Multilineage mixed hematopoietic chimerism induces tolerance to alloantigens in rodents, large animals and kidney-transplanted patients. Here we combined mixed chimerism with neural stem cell (NSC) transplantation to determine whether tolerance of alloantigens will extend to autoantigens involved in experimental autoimmune encephalomyelitis (EAE) in mice, a model relevant to multiple sclerosis (MS). Using 6-week old female SJL mice, we induced EAE with proteolipid peptide (PLP) 139-151 in Complete Freund's Adjuvant. Upon entering the first remission from disease, we induced mixed chimerism using CD8⁺ T cell depletion, 3 Gy total body irradiation, anti-CD40L antibodies and infusion of 30×10⁶ bone marrow cells (BMT) from C57BL/6 donors.

Thirty days post-BMT, mice in the treatment group received 1×10⁶ C57BL/6 NSCs. Sixty days post-BMT, the mice were reimmunized with PLP139-151. Mice were divided into four groups: Control conditioning, NSCs alone, mixed chimerism alone, and NSCs + mixed chimerism. All sham treated and NSC alone-injected mice (n= 6 and 7 respectively), as well as one third of mice (n = 14) treated by induction of mixed chimerism alone, experienced EAE relapses. In contrast, none of the mice (n= 8) treated with combined mixed chimerism and NSCs displayed relapses.

Furthermore, upon reimmunization, mixed chimeras that had received NSCs had a significant delay in disease onset, and significantly less severe disease than mice treated by mixed chimerism alone. Therefore, combining NSC transplantation along with induction of mixed chimerism significantly increases the strength and durability of self-tolerance in this autoimmune disease model.

CITATION INFORMATION: Orent W, Marino J, Gonzalez Nolasco B, Paster J, Harney A, Sachs D, Benichou G. Combining Neural Stem Cell Transplantation with Mixed Hematopoietic Chimerism Promotes Restoration of Self-Tolerance in Established Experimental Autoimmune Encephalomyelitis. Am J Transplant. 2017;17 (suppl 3).

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