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We hypothesized that immunomodulatory properties of mesenchymal stromal cells (MSC) may be considered for desensitization.Autologous or allogeneic bone marrow derived MSC were infused via tail vein at 0.5 M (0.5 × 106), 1 M, or 2 M cells/dose on days −2, 3, 6, 9, 12 (prevention) or 14, 17, 20, 23, 26 (treatment) relative to transfusion in a Brown Norway to Lewis rat model (10 groups total, n = 6 per group).At 4 weeks, pooled analyses demonstrated that autologous and allogeneic MSC were equally effective in reducing IgG1 and IgG2a de novo donor-specific antibody (dnDSA, P < 0.001). Dose-response studies indicated that moderate-dose MSC (5 M total) was most effective in reducing IgG1, IgG2a, and IgG2c dnDSA (P ≤ 0.01). Time course studies determined that preventive and treatment strategies were equally effective in reducing IgG1 and IgG2a dnDSA (P ≤ 0.01). However, individual group analyses determined that moderate-dose (5 M) treatment with autologous MSC was most effective in reducing IgG1, IgG2a, and IgG2c dnDSA (P ≤ 0.01). In this group, dnDSA decreased after 1 week of treatment; regulatory B cells increased in the spleen and peripheral blood mononuclear cells; and transitional B cells increased in the spleen, peripheral blood mononuclear cells, and bone marrow (P < 0.05 for all).Our findings indicate that autologous MSC prevent transfusion-elicited sensitization and upregulate transitional, and regulatory B cells. Additional studies are needed to determine the biological relevance of these changes after kidney transplantation.