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Prevention of vascular-allograft rejection by protecting the endothelial glycocalyx with immunosuppressive polymers

Nature Biomedical Engineering volume 5, pages 1202–1216 (2021)Cite this article

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Abstract

Systemic immunosuppression for the mitigation of immune rejection after organ transplantation causes adverse side effects and constrains the long-term benefits of the transplanted graft. Here we show that protecting the endothelial glycocalyx in vascular allografts via the enzymatic ligation of immunosuppressive glycopolymers under cold-storage conditions attenuates the acute and chronic rejection of the grafts after transplantation in the absence of systemic immunosuppression. In syngeneic and allogeneic mice that received kidney transplants, the steric and immunosuppressive properties of the ligated polymers largely protected the transplanted grafts from ischaemic reperfusion injury, and from immune-cell adhesion and thereby immunocytotoxicity. Polymer-mediated shielding of the endothelial glycocalyx following organ procurement should be compatible with clinical procedures for transplant preservation and perfusion, and may reduce the damage and rejection of transplanted organs after surgery.

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Fig. 1: Surface engineering of the endothelial glycocalyx for transplant protection.
Fig. 2: CSE of the endothelial glycocalyx using gtTGase.
Fig. 3: Polymer-mediated CSE of endothelial monolayers reduces immune-cell-mediated cytotoxicity.
Fig. 4: Polymer-mediated CSE of endothelial monolayers inhibits activation of immune cells in co-cultures.
Fig. 5: Organ engineering via polymer-based CSE of blood vessel lumen prevents inflammation and immune-mediated damage that causes vascular rejection.
Fig. 6: Organ engineering via polymer-based CSE of blood vessel lumen imparts improved protection against ischaemia-mediated injury in a syngeneic renal transplant mouse model.
Fig. 7: Organ engineering via polymer-based CSE imparts improved protection against immune-mediated injury in an allogenic renal transplant mouse model.

Data availability

The main data supporting the results of this study are available within the Article and its Supplementary Information. The raw and analysed datasets generated during the study are too large to be publicly shared, but are available for research purposes from the corresponding authors on reasonable request. RNA sequencing data are available as Supplementary Information.

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Acknowledgements

We thank the Macromolecular Hub, CBR, for the use of their research facilities, and I. R. Nabi for access to the UBC imaging facility. We acknowledge funding from the Canadian Institutes of Health Research (CIHR; to J.N.K., J.C.C., CIHR FDN-154304 to M.K.L. and CIHR foundation grant to S.G.W.), the Natural Sciences and Engineering Council of Canada (NSERC; to J.N.K.), the Heart and Stroke Foundation of Canada (to J.C.C.) and the Canadian Glycomics Network of Centres of Excellence, GlycoNet. The infrastructure facility is supported by the Canada Foundation for Innovation (CFI) and the British Columbia Knowledge Development Fund (BCKDF). J.N.K. holds a Career Investigator Scholar award from the Michael Smith Foundation for Health Research (MSFHR). E.M.J.S. acknowledges support from a Centre for Blood Research graduate award. H.D.L. acknowledges funding from NSERC CGS-M, the NSERC CREATE NanoMat Program and NSERC PGS-D. H.M. acknowledges funding from the NSERC CREATE NanoMat Program and the Canadian Blood Services. M.K.L. receives a salary award from the BC Children’s Hospital Research Institute.

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  1. These authors contributed equally: Erika M. J. Siren, Haiming D. Luo.

Authors and Affiliations

  1. Centre for Blood Research, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, Canada

    Erika M. J. Siren, Haiming D. Luo, Haisle Moon & Jayachandran N. Kizhakkedathu

  2. Department of Chemistry, The University of British Columbia, Vancouver, British Columbia, Canada

    Erika M. J. Siren, Haiming D. Luo, Lyann Sim, Stephen G. Withers & Jayachandran N. Kizhakkedathu

  3. Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada

    Franklin Tam, Ashani Montgomery, Winnie Enns, Kevin Rey & Jonathan C. Choy

  4. Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, British Columbia, Canada

    Haisle Moon & Jayachandran N. Kizhakkedathu

  5. Department of Urologic Sciences, The University of British Columbia, Vancouver, British Columbia, Canada

    Qiunong Guan & Caigan Du

  6. Comprehensive Transplant Center, Northwestern University, Chicago, IL, USA

    Jiao-Jing Wang & Zheng J. Zhang

  7. BC Children’s Hospital Research Institute, Vancouver, British Columbia, Canada

    Christine M. Wardell, Mahdis Monajemi, Majid Mojibian & Megan K. Levings

  8. Department of Surgery, The University of British Columbia, Vancouver, British Columbia, Canada

    Christine M. Wardell, Mahdis Monajemi, Majid Mojibian & Megan K. Levings

  9. School of Biomedical Engineering, The University of British Columbia, Vancouver, British Columbia, Canada

    Megan K. Levings & Jayachandran N. Kizhakkedathu

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  1. Erika M. J. Siren
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Contributions

E.M.J.S., H.D.L. and J.N.K. designed the experiments and wrote the manuscript. E.M.J.S. and H.D.L. performed synthesis, cell culture work and analysed the data. H.M. performed cytokine analysis studies and analysed the data. F.T. and W.E. performed the skin-graft study and its analysis. L.S. provided sialic acid derivatives with supervision from S.G.W. A.M., W.E. and F.T. performed the vascular-allograft studies and A.M. and J.C.C. analysed the data. K.R. performed donor-specific antibody quantification under the supervision of J.C.C. C.M.W., M. Monajemi and M. Mojibian generated CAR T cells with supervision from M.K.L. J.-J.W. and Z.J.Z. performed syngeneic and allogeneic kidney-transplant studies and Q.G., C.D. and Z.J.Z. analysed the data. All authors contributed to editing the manuscript. J.C.C. provided supervision and grant support. J.N.K. conceived the project, and provided supervision and grant support for the project.

Corresponding authors

Correspondence to Jonathan C. Choy or Jayachandran N. Kizhakkedathu.

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Competing interests

The University of British Columbia has filed for patent protection on the technology described here. E.M.J.S., H.D.L., W.E., C.D., S.G.W., J.C.C. and J.N.K are named as inventors on the provisional patent application US63/213,322. The rest of the authors declare no competing interests.

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Peer review information Nature Biomedical Engineering thanks Nithin Joshi, James Paulson, Olivier Thaunat and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

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Supplementary Table 1

RNA-seq analysis of surface-modified endothelial cells.

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Siren, E.M.J., Luo, H.D., Tam, F. et al. Prevention of vascular-allograft rejection by protecting the endothelial glycocalyx with immunosuppressive polymers. Nat Biomed Eng 5, 1202–1216 (2021). https://doi.org/10.1038/s41551-021-00777-y

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