The Bio-Signals of Mesenchymal Stem Cells Induce Immuno-Modulation and Prolong Allograft Survival in Composite Tissue Allotransplantation

Composite tissue allo-transplantation (CTA) (included skin, muscle, peripheral nerve, or even bone and joint) has tremendous potential application for reconstructive surgery. However, the practice of CTA is currently limited by the risks of the side effects resulting from therapeutic immunosuppression used to prevent graft failure. Tolerance induction could potentially eliminate graft rejection without the long-term immunosuppressants. In our previous study (NSC 95-2314-B-182A-036-MY3); we used orthotopic hind-limb transplants as a rodent model. We have found that treatment with donor alloantigen-pulsed recipient immature dendritic cells (DC) in combination with transient immunosuppression effectively prolonged CTA survival by inducing T-cell regulation. However, matured DC is strong antigen presenting cells (APC) and highly potent immuno-stimulatory cells to induce allograft rejection. Therefore, how to modulate the DC maturation might be the key role for clinical application. Studies have shown that mesenchymal stem cells (MSCs) inhibit T-cell proliferation and prolong skin allograft survival. Our recent study revealed that MSCs combined with irradiation and short term immunosuppressant have a positive effect in prolongation of CTA survival by using miniature swine CTA model (Transplantation, 2008, in revision). However, the role of MSC in this experiment has not yet been elucidated because porcine antibody or related-cytokine assay is rarely available. Furthermore, the bio-mechanisms of MSCs induced immune tolerance in CTA survival are still unclear. Recent study demonstrated that MSC could inhibit maturation and migration of the DC in vitro. Therefore, these proposals are aimed to investigate whether MSCs prolong allograft survival in a rodent hind-limb CTA model. In contrast, we propose MSCs could modulate DC maturation and regulation of T-cells proliferation to prolong allograft survival. We also investigate the bio-signals of potential immuno-modulatory effects of MSC in terms of immune tolerance. The scheme and specific aims are as follows: First year: 1. To investigate the role of MSCs as an immunosuppressive therapy in a rodent CTA model (in vivo). 2. To investigate the localization and migration of MSCs in a rodent CTA model. 表 C011 共 2 頁第 1 頁 Related cytokine Mesenchymal (e.g. TGF-β, IL-10 etc) stem cells Composite tissue allotransplantation APC (DC) Immune tolerance and allograft survival Treg –cells Second year: 3. To detect whether MSCs could modulate DC maturation (in vitro) 4. To detect the bio-mechanisms of MSCs in regulation of T-cells function and related-cytokine expressions (e.g. IL-4, IL-10, IL-12, TGF-β, PGE2, IFN-γ etc) (in vivo and in vitro studies) Third years 5. To investigate the role of interferon-γ (IFN-γ) and indoleamine 2, 3-dioxygenase (IDO) in the immuno-modulatory effect of MSCs-induced T-cells regulation. 6. To investigate the bio-signal pathway on MSCs could drive the immuno-modulating response in CTA Results obtained from this project will provide important information regarding the bio-mechanisms and effects of MSCs in tolerance induction of CTA.

Project ID:PC10001-0135
External Project ID:NSC98-2314-B182A-102-MY3