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Stem cell transplantation

Selective targeting of α4β1 integrin attenuates murine graft versus host disease

Leukemia volume 34, pages 3100–3104 (2020)Cite this article

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In mixed lymphocyte reaction (MLR) assays using pan T cells, we found that α4(−/−) CD4+ T cells expressed more β1-integrin than WT T cells. In contrast, we observed a significant reduction in the expression of β7-integrin in both CD4 and CD8 subsets in α4(−/−) T cells compared with WT T cells (Supplementary Fig. 7A). Although these findings are consistent with a previous report, which showed that α4-integrin regulates the expression of β1 and β7-integrins [13], we are the first to show the α4-integrin-mediated regulation of β1 and β7-integrin expression as a consequence of allo-reactivity. We observed an alteration in some of the inhibitory and co-stimulatory molecules during allo-responses (Supplementary Fig. 7B, C). For example, PD-L1 expression was significantly reduced in α4(−/−) T cells compared with WT T cells but no difference in PD-1 expression. We tested the impact of α4-integrin deletion on the expression of T-cell differentiation markers in MLR assay using CD4+CD25− T cells (CD4+CD25+ Tregs were depleted). Compared with WT T cells, α4(−/−) T cells demonstrated decreased expression of IFNγR, T-bet, GATA3, and RORγt (Supplementary Fig. 8A), which is consistent with the previously reported role of α4β1 ligation in T-cell activation and differentiation into Th1 cells [14]. Interestingly, we observed a 3-fold decrease in FOXP3 expression in α4(−/−) T cells compared with WT T cells (p = 0.0462). However, in MLR assay using CD4+CD25+ Treg-replete pan T cells, we observed a modest increase (1.5-fold) in FOXP3 expression in CD4+ α4(−/−) T cells compared with WT T cells (p = 0.0013) (Supplementary Fig. 8B). These data suggest that deletion of α4 in T-cell population might result in the enhanced proliferation of pre-existing natural Tregs but restrict the generation of induced Tregs during allo-responses. Although deletion of α4 resulted in altered expression of T-cell activation and differentiation markers, there were no significant changes in overall T-cell proliferation (Supplementary Fig. 8C).

In summary, we demonstrate for the first time that genetic deletion of the α4-integrin gene in donor T cells or pharmacologic blockade of α4β1-integrin using BIO5192 results in significant improvement in GVHD and survival. In addition, α4(−/−) T cells have impaired trafficking to the GI tract. The anti-α4 monoclonal antibody, natalizumab, was explored in a clinical study for high-risk acute GVHD with promising activities [15]. Our current findings support future targeting of α4β1-integrin on donor T cells in the clinic for the prevention and treatment of GVHD.

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Fig. 1: α4(−/−) T cells reduce GVHD after major MHC-mismatched murine allo-HCT.
Fig. 2: Pharmacologic blockade of α4β1 mitigates murine GVHD post allo-HCT.

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Acknowledgements

JC is supported by Washington University SPORE-CDP (P50 CA171963-01), the Bryan Thomas Campbell Foundation, The Amy Strelzer Manasevit Research Program (Be The Match Foundation and National Marrow Donor Program), The Rays of Hope St. Baldrick’s Research Grant (St. Baldrick’s Foundation), and Alvin J. Siteman Cancer Center Siteman Investment Program (supported by the Foundation for Barnes-Jewish Hospital Cancer Frontier Fund, National Cancer Institute Cancer Center Support Grant, P30 CA091842, and Barnard Trust). JFD is supported by the National Cancer Institute (P50 CA94056-09, P50 CA171963-01, and R35 CA210084-01) and the Bryan Thomas Campbell Foundation. We thank Joel Eissenberg for critical reading of the manuscript.

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Authors and Affiliations

  1. Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO, 63110, USA

    Bader Alahmari, Matthew L. Cooper, Kiran Vij, Julie Ritchey, Peter Ruminski, Jaebok Choi & John F. DiPersio

  2. Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO, 63110, USA

    Feng Gao

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Contributions

JC and JFD conceived and supervised the project. BA, MLC, PR, JC and JFD designed the study. BA, JC and JFD wrote the manuscript. BA, MLC, JR and JC performed the experiments. KV performed histopathological examination. BA and FG performed statistical analyses. All authors were involved in the interpretation of data and preparation of this manuscript.

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Correspondence to Jaebok Choi or John F. DiPersio.

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Conflict of interest

JC received honorarium from Incyte Corporation, received research funding from Mallinckrodt Pharmaceuticals, and served as a consultant for Daewoong Pharmaceutical. JFD served on advisory boards for Incyte Corporation, CellWorks, Macrogenics, Amphivena, Arch, Rivervest, and Bioline and is a co-founder of Magenta Therapeutics and WUGen. Other authors declare that there is no conflict of interest.

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Alahmari, B., Cooper, M.L., Vij, K. et al. Selective targeting of α4β1 integrin attenuates murine graft versus host disease. Leukemia 34, 3100–3104 (2020). https://doi.org/10.1038/s41375-020-0786-0

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