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Alloreactive T Cells Display a Distinct Chemokine Profile in Response to Conditioning in Xenogeneic GVHD Models

Kawasaki, Yasufumi MD, PhD1; Sato, Kazuya MD, PhD1; Nakano, Hirofumi MD1; Hayakawa, Hiroko PhD2; Izawa, Junko1; Takayama, Norihito1; Mashima, Kiyomi MD, PhD1; Oh, Iekuni MD, PhD1; Minakata, Daisuke MD1; Yamasaki, Ryoko MD1; Morita, Kaoru MD, PhD1; Ashizawa, Masahiro MD1; Yamamoto, Chihiro MD, PhD1; Hatano, Kaoru MD, PhD1; Fujiwara, Shin-ichiro MD, PhD1; Ohmine, Ken MD, PhD1; Muroi, Kazuo MD, PhD1; Ito, Ryoji PhD3; Hayakawa, Morisada PhD4; Ohmori, Tsukasa MD, PhD4; Kanda, Yoshinobu MD, PhD1

doi: 10.1097/TP.0000000000002756
Original Basic Science—General
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Background. Chemokines and chemokine receptors are potential targets for the prevention and treatment of graft-versus-host disease (GVHD). The objective of the current study is to determine the clinical relevance of xenogeneic transplantation models in terms of host and donor chemokine profiles and, if this is the case, to assess the clinical efficacy of C–C chemokine receptor (CCR) 5 antagonist maraviroc for the prevention of GVHD using this model.

Methods. Xenogeneic GVHD was induced by intravenous injection of 5 × 106 human pan T cells into NOD/Shi-scid-IL2rγnull (NOG) mice or MHC class I/II-deficient NOG mice in the presence or absence of total body irradiation before transplantation.

Results. Extensive tissue destruction with human T-cell infiltration was observed throughout the body, particularly in lungs and liver, but relatively mild in gut. Consistent with this finding, quantitative polymerase chain reaction confirmed the upregulation of mouse CXC chemokine ligand (CXCL) 9 and CXCL10 in lungs and CCL4 in lungs and liver but not in gut. The addition of total body irradiation (1) led to the early release of mouse CCL4 and CXCL10, (2) upregulated a number of chemokine-related genes in human T cells, (3) induced higher expression of CCR5 on human CD4+ and CD8+ T cells and CXCR3 on human CD4+ T cells, and (4) promoted their migration and proliferation in organs, resulting in more severe tissue damage. In this context, pharmacological CCR5 blockade neither ameliorated GVHD nor prolonged survival in NOG mice.

Conclusions. Our experimental data do not demonstrate clinical benefit of CCR5 antagonist for the prevention of GVHD in a myeloablative setting.

1 Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi, Japan.

2 Core Center of Research Apparatus, Jichi Medical University, Tochigi, Japan.

3 Central Institute for Experimental Animals, Kawasaki, Kanagawa, Japan.

4 Department of Biochemistry, Jichi Medical University, Tochigi, Japan.

Received 25 January 2019. Revision received 12 March 2019.

Accepted 26 March 2019.

The authors declare no funding or conflicts of interest.

Y.K. performed experiments, acquired and analyzed the data, and edited the manuscript. K.S. designed the research, analyzed the data, and wrote the manuscript. H.N., H.H., J.I., N.T., K.M., I.O., D.M., R.Y., K.M., M.A., C.Y., K.H., S.F., K.O., and K.M. performed experiments and provided guidance. R.I. and T.O. supervised the research and contributed to manuscript writing. Y.K. designed and supervised the research and edited the manuscript. K.S. designed the research, analyzed the data, and wrote the manuscript.

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

Correspondence: Yoshinobu Kanda, MD, PhD, Division of Hematology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan. (ycanda-tky@umin.ac.jp).

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