Thrombalexin and Mirococept Synergistically Reduce IBMIR in a Porcine to Rhesus Xenoislet Model.

M. Manook,^1,2 J. Kwun,¹ J. Yoon,¹ K. Samy,¹ A. MacDonald,¹ H. Xu,¹ R. Smith,³ A. Dorling,³ A. Kirk,¹ N. Mamode,² S. Knechtle.¹

¹Surgery, Duke Transplant Center, Durham, NC
²Renal and Transplant, Guy's and St Thomas'NHS Foundation Trust, London, United Kingdom
³MRC Centre for Transplantation, King's College, London, United Kingdom

Meeting: 2017 American Transplant Congress

Abstract number: B308

Keywords: Anticoagulation, Islets, Xenotransplantation

Session Information

Session Name: Poster Session B: Xenotransplantation

Session Type: Poster Session

Date: Sunday, April 30, 2017

Session Time: 6:00pm-7:00pm

Presentation Time: 6:00pm-7:00pm

Location: Hall D1

Introduction: Early activation of coagulation and complement are important factors in the initiation of instant blood mediated inflammation (IBMIR) in xenoislet models. Two novel 'cytotopic' agents, 'Thrombalexin',(TLN, PTL060) and Mirococept (APT070) combine cell-membrane binding properties via a mirystoyl tail with anti-thrombin and anti-C3 convertase peptides respectively, allowing perfusion of donor cells to provide targeted inhibition of coagulation or complement.

Methods: Neonatal porcine islets (NPI) were isolated from either wild type (WT), Gal-knockout (GKO) or Gal-knockout-CD46transgenic (GKOCD46) animals. NPI were incubated with either TLN (20uM), Mirococept (100ug/ml) or combination therapy (TLN+Mirococept) vs. negative controls. After washing, cells were added to rhesus blood to measure time to clot formation (r time). Islet function was tested with C-peptide, and membrane binding confirmed with immunohistochemistry.

Results: Compared to PBS controls, NPI shorten time to clot formation significantly. Monotherapy with TLN or Mirococept did not prolong time to clot formation compared to PBS treated NPI for any type of NPI. High dose combination treatment of NPI with TLN and Mirococept prolonged time to clot formation in both types of genetically manipulated islets (median r time (min): WT=2.3; GKO=2.7; GKOCD46=4.5) compared to PBS treated controls (2.0min), and was statistically significant for the GKOCD46 (p=0.028). Detection of membrane-bound TLN & Mirococept was confirmed by immunohistochemistry, and c-peptide levels confirm preservation of function.

Conclusions: IBMIR results in rapid clot formation in a xenotransplant model, irrespective of genetic modification. Monotherapy with either cytotopic anticoagulation or anti-complement therapy is ineffective to inhibit IBMIR, however high dose combination therapy prolongs time to clot formation significantly in genetically modified islets.

CITATION INFORMATION: Manook M, Kwun J, Yoon J, Samy K, MacDonald A, Xu H, Smith R, Dorling A, Kirk A, Mamode N, Knechtle S. Thrombalexin and Mirococept Synergistically Reduce IBMIR in a Porcine to Rhesus Xenoislet Model. Am J Transplant. 2017;17 (suppl 3).

To cite this abstract in AMA style:

Manook M, Kwun J, Yoon J, Samy K, MacDonald A, Xu H, Smith R, Dorling A, Kirk A, Mamode N, Knechtle S. Thrombalexin and Mirococept Synergistically Reduce IBMIR in a Porcine to Rhesus Xenoislet Model. [abstract]. Am J Transplant. 2017; 17 (suppl 3). https://atcmeetingabstracts.com/abstract/thrombalexin-and-mirococept-synergistically-reduce-ibmir-in-a-porcine-to-rhesus-xenoislet-model/. Accessed November 22, 2024.

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