Clonidine inhibits anti-non-Gal IgM xenoantibody elicited in multiple pig-to-primate models

被引:1
作者
Stewart, John M. [1 ]
Tarantal, Alice F. [2 ,3 ,4 ]
Hawthorne, Wayne J. [5 ,6 ]
Salvaris, Evelyn J. [7 ]
O'Connell, Philip J. [5 ,6 ]
Nottle, Mark B. [8 ]
d'Apice, Anthony J. F. [7 ,9 ]
Cowan, Peter J. [7 ,9 ]
Kearns-Jonker, Mary [1 ]
机构
[1] Loma Linda Univ, Sch Med, Dept Human Anat, Loma Linda, CA 92350 USA
[2] Univ Calif Davis, Dept Pediat, Davis, CA 95616 USA
[3] Univ Calif Davis, Dept Cell Biol & Human Anat, Davis, CA 95616 USA
[4] Univ Calif Davis, Calif Natl Primate Res Ctr, Davis, CA 95616 USA
[5] Westmead Millennium Inst, Ctr Transplant & Renal Res, Westmead, NSW, Australia
[6] Univ Sydney, Westmead Hosp, Natl Pancreas Transplant Unit, Westmead, NSW 2145, Australia
[7] St Vincents Hosp, Immunol Res Ctr, Melbourne, Vic, Australia
[8] Univ Adelaide, Discipline Obstet & Gynaecol, Adelaide, SA, Australia
[9] Univ Melbourne, Dept Med, Melbourne, Vic, Australia
关键词
baboon; clonidine; endothelial cell; islet; kidney; pig; rhesus monkey; small molecule; xenotransplantation; ISLET XENOTRANSPLANTATION; SCORING FUNCTION; TRANSPLANTATION; SURVIVAL; CELLS; XENOGRAFTS; ANTIBODIES; AGONISTS; DISEASE; BINDING;
D O I
10.1111/xen.12199
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
BackgroundSurvival of vascularized xenografts is dependent on pre-emptive inhibition of the xenoantibody response against galactosyltransferase knockout (GTKO) porcine organs. Our analysis in multiple GTKO pig-to-primate models of xenotransplantation has demonstrated that the anti-non-gal--1,3-gal (anti-non-Gal) xenoantibody response displays limited structural diversity. This allowed our group to identify an experimental compound which selectively inhibited induced anti-non-Gal IgM xenoantibodies. However, because this compound had an unknown safety profile, we extended this line of research to include screening small molecules with known safety profiles allowing rapid advancement to large animal models. MethodsThe NIH clinical collections of small molecules were screened by ELISA for their ability to inhibit xenoantibody binding to GTKO pig endothelial cells. Serum collected from non-immunosuppressed rhesus monkeys at day 14 post-injection with GTKO pig endothelial cells was utilized as a source of elicited xenoantibody for initial screening. Virtual small molecule screening based on xenoantibody structure was used to assess the likelihood that the identified small molecules bound xenoantibody directly. As a proxy for selectivity, ELISAs against tetanus toxoid and the natural antigens laminin, thyroglobulin, and single-stranded DNA (ssDNA) were utilized to assess the ability of the identified reagents to inhibit additional antibody responses. The identified inhibitory small molecules were further tested for their ability to inhibit xenoantibody elicited in multiple settings, including rhesus monkeys pre-treated with an anti-non-Gal selective anti-idiotypic antibody, non-immunosuppressed rhesus monkeys immunized with wild-type fetal pig isletlike cell clusters, and non-immunosuppressed baboons transplanted with GTKO multiple transgenic pig kidneys. ResultsFour clinically relevant small molecules inhibited anti-non-Gal IgM binding to GTKO pig endothelial cells in vitro. Three of these drugs displayed a limited region of structural similarity suggesting they may inhibit xenoantibody by a similar mechanism. One of these, the anti-hypertensive agent clonidine, displayed only minimal inhibition of antibodies elicited by vaccination against tetanus toxoid or pre-existing natural antibodies against laminin, thyroglobulin, or ssDNA. Furthermore, clonidine inhibited elicited anti-non-Gal IgM from all animals that demonstrated a xenoantibody response in each experimental setting. ConclusionsClinically relevant small molecule drugs with known safety profiles can inhibit xenoantibody elicited against non-Gal antigens in diverse experimental xenotransplantation settings. These molecules are ready to be tested in large animal models. However, it will first be necessary to optimize the timing and dosing required to inhibit xenoantibodies in vivo.
引用
收藏
页码:413 / 426
页数:14
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