619. Immunogenicity and Immunomodulatory Effects of the Allogeneic Human Chondrocytes, hChonJ

Abstract

Osteoarthritis is one of the most frequently occurring degenerative diseases in elderly people. The degeneration of articular cartilage is the leading cause of osteoarthritis. However, damaged articular cartilage has a limited capability to heal itself. As one way to overcome this barrier, we have developed TissueGene-C (TG-C, Invossa™) which is a cell-mediated gene therapy for the regeneration of the cartilage tissue. Invossa™ is a mixture of non-transduced human chondrocytes (hChonJ cells) and retrovirally transduced chondrocytes (hChonJb#7 cells), respectively. Since the hChonJ cells are allogeneic, the possibility of immune rejection has been raised. In this study, we investigated the immunological properties of hChonJ cells. First, we showed that hChonJ cells did not express T cell co-stimulatory molecules CD80 and CD86, but expressed the co-inhibitory molecule CD 273 (PD-L2). Even when hChonJ cells were exposed to a pro-inflammatory cytokine IFN-gamma, they did not express co-stimulatory molecules. IFN-gamma treatment induced the expression of CD274 (PD-L1), and up-regulated the expression of PD-L2. Second, we observed that hChonJ cells did not stimulate T cell proliferation with PBMCs from a MHC-mismatched donor. Further, they could suppress the proliferation of activated T cells. We reasoned that co-inhibitory molecules PD-L1 and PD-L2 play an immunosuppressive role against activated T cells, (figure 1) and we demonstrated that the blockade of PD-L1 and/or PD-L2 with specific neutralizing antibody could lead to the restoration of allo-reactive T cell proliferation. In conclusion, we showed that hChonJ cells are not immunogenic but immunosuppressive, and that this phenomenon is mediated by co-inhibitory molecules PD-L1 and PD-L2 on hChonJ cells in a contact-dependent manner. Therefore, because hChonJ cells do not elicit alloantigen-specific T cell proliferation and suppress alloreactive T cells, these findings indicate that allogeneic hChonJ cells might be appropriate for osteoarthritis therapeutics.