Antibody‐Mediated Rejection in Sensitized Nonhuman Primates: Modeling Human Biology. Issue 6 (25th March 2016)

• Record Type: Journal Article
• Authors: Burghuber, C. K.; Kwun, J.; Page, E. J.; Manook, M.; Gibby, A. C.; Leopardi, F. V.; Song, M.; Farris, A. B.; Hong, J. J.; Villinger, F.; Adams, A. B.; Iwakoshi, N. N.; Knechtle, S. J.
• Is Part Of: American journal of transplantation. Volume 16:Issue 6(2016:Jun.)
• Page Start: 1726
• Page End: 1738
• Publication Date: 2016-03-25
• Subjects: Transplantation of organs, tissues, etc -- Periodicals; 617.95
• DOI: 10.1111/ajt.13688
• Languages: English
• ISSNs: 1600-6135

Abstract

Abstract : We have established a model of sensitization in nonhuman primates and tested two immunosuppressive regimens. Animals underwent fully mismatched skin transplantation, and donor‐specific antibody (DSA) response was monitored by flow cross‐match. Sensitized animals subsequently underwent kidney transplantation from their skin donor. Immunosuppression included tacrolimus, mycophenolate, and methylprednisolone. Three animals received basiliximab induction; compared with nonsensitized animals, they showed a shorter mean survival time (4.7 ± 3.1 vs. 187 ± 88 days). Six animals were treated with T cell depletion (anti‐CD4/CD8 mAbs), which prolonged survival (mean survival time 21.6 ± 19.0 days). All presensitized animals showed antibody‐mediated rejection (AMR). In two of three basiliximab‐injected animals, cellular rejection (ACR) was prominent. After T cell depletion, three of six monkeys experienced early acute rejection within 8 days with histological evidence of thrombotic microangiopathy and AMR. The remaining three monkeys survived 27–44 days, with mixed AMR and ACR. Most T cell–depleted animals experienced a rebound of DSA that correlated with deteriorating kidney function. We also found an increase in proliferating memory B cells (CD20 + CD27 + IgD − Ki67 + ), lymph node follicular helper T cells (ICOS + PD‐1 hi CXCR5 + CD4 + ), and germinal center (GC) response. Depletion controlled cell‐mediated rejection in sensitized nonhuman primates better than basiliximab, yet grafts were rejected with concomitant DSA rise. This model provides an opportunity to test novel desensitization strategies. Abstract : The authors establish a preclinical model of sensitization in mismatched nonhuman primates through skin transplants and compare a T cell–depleting and a nondepleting immunosuppressive regimen after kidney transplantation in the sensitized animals.