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Long‐term survival of pig‐to‐rhesus macaque renal xenografts is dependent on CD4 T cell depletion
Author(s) -
Kim Steven C.,
Mathews David V.,
Breeden Cynthia P.,
Higginbotham Laura B.,
Ladowski Joseph,
Martens Gregory,
Stephenson Allison,
Farris Alton B.,
Strobert Elizabeth A.,
Jenkins Joe,
Walters Eric M.,
Larsen Christian P.,
Tector Matthew,
Tector Alfred J.,
Adams Andrew B.
Publication year - 2019
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.15329
Subject(s) - medicine , immunosuppression , cd8 , immunology , cd154 , t cell , transplantation , andrology , immune system , cytotoxic t cell , in vitro , biology , cd40 , biochemistry
The shortage of available organs remains the greatest barrier to expanding access to transplant. Despite advances in genetic editing and immunosuppression, survival in experimental models of kidney xenotransplant has generally been limited to <100 days. We found that pretransplant selection of recipients with low titers of anti‐pig antibodies significantly improved survival in a pig‐to–rhesus macaque kidney transplant model (6 days vs median survival time 235 days). Immunosuppression included transient pan–T cell depletion and an anti‐ CD 154–based maintenance regimen. Selective depletion of CD 4 + T cells but not CD 8 + T cells resulted in long‐term survival (median survival time >400 days vs 6 days). These studies suggested that CD 4 + T cells may have a more prominent role in xenograft rejection compared with CD 8 + T cells. Although animals that received selective depletion of CD 8 + T cells showed signs of early cellular rejection (marked CD 4 + infiltrates), animals receiving selective CD 4 + depletion exhibited normal biopsy results until late, when signs of chronic antibody rejection were present. In vitro study results suggested that rhesus CD 4 + T cells required the presence of SLA class II to mount an effective proliferative response. The combination of low pretransplant anti‐pig antibody and CD 4 depletion resulted in consistent, long‐term xenograft survival.