Objective: To analyze the mechanisms of surrogate tolerogenesis induced by chimeric donors.
Methods: Hematopoietic stem cells (HSCs) from human cord blood were transplanted into fetal rats via intrauterine injection and infused into the liver of the neonatal rats to establish chimeric rat models with human HSCs. Four weeks after birth, flow cytometry was performed to analyze the percentages of human CD45 (hCD45), CD55 (hCD55) and CD59 (hCD59)-positive cells in the peripheral blood cells of the chimeric rats. The distributions of hCD55- and hCD59-positive cells in different hCD45/SSC gating regions were observed. The resistance of the peripheral blood lymphocytes to complements-mediated cytolysis was assessed by complement-dependent cytotoxicity (CDC) test in the chimeric rats and compared with that in control rats. The correlation between CDC and the human complement-regulating proteins in the chimeric rats were analyzed statistically.
Results: On hCD45/SSC gating, the percentages of hCD55- and hCD59-positive cells in hCD45-positives region were (53.69-/+18.23)% and (31.8-/+27.5)%, accounting for (2.0-/+1.32)% and (0.76-/+0.56)% of the total cell population, respectively, which were significantly lower than the cell percentages in the extensive region (t=2.71, P=0.043 and t=3.64, P=0.015). The cytolytic rate of PBLs incubated with normal human serum was (22.32-/+15.10)% in the chimeric rats, significantly lower than that in the non-chimeric rats [(60.7-/+22.65)%, t=4.16, P<0.001). In the chimeric rats, hCD55-positive cell percentage was inversely correlated in the peripheral blood karyocytes the cytolysis rate in CDC (r=-0.679, P=0.031), and positively correlated to hCD45-positive cell percentage (r=0.658, P=0.038).
Conclusion: The hCD45-positives region is the cluster of chimeric human cells expressing human complement-regulating proteins. The peripheral blood lymphocytes from chimeric donor can resist the cytolysis mediated by human complement. The presence of allogenic CD55 and CD59 antigens in chimeric donors may be the basis of surrogate tolerogenesis for xenotransplantation.
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