Pig-to-baboon heterotopic heart transplantation - exploratory preliminary experience with pigs transgenic for human thrombomodulin and comparison of three costimulation blockade-based regimens

被引：101

作者：

Iwase, Hayato ^{[1
]}

Ekser, Burcin ^{[1
,2
]}

Satyananda, Vikas ^{[1
]}

Bhama, Jay ^{[3
]}

Hara, Hidetaka ^{[1
]}

Ezzelarab, Mohamed ^{[1
]}

Klein, Edwin ^{[4
]}

Wagner, Robert ^{[4
]}

Long, Cassandra ^{[1
]}

Thacker, Jnanesh ^{[3
]}

Li, Jiang ^{[1
]}

Zhou, Hao ^{[1
,5
]}

Jiang, Maolin ^{[1
,5
]}

Nagaraju, Santosh ^{[1
]}

Zhou, Huidong ^{[1
,5
]}

Veroux, Massimiliano ^{[2
]}

Bajona, Pietro ^{[1
]}

Wijkstrom, Martin ^{[1
]}

Wang, Yi ^{[5
]}

Phelps, Carol ^{[6
]}

Klymiuk, Nikolai ^{[7
]}

Wolf, Eckhard ^{[7
]}

Ayares, David ^{[6
]}

Cooper, David K. C. ^{[1
]}

机构：

[1] Univ Pittsburgh, Thomas E Starzl Transplantat Inst, Pittsburgh, PA 15261 USA

[2] Univ Hosp Catania, Dept Surg Transplantat & Adv Technol, Vasc Surg & Organ Transplant Unit, Catania, Italy

[3] Univ Pittsburgh, Dept Cardiothorac Surg, Pittsburgh, PA 15261 USA

[4] Univ Pittsburgh, Div Lab Anim Resources, Pittsburgh, PA 15261 USA

[5] Univ South China, Affiliated Hosp 2, Ctr Kidney Transplantat, Hengyang, Hunan, Peoples R China

[6] Revivicor, Blacksburg, VA USA

[7] Univ Munich, Gene Ctr, Munich, Germany

来源：

XENOTRANSPLANTATION | 2015年 / 22卷 / 03期

关键词：

baboon; complement-regulatory proteins; costimulation blockade; heart; pig; thrombomodulin; thrombotic microangiopathy; xenotransplantation; alpha 1,3-galactosyltransferase gene-knockout; GENE-KNOCKOUT PIGS; ANTI-CD154; MONOCLONAL-ANTIBODY; NON-GAL ANTIGENS; THROMBOTIC MICROANGIOPATHY; ALLOGRAFT-REJECTION; HUMORAL REJECTION; IMMUNE-RESPONSE; SURVIVAL; PORCINE; CELLS;

D O I：

10.1111/xen.12167

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：

BackgroundThree costimulation blockade-based regimens have been explored after transplantation of hearts from pigs of varying genetic backgrounds to determine whether CTLA4-Ig (abatacept) or anti-CD40mAb+CTLA4-Ig (belatacept) can successfully replace anti-CD154mAb. MethodsAll pigs were on an 1,3-galactosyltransferase gene-knockout/CD46 transgenic (GTKO.CD46) background. Hearts transplanted into Group A baboons (n=4) expressed additional CD55, and those into Group B (n=3) expressed human thrombomodulin (TBM). Immunosuppression included anti-thymocyte globulin with anti-CD154mAb (Regimen 1: n=2) or abatacept (Regimen 2: n=2) or anti-CD40mAb+belatacept (Regimen 3: n=2). Regimens 1 and 2 included induction anti-CD20mAb and continuous heparin. One further baboon in Group B (B16311) received a modified Regimen 1. Baboons were followed by clinical/laboratory monitoring of immune/coagulation parameters. At biopsy, graft failure, or euthanasia, the graft was examined by microscopy. ResultsGroup A baboons survived 15 to 33days, whereas Group B survived 52, 99, and 130days, respectively. Thrombocytopenia and reduction in fibrinogen occurred within 21days in Group A, suggesting thrombotic microangiopathy (TM), confirmed by histopathology. In Group B, with follow-up for >4m, areas of myofiber degeneration and scarring were seen in two hearts at necropsy. A T-cell response was documented only in baboons receiving Regimen 2. ConclusionsThe combination of anti-CD40mAb+belatacept proved effective in preventing a T-cell response. The expression of TBM prevented thrombocytopenia and may possibly delay the development of TM and/or consumptive coagulopathy.

