Ex Vivo Generation of Donor Antigen-Specific Immunomodulatory Cells: A Comparison Study of Anti-CD80/86 mAbs and CTLA4-lg Costimulatory Blockade

• Published in: Cell transplantation 2018-11, Vol.27 (11), p.1692-1704
• Main Authors: Watanabe, M., Kumagai-Braesch, Makiko, Yao, M., Thunberg, S., Berglund, D., Sellberg, F., Jorns, C., Enoksson, S. Lind, Henriksson, J., Lundgren, T., Uhlin, M., Berglund, E., Ericzon, B.-G.
• Format: Article
• Language: English
• Subjects: anti-CD80/86 antibodies; CTLA4-Ig; donor antigen specificity; ex vivo generation; FOXP3; Immunomodulatory cells; Medicin och hälsovetenskap; Original
• ISSN: 0963-6897; 1555-3892; 1555-3892
• DOI: 10.1177/0963689718794642

Adoptive transfer of alloantigen-specific immunomodulatory cells generated ex vivo with anti-CD80/CD86 mAbs (2D10.4/IT2.2) holds promise for operational tolerance after transplantation. However, good manufacturing practice is required to allow widespread clinical application. Belatacept, a clinically approved cytotoxic T-lymphocyte antigen 4-immunoglobulin that also binds CD80/CD86, could be an alternative agent for 2D10.4/IT2.2. With the goal of generating an optimal cell treatment with clinically approved reagents, we evaluated the donor-specific immunomodulatory effects of belatacept- and 2D10.4/IT2.2-generated immunomodulatory cells. Immunomodulatory cells were generated by coculturing responder human peripheral blood mononuclear cells (PBMCs) (50 × 106 cells) with irradiated donor PBMCs (20 × 106 cells) from eight human leukocyte antigen-mismatched responder–donor pairs in the presence of either 2D10.4/IT2.2 (3 μg/106 cells) or belatacept (40 μg/106 cells). After 14 days of coculture, the frequencies of CD4+ T cells, CD8+ T cells, and natural killer cells as well as interferon gamma (IFN-γ) production in the 2D10.4/IT2.2- and belatacept-treated groups were lower than those in the control group. The percentage of CD19+ B cells was higher in the 2D10.4/IT2.2- and belatacept-treated groups than in the control group. The frequency of CD4+CD25+CD127lowFOXP3+ T cells increased from 4.1±1.0% (preculture) to 7.1±2.6% and 7.3±2.6% (day 14) in the 2D10.4/IT2.2- and belatacept-treated groups, respectively (p