Interaction Between Donor Mesenchymal Stem Cells And Recipient-derived T Cells In The Pathogenesis Of Ocular Chronic Graft Versus Host Disease

Abstract

Purpose: : We have recently reported mismatched mesenchymal stem cells (MSCs) can trigger ocular chronic graft-versus-host disease (cGVHD). In this study, we investigated the origin of T cells interacting with mismatched donor MSCs in cGVHD lacrimal gland and ocular surface tissue after mismatched transplantation.

Methods: : In order to establish the role of recipient-derived T cells, we transplanted prospectively isolated MSCs and HSCs. B10.D2 mice were used mismatched donor MSCs. We used BALB/c background RAG2KO mice that lack T and B cells as recipient/donors. The expression levels of IL-6, a fibrogenic cytokine, in supernatant of co-cultures using various sources of T cells (from mismatched MSC-transplanted, autologous MSC-transplanted, wild type B10.D2 or wild type BALB/c) with freshly isolated MSCs (from BALB/c or B10.D2) were measured. We further evaluated the recipient T cells in the peripheral blood from human cGVHD and non GVHD recipients by using Y and X chromosome fluorescein in situ hybridization.

Results: : At 3 weeks after transplantation, mismatched MSCs did not mediate progressive fibrosis in lacrimal gland and ocular surface from RAG2KO mice recipients, indicating that mismatched MSCs alone do not induce clinical signs of cGVHD without competent recipient-derived T cells. Typical signs of tissue fibrosis were observed when the same combination of donor cells (B10.D2 MSCs + RAG2KO SP) were transplanted into BALB/c recipient mice confirming the role of recipient T cells. The level of IL-6 in supernatants of co-cultures was greatest when T cells from mismatched MSC recipients (BALB/c origin) were co-cultured with freshly isolated B10.D2 MSCs, however, a similar increase in IL-6 was observed using autologous BALB/c MSCs. These results clearly show that mismatched MSCs can activate host T cells in vivo, leading to the contrasting proliferation in vitro. Percentage of recipient derived T cells was significantly higher in the PBMC from cGVHD patients than from non GVHD patients.

Conclusions: : These results suggest that host T cells may be involved in the auto-immune phenotype observed in ocular cGVHD.

Keywords: cell-cell communication • lacrimal gland • immunomodulation/immunoregulation