引用

页码：211 / 220

页数：10

共 49 条

[1] Development of a chimeric anti-CD40 monoclonal antibody that synergizes with LEA29Y to prolong islet allograft survival [J].

Adams, AB ;

Shirasugi, N ;

Jones, TR ;

Durham, MM ;

Strobert, EA ;

Cowan, S ;

Rees, P ;

Hendrix, R ;

Price, K ;

Kenyon, NS ;

Hagerty, D ;

Townsend, R ;

Hollenbaugh, D ;

Pearson, TC ;

Larsen, CP .

JOURNAL OF IMMUNOLOGY, 2005, 174 (01) :542-550

[2]

[Anonymous], XENOTRANSPLANTATION

[3]

Bühler L, 2000, TRANSPLANTATION, V69, P2296

[4] Acute rejection is associated with antibodies to non-Gal antigens in baboons using Gal-knockout pig kidneys [J].

Chen, G ;

Qian, H ;

Starz, T ;

Sun, HT ;

Garcia, B ;

Wang, XM ;

Wise, Y ;

Liu, YQ ;

Xiang, Y ;

Copeman, L ;

Liu, WH ;

Jevnikar, A ;

Wall, W ;

Cooper, DKC ;

Murase, N ;

Dai, YF ;

Wang, WY ;

Xiong, YL ;

White, DJ ;

Zhong, R .

NATURE MEDICINE, 2005, 11 (12) :1295-1298

[5]

Cooper David K. C., 1994, P173

[6] THE GENERATION OF TRANSGENIC PIGS AS POTENTIAL ORGAN DONORS FOR HUMANS [J].

COZZI, E ;

WHITE, DJG .

NATURE MEDICINE, 1995, 1 (09) :964-966

[7] Comparison of hematologic, biochemical, and coagulation parameters in α1,3-galactosyltransferase gene-knockout pigs, wild-type pigs, and four primate species [J].

Ekser, Burcin ;

Bianchi, John ;

Ball, Suyapa ;

Iwase, Hayato ;

Walters, Anneke ;

Ezzelarab, Mohamed ;

Veroux, Massimiliano ;

Gridelli, Bruno ;

Wagner, Robert ;

Ayares, David ;

Cooper, David K. C. .

XENOTRANSPLANTATION, 2012, 19 (06) :342-354

[8] Genetically-Engineered Pig-to-Baboon Liver Xenotransplantation: Histopathology of Xenografts and Native Organs [J].

Ekser, Burcin ;

Klein, Edwin ;

He, Jing ;

Stolz, Donna B. ;

Echeverri, Gabriel J. ;

Long, Cassandra ;

Lin, Chih Che ;

Ezzelarab, Mohamed ;

Hara, Hidetaka ;

Veroux, Massimiliano ;

Ayares, David ;

Cooper, David K. C. ;

Gridelli, Bruno .

PLOS ONE, 2012, 7 (01)

[9] Human T-cell proliferation in response to thrombin-activated GTKO pig endothelial cells [J].

Ezzelarab, Corin ;

Ayares, David ;

Cooper, David K. C. ;

Ezzelarab, Mohamed B. .

XENOTRANSPLANTATION, 2012, 19 (05) :311-316

[10] Antibodies directed to pig non-Gal antigens in naive and sensitized baboons [J].

Ezzelarab, M. ;

Hara, H. ;

Busch, J. ;

Rood, P. P. M. ;

Zhu, X. ;

Ibrahim, Z. ;

Ball, S. ;

Ayares, D. ;

Awwad, M. ;

Cooper, D. K. C. .

XENOTRANSPLANTATION, 2006, 13 (05) :400-407

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