is not known. Using a well-established murine model of GVHD (B6→bm12 mice), we sought to elucidate the role of the donor non-T cell compartment and molecular determinants therein in the pathogenesis of GVHD. In this model the acute GVHD-inducing effects of purified B6 wild-type (wt) CD4+ T cells was inhibited by wt non-T cells in a dose-dependent manner. Paradoxically, unlike the chronic GVHD phenotype observed in bm12 mice transplanted with B6wt unfractionated splenocytes, bm12 recipients of B6ccr2-null unfractionated splenocytes developed acute GVHD and died of IFN-γ-mediated bone marrow aplasia. This switch from chronic to acute GVHD was associated with increased target organ infiltration of activated CD4+ T cells as well as enhanced expression of Th1/Th2 cytokines, chemokines, and the antiapoptotic factor bfl1. In vitro, ccr2-/- CD4+ T cells in unfractionated splenocytes underwent significantly less activation-induced cell death than B6wt CD4+ T cells, providing another potential mechanistic basis along with enhanced expression of bfl1 for the increased numbers of activated T cells in target organs of B6ccr2 -/- splenocyte→bm12 mice. Collectively, these findings have important clinical implications, as they implicate the donor non-T cell compartment as a critical regulator of GVHD and suggest that ccr2 expression in this cellular compartment may be an important molecular determinant of activation-induced cell death and GVHD pathogenesis.

Original languageEnglish (US)
Pages (from-to)4875-4885
Number of pages11
JournalJournal of Immunology
Volume171
Issue number9
DOIs
StatePublished - Oct 1 2003

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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