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CD30/CD30 Ligand (CD153) Interaction Regulates CD4⁺ T Cell-Mediated Graft-versus-Host Disease¹

Bruce R. Blazar^2,3,*, Robert B. Levy^2,, Tak W. Mak, Angela Panoskaltsis-Mortari^*, Hiromi Muta^4,, Monica Jones, Melinda Roskos, Jonathan S. Serody, Hideo Yagita^¶, Eckhard R. Podack and Patricia A. Taylor^*

^* Cancer Center and Department of Pediatrics, Division of Bone Marrow Transplantation, University of Minnesota, Minneapolis, MN 55455; University of Miami, Miami, FL 33101; Ontario Cancer Institute, Toronto, Ontario, Canada; Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599; and ^¶ Department of Immunology, School of Medicine, Juntendo University, Tokyo, Japan

CD30, a TNFR family member, is expressed on activated CD4⁺ and CD8⁺ T cells and B cells and is a marker of Hodgkin’s lymphoma; its ligand, CD30L (CD153) is expressed by activated CD4⁺ and CD8⁺ T cells, B cells, and macrophages. Signaling via CD30 can lead to proliferation or cell death. CD30-deficient (–/–) mice have impaired thymic negative selection and increased autoreactivity. Although human alloreactive T cells preferentially reside within the CD30⁺ T cell subset, implicating CD30 as a regulator of T cell immune responses, the role of CD30/CD153 in regulating graft-vs-host disease (GVHD) has not been reported. We used a neutralizing anti-CD153 mAb, CD30^–/– donor mice, and generated CD153^–/– recipient mice to analyze the effect of CD30/CD153 interaction on GVHD induction. Our data indicate that the CD30/CD153 pathway is a potent regulator of CD4⁺, but not CD8⁺, T cell-mediated GVHD. Although blocking CD30/CD153 interactions in vivo did not affect alloreactive CD4⁺ T cell proliferation or apoptosis, a substantial reduction in donor CD4⁺ T cell migration into the gastrointestinal tract was readily observed with lesser effects in other GVHD target organs. Blockade of the CD30/CD153 pathway represents a new approach for preventing CD4⁺ T cell-mediated GVHD.

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