title: Induction of mixed chimerism using combinatory cell-based immune modulation with mesenchymal stem cells and regulatory T cells for solid-organ transplant tolerance.
abstract: Establishment of mixed chimerism is an ideal approach to induce donor-specific tolerance while expanding its potential in various clinical settings. Despite the developments in partial conditioning regimens, improvements are still needed in reducing toxicity and bone marrow transplantation-related complications. Recently, cell-based therapies, including mesenchymal stem cells (MSCs), have been incorporated in establishing noncytoreductive mixed chimerism protocols; however, its efficacy is only partial and shows reversed immunosuppressive properties. This study demonstrates a novel approach to induce mixed chimerism and tolerance through combinatory cell-based immune modulation (CCIM) of MSCs and regulatory T cells (Tregs). We hypothesize that the interaction between these cells may lead to greater inhibition of host immune responses. Compared with single cell therapy, CCIM induced a higher engraftment rate and robust donor-specific tolerance to skin allografts across full major histocompatibility complex barriers. These regulatory effects were associated with inhibition of natural killer cell cytotoxic activity, CD4(+)IL-17(+) cells, memory B cells, plasma cells, and immunoglobulin production levels along with increased frequencies of CD4(+)Foxp3(+) cells, IL-10-producing mature B cells, and myeloid-derived suppressor cells. Furthermore, CCIM was able to regulate mortality in a graft-versus-host disease model through reciprocal regulation of Treg/Th17. Taken together, we suggest CCIM as a clinically applicable strategy for facilitating the induction of mixed chimerism and permanent tolerance.
authors.affiliation: 1 Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease, The Catholic University of Korea College of Medicine , Seoul, Korea.
authors.forename: Keon-Il
authors.initials: KI
authors.lastname: Im
authors.forename: Min-Jung
authors.initials: MJ
authors.lastname: Park
authors.forename: Nayoun
authors.initials: N
authors.lastname: Kim
authors.forename: Jung-Yeon
authors.initials: JY
authors.lastname: Lim
authors.forename: Hyun-Sil
authors.initials: HS
authors.lastname: Park
authors.forename: Sung-Hee
authors.initials: SH
authors.lastname: Lee
authors.forename: Young-Sun
authors.initials: YS
authors.lastname: Nam
authors.forename: Eun-Sol
authors.initials: ES
authors.lastname: Lee
authors.forename: Jung-Ho
authors.initials: JH
authors.lastname: Lee
authors.forename: Mi-La
authors.initials: ML
authors.lastname: Cho
authors.forename: Seok-Goo
authors.initials: SG
authors.lastname: Cho
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods; D005260:Female; D006085:Graft Survival / Q000276:immunology*; D006086:Graft vs Host Disease / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D008807:Mice, Inbred BALB C; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018183:Transplantation Chimera / Q000276:immunology*; D019172:Transplantation Conditioning / Q000379:methods