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X. Li et al.
cated that HLA-G could induce DC into tolerogenic DC. As shown before, HLA-G exerts an immunosuppressive effect through interaction with ILT in humans. Interestingly, HLA-G could also interact with the murine receptor paired immunoglobulin-like inhibitory receptor (PIR-B), which is expressed on myeloid cell lineage and B lymphocytes, and triggers inhibitory signaling pathways. By binding with PIR-B, HLA-G aggregation could mimic the active polymeric structure found in vivo and has shown effectiveness in the context of allogeneic transplantation in mice.42 Moreover, the inhibitory ability of HLA-G poly- mers was about 100-fold higher than HLA-G monomer in arthritis mouse model.53 Here we demonstrated a single administration of HLA-G aggregated onto nanoparticles could alleviate thrombocytopenia in a murine model of ITP, further support the expectation of HLA-G as an immunosuppressive drug for autoimmune disease. PIR-B is absent on murine T and NK cells. Even though our in vitro study showed HLA-G could regulate T-cell differenti- ation, the HLA-G mediated effect on murine T and NK
Above all, the regulation of HLA-G and ILT expression is involved in the pathogenesis of ITP, and rhHLA-G could upregulate ILT expression and correct the dysfunction of immune cells. Several studies demonstrated that therapeu- tic reagents including dexamethasone and decitabine can induce HLA-G expression through different mecha- nisms.54,55 Our results also showed increased sHLA-G expression in patients responding to HD-DXM (Figure 1D). Moreover, Pedersen and colleagues56 found that dexamethasone combined with 1a, 25-Dihydroxyvitamin D3 induced ILT expression. Hence, whether HLA-G is
involved in HD-DXM response in ITP is worthwhile investigating in the future.
Conclusions
Decreased expression of HLA-G and ILT are involved in the immunopathogenesis of ITP. rhHLA-G upregulated HLA-G and ILT expression and corrected the dysfunction of immune cells in patients with ITP. Our study sheds new light on prognosis and treatment targeting HLA-G in the management of ITP.
Disclosures
No conflicts of interest to disclose.
Contributions
QF and JM designed the experiments, analyzed the data, and wrote the manuscript; XL and ZS performed the experiments, analyzed the data, and prepared the manuscript; JP, MH, HN evaluated the data and prepared the manuscript; MX corrected the manuscript; YS, YW, ZZ, HL, LS, YZ performed the exper- iment and analyzed data; JY, CM and CG analyzed data, and contributed to the manuscript preparation. All authors read and approved the final manuscript.
Acknowledgments
ZZ acknowledges the Qilu Young Scholar program for fun- ding.
Funding
This work was supported by grants from the Natural Science Foundation of China (81800112, 91942306, 81770133, 81500096, 81900124, 81770114 and 81500094), State Key Clinical Specialty of China for Blood Disorders, and Tai Shan Scholar Foundation. HN was funded by the Canadian Institutes of Health Research Foundation grant (389035). HL acknow- ledges the Chinese "post-doctoral international exchange pro- gram" for a post-doctoral scholarship. Limei Wang (Advanced Medical Research Institute/Translational Medicine Core Facility of Advanced Medical Research Institute, Shandong University) provided help in flow cytometry.
cells may be indirect.
Our data also demonstrated the safety of HLA-G pro-
tein (about 7.5 mg/per mouse) in the murine model of ITP. Liang et al.51 showed the effectiveness of HLA-G in indu- cing transplantation tolerance at a dosage of 20 ng per mouse. Kuroki et al.53 found HLA-G displayed significant anti-rheumatoid arthritis with a safety profile, even at a higher dose of 150 mg per mouse. Even though the optimal dosage of rhHLA-G used as a treatment option for ITP still needs to be further investigated, the recombinant HLA-G protein is expected to be safe in vivo.
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