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Breaking of CD8⁺ T Cell Tolerance through In Vivo Ligation of CD40 Results in Inhibition of Chronic Graft-versus-Host Disease and Complete Donor Cell Engraftment¹

Juyang Kim^*, Keunhee Park, Hyun J. Kim, Jiyoung Kim, Hyun-A Kim, Daehee Jung, Hye J. Kim, Hye-Jeong Choi, Suck-Young Choi, Kwang W. Seo^,¶, Hong R. Cho^2,*,|| and Byungsuk Kwon^2,*,

^* Biomedical Research Center, Ulsan University Hospital, School of Medicine; Department of Biological Science; Department of Food Nutrition; and Department of Pathology, ^¶ Department of Internal Medicine, and ^|| Department of Surgery, Ulsan University Hospital, School of Medicine, University of Ulsan, Ulsan, Republic of Korea

In the DBA/2 unirradiated (C57BL/6 x DBA/2)F₁ model of chronic graft-vs-host disease (cGVHD), donor CD4⁺ T cells play a critical role in breaking host B cell tolerance, while donor CD8⁺ T cells are rapidly removed and the remaining cells fall into anergy. Previously we have demonstrated that in vivo ligation of GITR (glucocorticoid-induced TNF receptor-related gene) can activate donor CD8⁺ T cells, subsequently converting the disease pattern from cGVHD to an acute form. In this study, we investigated the effect of an agonistic mAb against CD40 on cGVHD. Treatment of anti-CD40 mAb inhibited the production of anti-DNA IgG1 autoantibody and the development of glomerulonephritis. The inhibition of cGVHD occurred because anti-CD40 mAb prevented donor CD8⁺ T cell anergy such that subsequently activated donor CD8⁺ T cells deleted host CD4⁺ T cells and host B cells involved in autoantibody production. Additionally, functionally activated donor CD8⁺ T cells induced full engraftment of donor hematopoietic cells and exhibited an increased graft-vs-leukemia effect. However, induction of acute GVHD by donor CD8⁺ T cells seemed to be not so apparent. Further CTL analysis indicated that there were lower levels of donor CTL activity against host cells in mice that received anti-CD40 mAb, compared with mice that received anti-GITR mAb. Taken together, our results suggest that a different intensity of donor CTL activity is required for removal of host hematopoietic cells, including leukemia vs induction of acute GVHD.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Korea Research Foundation (C00088, E00010, and J00302) and the Korea Health 21 Research and Development project of the Korean Ministry of Health and Welfare (A040004).

² Address correspondence and reprint requests to Dr. Byungsuk Kwon and Dr. Hong R. Cho, Department of Biological Science, University of Ulsan, San 29 Mukeo-dong Nam-ku, Ulsan, Ulsan 680-749, Republic of Korea. E-mail addresses: bkwon{at}mail.ulsan.ac.kr and hrcho{at}mail.ulsan.ac.kr

³ Abbreviations used in this paper: GVHD, graft-vs-host disease; BDF₁, (C57BL/6 x DBA/2)F₁; cGVHD, chronic GVHD; aGVHD, acute GVHD; DC, dendritic cell; AICD, activation-induced cell death; GITR, glucocorticoid-induced TNF receptor-related gene; GVL, graft-vs-leukemia.