© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
Wild-type but not interferon-
-deficient T cells induce graft arterial disease in the absence of B cells
aLeducq Center for Cardiovascular Research, Cardiovascular Division, Department of Medicine, USA
bImmunology Research Division, Department of Pathology, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, NRB 730D, Boston, MA 02115, USA
* Corresponding author. Tel.: +1-617-525-4303; fax: +1-617-525-4329. Email address: rmitchell{at}rics.bwh.harvard.edu
Objective: Interferon-
(IFN-), a cytokine produced primarily by T cells and by activated macrophages, plays a central role in the pathogenesis of graft arterial disease (GAD). This study investigated whether T cells can induce GAD in the absence of humoral alloresponses and whether activated macrophages or other host cell types can substitute as sources of IFN- in GAD. Methods: Wild-type (WT), IFN-–/–, or recombination-activating-gene-1–/– (RAG-1–/–; lacking mature T and B cells) mice received MHC II-disparate hearts. The grafts were harvested 8 weeks post-transplant and histological and immunohistochemical analyses, RNase protection assay (RPA), and flow cytometry were used to evaluate GAD lesions, infiltrating cell populations, and IFN- expression by infiltrating cells. Results: Moderate-to-severe GAD developed in WT recipient allografts, associated with abundant IFN- expression by both infiltrating T cells and macrophages. No GAD developed in IFN-–/– or in RAG-1–/– hosts, nor was any IFN- expression evident. RAG-1–/– hosts receiving naïve WT or IFN-–/– T cells (107) after heart transplantation demonstrated no mature B cells but showed persistence of transferred T cells up to 8 weeks post-transplant. In the complete absence of B cells and alloantibody, transfer of WT T cells into RAG-1–/– recipients yielded GAD, with associated IFN- expression by the transferred T cells and the host macrophages. Transfer of IFN-–/– T cells induced neither GAD nor host macrophage IFN- expression. Conclusions: T cells, even in the absence of B cells, suffice to induce GAD, and T cell-derived IFN- plays a critical role in GAD pathogenesis.
KEYWORDS Transplantation; Leukocytes; Cytokines; Atherosclerosis
1 Current address: Dr. Yutaka Furukawa, Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Kawaharacho, Sakyo-ku, Kyoto 606-8097, Japan.
2 Current address: Dr. Yoshihiro Fukumoto, Department of Cardiovascular Medicine, Kyushu University Graduate School of Medicine, Fukuoka, Japan.