The laboratory of VISICORT researcher Prof. Thomas Ritter has demonstrated that intravenous infusion of mesenchymal stem cells (MSCs) can reduce the rate of rejection of experimental corneal transplants (Treacy et al., Am J Transplant. 2014 Sep;14(9):2023-36) and we are now actively working toward performing a clinical trial of MSCs in human corneal transplant recipients at high risk for rejection. One of the most important research questions regarding MSC therapies in corneal transplantation and other immunological conditions relates to the fact that these cells can exert long-lasting effects on the immune system while persisting in the body for only 1 or 2 days after administration. An important new study from the Department of Ophthalmology at Seoul National University Hospital, South Korea (Ko et al., Proc. Natl. Acad. Sci. USA, 2016 Jan 5;113(1):158-63) has shed new light on this question.
“Regulatory immune cells may be critically important to promote improved survival of an allograft such as a corneal transplant. One such immune cell population is myeloid cells including regulatory monocytes and macrophages. In this paper, Ko and colleagues aimed to investigate whether MSC-educated myeloid cells can induce immune tolerance to allogeneic corneal transplants and to determine the mechanism by which this might occur.
The authors administered one million human MSC intravenously to mice 7 and 3 days prior to transplantation of corneas from an unrelated mouse strain. The results showed that MSC-treated transplant recipients had improved rejection-free graft survival compared to non-MSC treated recipients. Additionally, human MSC-treated recipients had less inflammation in the grafts and draining lymph nodes, a more intact corneal endothelium, and less corneal oedema. However, the authors did not attribute these effects to MSCs migrating to the site of transplantation and acting directly on the rejection process as less than 10 MSCs per cornea were detectable. Therefore it appeared likely that the immune modulatory effects of intravenous MSCs take place elsewhere in the body.
The authors found an increased percentage of myeloid cells co-expressing the surface marker combination MHC-II, B220 and CD11b in the lungs of animals treated with human MSCs. To investigate if these cells had the ability to modulate an immune response leading to corneal transplant rejection, B220+ and B220– myeloid cells were isolated from the lungs of human MSC-treated mice. When these isolated lung cells were cultured with stimulated T cells, it was found that B220+ cells significantly suppressed T cell activity, thereby confirming their immune regulatory potential. They next transferred B220+ myeloid cells to mice at the time of a corneal transplant and found that they resulted in a significantly increased rate of rejection-free survival. Furthermore, human MSC administration failed to prevent corneal transplant rejection in mice lacking myeloid cells.
Previous studies have indicated that MSC therapeutic effects are mediated through secretion of soluble molecules. The authors of this study found that expression of a gene known as TSG-6 was increased in the lungs of human MSC-treated corneal transplant recipient mice. The involvement of TSG-6 in generating regulatory myeloid cells was confirmed by the observation that blocking production of TSG-6 in human MSCs prevented the increase of B220+ cells in the lungs of treated mice.
This study provides an explanation for a paradox in the MSC field, i.e. the fact that MSCs only survive a matter of hours or days in the recipient but can have long-lasting effects in immunological diseases. If a similar mechanism occurs in human transplant recipients, then it will represent a powerful new approach to preventing rejection.”