Journal
AMERICAN JOURNAL OF TRANSPLANTATION
Volume 16, Issue 6, Pages 1726-1738Publisher
WILEY
DOI: 10.1111/ajt.13688
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Funding
- NIH [U19AI051731, P51OD11132]
- Austrian Science Fund (EWE) [J3414]
- Austrian Society of Surgery
- Austrian Science Fund (FWF) [J 3414] Funding Source: researchfish
- National Research Council of Science & Technology (NST), Republic of Korea [KGM4241642] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- Austrian Science Fund (FWF) [J3414] Funding Source: Austrian Science Fund (FWF)
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We have established a model of sensitization in non-human 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 +/- 1 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.
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