Mesenchymal Stem Cells Relieve Chronic GVHD Via Modulation the Ratio of CD8+CD28-/CD8+CD28+T Cells.

Abstract 4501

Chronic graft-versus-host disease (GVHD) is a major complication of allogeneous hematopoietic stem cell transplantation, and it is regarded as a type of Th2 disease and seems to be a T-cell-mediated disorder in which immune tolerance to self-antigens is broken. Mesenchymal stem cells (MSCs) are multipotent cells which can extenuate refractory (GVHD) have been recently reported; however, the clinical data on MSC relieves chronic GVHD are generally lacking, and the machanisms remain to be investigated. One area of recent interest and controversy is the role of regulatory T cells (CD4+/CD25high T cells) in chronic GVHD. We examined the lymphocyte subsets and regulatory T cells of patients with refractory chronic GVHD were treated with basic immunosuppression plus MSCs derived from volunteer donors. Between April 2005 and October 2008, 19 patients were treated with their basic immunosuppression plus in vitro expanded bone-marrow-derived MSC as a compassionate treatment for resistant chronic GVHD. The median MSC dose given was 0.6×10⁶/kg per body weight. Flow cytometric analysis was perfromed to analysis lymphocyte composition and activation at the time before MSC infusion(pre-MSC) and 3 months after MSC infusion (post-MSC). The study was approved by the Ethics Committee of the Guangdong General Hospital. All patients and the MSC donors provided written informed consent. In the present study, there were no significant changes in the proportion of T cells, B cells, NK cells and activation in no-response patients between pre-MSC and post-MSC. In the patients with response, the total lymphocyte was greater post-MSC transfusion than pre-MSC transfusion, and the proportion of CD4+ T cells were increased CD+8 T cells were decreased (the P value was 0.001 and 0.018, respectively). However, the proportion of CD4+CD25+ T cell and CD8+CD25+ T cells hadn't significantly changed post-MSC transfusion compared to pre-MSC infusion in patients with response. The T lymphocyte subsets of CD8+CD28+ cells, which are active CTLs that participate transplantation immunity and rejection reaction, were down-regulated when the chronic GVHD improved post-MSC infusion (P=0.023). By contrast, CD8+CD28- cells, which regulate cells to induce immune tolerance and inhibit antibody production and imbalance in the production of Th1 and Th2 cytokines, were increased in patients responsed to MSC infusion (P=0.025), and the ratio of CD8+CD28- cells to CD8+CD28+ was increased. Importantly, the increase of CD8+CD28- T cells and decrease of CD8+CD28+ T cells with improvement of cGVHD indicate that these factors may be involved in the development of chronic GVHD and that MSC suppresses chronic GVHD via modulation of the ratios of CD8+CD28- to CD8+CD28+ T cells. However, further immunological studies specifically addressing this issue are needed to confirm this possibility.

This work was supported by Science and Technology Planning Project of Guangdong Province (2006B36005003,2007A032100003) and Science and Technology Planning Project of Guangzhou (2006Z2-E4071,2008A1-E4011-4,2008A1-E4011-5).