Premium
Xenotransplantation: immunological barriers and strategies to overcome them
Author(s) -
Schwinzer R.,
Plege A.
Publication year - 2008
Publication title -
xenotransplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.052
H-Index - 61
eISSN - 1399-3089
pISSN - 0908-665X
DOI - 10.1111/j.1399-3089.2008.00488_5.x
Subject(s) - xenotransplantation , immunology , immune system , t cell , biology , transgene , antigen , transplantation , thrombomodulin , microbiology and biotechnology , medicine , thrombin , gene , platelet , biochemistry
Hyperacute and acute vascular rejection of xenografts are well defined barriers to clinical pig‐to‐human xenotransplantation. Enormous progress has been made in recent years to overcome these immunological barriers. For example, transgenic expression of human complement regulatory molecules (e.g. CD46, CD55) in pigs has been shown to be an effective strategy to prevent hyperacute rejection in pre‐clinical models of xenotransplantation. Alpha1,3‐galactosyltransferase knock‐out pigs are available and provide a second possibility to avoid hyperacute rejection mediated by pre‐existing antibodies. Furthermore, transfer of protective genes (e.g. A20, HO‐1) to endothelial cells is expected to reduce their susceptibility to effector mechanisms leading to acute vascular rejection. In addition, the efficiency of strategies to avoid coagulation/thrombosis after pig‐to‐human xenotransplantation (e.g. transgenic expression of human thrombomodulin, CD39) is currently tested. Thus, for further development of clinical xenotransplantation immunological concepts are now required facilitating the control of human anti‐pig cellular immune responses. Our group focuses on the inhibition of human anti‐pig T cell responses by targeting “negative” costimulatory pathways. We tested the hypothesis that overexpression of the human negative costimulatory ligands PD‐L1 and PD‐L2 on pig antigen presenting cells will result in reduced human anti‐pig T cell responses. The data so far show that (i) human CD4 + T cells respond with reduced proliferation and cytokine synthesis to PD‐L1/PD‐L2 expressing pig cells, (ii) PD‐L1/PD‐L2 pig transfectants induce human regulatory T cells (T reg ) which suppress the activation of conventional T cells, and (iii) PD‐L1/PD‐L2 expressing pig cells are protected from lysis mediated by CD8 + human cells. Together these observations support the assumption that transgenic expression of human PD‐L1 and/or PD‐L2 in pig cells and tissues could be an approach to prevent T cell reactivity after pig‐to‐human xenotransplantation. Supported by the Deutsche Forschungsgemeinschaft (Transregio Forschergruppe “Xenotransplantation”, FOR 535).