Submitted August 30, 2006
Accepted September 29, 2006
Donor-derived thymic-dependent T cells cause chronic graft-versus-host disease
Yukimi Sakoda, Daigo Hashimoto, Shoji Asakura, Kengo Takeuchi, Mine Harada, Mitsune Tanimoto, and Takanori Teshima*
Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, Fukuoka, Japan
Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan
Biopathological Science, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
Pathology, Japanese Foundation for Cancer Institute, Tokyo, Japan
Kyushu University Hospital, Japan
* Corresponding author; email: tteshima{at}cancer.med.kyushu-u.ac.jp.
Chronic graft-versus-host disease (GVHD) is the most common cause for poor long-term outcomes after allogeneic bone marrow transplantation (BMT). But the pathophysiology of chronic GVHD still remains poorly understood. We tested the hypothesis that the impaired thymic negative selection of the recipients will permit the emergence of pathogenic T cells that cause chronic GVHD. Lethally irradiated C3H/HeN (H-2k) recipients were reconstituted with T cell-depleted (TCD) bone marrow cells from MHC class II-deficient (H2-Ab1-/-) B6 (H-2b) mice. These mice developed diseases that showed all of the clinical and histopathological features of human chronic GVHD. Thymectomy prevented chronic GVHD, thus confirming the causal association of the thymus. CD4+ T cells isolated from chronic GVHD mice were primarily donor-reactive and adoptive transfer of CD4+ T cells generated in these mice caused chronic GVHD in C3H/HeN mice in the presence of B6-derived antigen presenting cells. Our results demonstrate for the first time that T cells which escape from negative thymic selection could cause chronic GVHD after allogeneic BMT. These results also suggest that self reactivity of donor T cells play a role in this chronic GVHD and improvement in the thymic function may have a potential to decrease chronic GVHD.
