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 journalArticle

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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
StatePublished - Oct 1 2003

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CCR2 Receptors
Graft vs Host Disease
T-Lymphocytes
Cell Death
Chemokines
Bone Marrow
Cytokines

ASJC Scopus subject areas

  • Immunology

Cite this

Rao, A. R., Quinones, M. P., Garavito, E., Kalkonde, Y., Jimenez, F., Gibbons, C., ... Ahuja, S. S. (2003). CC Chemokine Receptor 2 Expression in Donor Cells Serves an Essential Role in Graft-versus-Host-Disease. Journal of Immunology, 171(9), 4875-4885.

CC Chemokine Receptor 2 Expression in Donor Cells Serves an Essential Role in Graft-versus-Host-Disease. / Rao, Arun R.; Quinones, Marlon P.; Garavito, Edgar; Kalkonde, Yogeshwar; Jimenez, Fabio; Gibbons, Caroline; Perez, Jennifer; Melby, Peter; Kuziel, William; Reddick, Robert L.; Ahuja, Sunil K; Ahuja, Seema S.

In: Journal of Immunology, Vol. 171, No. 9, 01.10.2003, p. 4875-4885.

Research output: Contribution to journalArticle

Rao, AR, Quinones, MP, Garavito, E, Kalkonde, Y, Jimenez, F, Gibbons, C, Perez, J, Melby, P, Kuziel, W, Reddick, RL, Ahuja, SK & Ahuja, SS 2003, 'CC Chemokine Receptor 2 Expression in Donor Cells Serves an Essential Role in Graft-versus-Host-Disease', Journal of Immunology, vol. 171, no. 9, pp. 4875-4885.
Rao AR, Quinones MP, Garavito E, Kalkonde Y, Jimenez F, Gibbons C et al. CC Chemokine Receptor 2 Expression in Donor Cells Serves an Essential Role in Graft-versus-Host-Disease. Journal of Immunology. 2003 Oct 1;171(9):4875-4885.
Rao, Arun R. ; Quinones, Marlon P. ; Garavito, Edgar ; Kalkonde, Yogeshwar ; Jimenez, Fabio ; Gibbons, Caroline ; Perez, Jennifer ; Melby, Peter ; Kuziel, William ; Reddick, Robert L. ; Ahuja, Sunil K ; Ahuja, Seema S. / CC Chemokine Receptor 2 Expression in Donor Cells Serves an Essential Role in Graft-versus-Host-Disease. In: Journal of Immunology. 2003 ; Vol. 171, No. 9. pp. 4875-4885.
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