Xenoantibody response to porcine islet cell transplantation using GTKO, CD55, CD59, and fucosyltransferase multiple transgenic donors.
Xenoantibody response to porcine islet cell transplantation using GTKO, CD55, CD59, and fucosyltransferase multiple transgenic donors.
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DOI：
10.1111/xen.12091
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发表时间：
2014-05
影响因子：
3.9
通讯作者：
Kearns-Jonker M
中科院分区：
文献类型：
--
作者：
Chen Y;Stewart JM;Gunthart M;Hawthorne WJ;Salvaris EJ;O'Connell PJ;Nottle MB;d'Apice AJ;Cowan PJ;Kearns-Jonker M
Promising developments in porcine islet xenotransplantation could resolve the donor pancreas shortage for type 1 diabetic patients. Using GTKO donor pigs with multiple transgenes should extend xenoislet survival via reducing complement activation, thrombus formation, and the requirement for exogenous immune suppression. Studying the xenoantibody response to GTKO/hCD55/hCD59/hHT islets in the pig-to-baboon model, and comparing it with previously analyzed responses, would allow the development of inhibitory reagents capable of targeting conserved idiotypic regions. We generated IgM heavy and light chain gene libraries from ten untreated baboons and three baboons at 28 days following transplantation of GTKO/hCD55/hCD59/hHT pig neonatal islet cell clusters with immunosuppression. Flow cytometry was used to confirm the induction of a xenoantibody response. IgM germline gene usage was compared pre and post transplant. Homology modeling was used to compare the structure of xenoantibodies elicited after transplantation of GTKO/hCD55/hCD59/hHT pig islets with those induced by GTKO and wild type pig endothelial cells without further genetic modification. IgM xenoantibodies that bind to GTKO pig cells and wild type pig cells were induced after transplantation. These anti-nonGal antibodies were encoded by the IGHV3-66*02 (Δ28%) and IGKV1-12*02 (Δ25%) alleles, for the immunoglobulin heavy and light chains, respectively. IGHV3-66 is 86.7% similar to IGHV3-21 which was elicited by rhesus monkeys in response to GTKO endothelial cells. Heavy chain genes most similar to IGHV3-66 were found to utilize the IGHJ4 gene in 85% of V-D regions analyzed. However, unlike the wild type response, a consensus complementary determining region 3 was not identified. Additional genetic modifications in transgenic GTKO pigs do not substantially modify the structure of the restricted group of anti-nonGal xenoantibodies that mediate induced xenoantibody responses with or without immunosuppression. The use of this information to develop new therapeutic agents to target this restricted response will likely be beneficial for long term islet cell survival and for developing targeted immunosuppressive regimens with less toxicity.
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影响因子：
5.1
作者：
Fischer-Lougheed, J. Y.;Tarantal, A. F.;Kearns-Jonker, M.
通讯作者：
Kearns-Jonker, M.
DOI：
10.1111/j.1600-6143.2011.03846.x
发表时间：
2012-03
期刊：
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
影响因子：
--
作者：
Mohiuddin MM;Corcoran PC;Singh AK;Azimzadeh A;Hoyt RF Jr;Thomas ML;Eckhaus MA;Seavey C;Ayares D;Pierson RN 3rd;Horvath KA
通讯作者：
Horvath KA
影响因子：
3
作者：
Zahorsky-Reeves JL;Gregory CR;Cramer DV;Patanwala IY;Kyles AE;Borie DC;Kearns-Jonker MK
通讯作者：
Kearns-Jonker MK
DOI：
10.1111/j.1600-6143.2008.02337.x
发表时间：
2008-09
期刊：
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
影响因子：
--
作者：
Kiernan K;Harnden I;Gunthart M;Gregory C;Meisner J;Kearns-Jonker M
通讯作者：
Kearns-Jonker M
影响因子：
6.7
作者：
Gharagozlou, S;Kardar, GA;Shokri, F
通讯作者：
Shokri, F