Korean J Transplant.  2023 Nov;37(Suppl 1):S268. 10.4285/ATW2023.F-8702.

Interspecies incompatibility of CD200 contribute to the xenogeneic immune response

• Kim B
• Yan JJ
• Lee WB
• Kang TK
• Kim BS
• Yang J

• KMID: 2551897
• DOI: http://doi.org/10.4285/ATW2023.F-8702

Abstract

Background
CD200 is a cell surface glycoprotein that suppresses the xenogeneic immune response, including vascular xenograft rejection. In pig-to-human organ xenografts, the functional and molecular incompatibility between pig CD200 and human CD200R is believed to contribute to dysregulated immune xenoresponse.
Methods
To investigate this, we conducted an in vitro study examining the effect of human CD200 and pig CD200 on the xenoimmune interaction between pig endothelial cells (pECs) and human macrophages.
Results
Both hCD200 and pCD200 in pECs were found to suppress the phagocytic activity of macrophages against pECs. The presence of hCD200 in pECs further suppressed the cytotoxic activity and led to a decrease in the secretion of M1-associated macrophage cytokines, such as tumor necrosis factor-alpha, interleukin (IL)-1beta, and interferon-gamma. Additionally, hCD200 reduced the expression of M1-associated macrophage polarization markers, including iNOS, Dectin-1, and CD86. However, there was no significant change observed in the secretion of the M2-related cytokine IL-10 or the expression of M2 phenotype markers, CD163 and CD206. In contrast, pCD200 did not exhibit any inhibitory effect on cytotoxicity, and it did not significantly affect the expression or activation of M1 or M2 associated markers. In response to CD200-CD200R signaling, we investigated Dok2 phosphorylation in macrophages and observed an increase in Dok2 phosphorylation in the presence of hCD200 compared to the control. Additionally, we confirmed a reduction in AKT phosphorylation and IKB degradation. However, these changes were not observed in the presence of pCD200.
Conclusions
These results suggest that hCD200 suppresses xenogeneic immune responses via the CD200-CD200R signaling pathway, while pCD200 exhibits weaker inhibitory effects due to its inadequate binding to the CD200R receptor in comparison to hCD200, and pCD200 may not be compatible with the CD200R binding process. The genetic induction of human CD200 on pig cells could offer a novel approach for mitigating macrophage-mediated xenograft rejection.