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Role and expression of non-classical human leukocyte antigen-G in renal transplanted allografts

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Abstract

Background

The non-classical class I molecule human leukocyte antigen-G (HLA-G) has great potential to modulate the immune response. However, the mechanism underlying HLA-G induction remains unknown. Therefore, this study aimed to determine the factors that induce HLA-G expression on proximal tubular epithelial cells (pTECs) in renal transplanted allografts in vivo and in vitro.

Methods

This study included 40 adult Japanese patients with renal allografts (35 and five patients with kidneys from living and deceased donors, respectively) who survived for at least 1 year. We evaluated HLA-G1/5 expression using an immunofluorescence method and investigated the induction of HLA-G expression in primary cultured human pTECs by cytokines and immunosuppressants.

Results

The HLA-G expression was identified in the perinuclear region or on the basement membrane of pTECs of renal biopsy tissue in 12 (30%) of 40 patients at 2–4 weeks and at 1 year following transplantation. A reduction of 30% in the estimated glomerular filtration rate was lower in the HLA-G-positive group than that of the negative group (p = 0.016). Cox proportional hazard models also demonstrated that HLA-G1/5 expression on pTECs was an independent predictor of improved renal allograft function (hazard ratio, 0.189; 95% CI 0.041–0.850, p = 0.030). Interferon-beta was the most powerful inducer of HLA-G expression in vitro, whereas the immunosuppressants everolimus, tacrolimus, cyclosporin, and dexamethasone did not induce any expression.

Conclusion

Unlike immunosuppressants, acquired HLA-G expression might confer long-term renal preservation effects in renal transplanted allografts.

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Acknowledgements

The authors are grateful for the assistance of their colleagues at the Department of Nephrology.

Funding

This study was supported in part by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science, (C) 18K08256 (HY); Grants for Intractable Renal Disease Research and for Health and Labour Sciences Research from the Ministry of Health, Labour, and Welfare of Japan (HY); a Grant-in-Aid for Investigating New Evidence to Understand the safety of Renal Transplantation from marginal Donors; Promotion of Renal Disease Control Grants from the Japan Agency for Medical Research and Development (K Furuichi, HY); and Grants for a Cooperative Study from Kanazawa Medical University (No. C2017-4, C2018-2) (HY).

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Authors and Affiliations

  1. Department of Nephrology, Kanazawa Medical University School of Medicine, 1-1 Daigaku, Uchinada, Ishikawa, 920-0293, Japan

    Sho Kumano, Yuki Okushi, Keiji Fujimoto, Hiroki Adachi, Kengo Furuichi & Hitoshi Yokoyama

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  1. Sho Kumano
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  2. Yuki Okushi
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  3. Keiji Fujimoto
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  4. Hiroki Adachi
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  6. Hitoshi Yokoyama
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Contributions

SK drafted and wrote the manuscript with input as appropriate from the other investigators, interpreted clinical data, and conducted in vitro experiments. YO and HA performed kidney biopsies, and helped to collect clinical data. KF provided advice about the statistics for clinical research and in vitro experiments, and helped to collect clinical data. KF interpreted histopathological findings and edited the manuscript. HY designed the study and edited the manuscript.

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Correspondence to Sho Kumano or Hitoshi Yokoyama.

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The authors have declared that no conflict of interest exists.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee at which the studies were conducted (IRB approval number 186) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Supplementary Information

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10157_2020_1999_MOESM1_ESM.pptx

Supplementary file1 Supplementary Fig. 1 Characteristics of human primary cultured proximal tubular epithelial cells. Morphological characteristics of these cells were defined as cobblestone and/or tubular-like formations, cytokeratin 18 expression was detected using rabbit monoclonal E431-1 (a), alkaline phosphatase production detected using Vector Red AP substrate (b), HLA-G expression as green stain (Cytosol) and orange in cis-Golgi (c). Supplementary Fig. 2 HLA-G mRNA expression in primary cultured human proximal tubular epithelial cells. Expression of HLA-G mRNA cells was detected by RT-PCR. Positive control HLA-DR and control GAPDH (A); HLA-G mRNA RQ stimulated at 48 h with cytokines (B). The representative data of at least 3 times experiments was shown in figure (PPTX 2298 kb)

Supplementary file2 Supplementary Table. Changes in tissue expression of HLA-G (DOCX 20 kb)

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Kumano, S., Okushi, Y., Fujimoto, K. et al. Role and expression of non-classical human leukocyte antigen-G in renal transplanted allografts. Clin Exp Nephrol 25, 428–438 (2021). https://doi.org/10.1007/s10157-020-01999-1

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  • DOI: https://doi.org/10.1007/s10157-020-01999-1

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