Expression of Multiple Human Complement Regulatory Proteins Results in Prolonged Heterotopic Xenoheart Survival in an NHP Model

K. Ahrens¹, J. M. O¹, W. Sommer², D. Becerra¹, P. M. Patel¹, A. Dehnadi¹, Y. Kan³, J. Layer³, J. Morrissette¹, T. Costa¹, I. M. Hanekamp¹, J. S. Allan⁴, M. Youd³, R. N. Pierson⁵, W. Qin³, L. Burdorf⁵, A. M. Azimzadeh¹, W. Westlin³, L. Yang³, J. C. Madsen⁵

¹Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, ²Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany, ³eGenesis Inc., Cambridge, MA, ⁴Center for Transplantation Sciences, Division of Thoracic Surgery, Massachusetts General Hospital, Boston, MA, ⁵Center for Transplantation Sciences, Division of Cardiac Surgery, Massachusetts General Hospital, Boston, MA

Meeting: 2020 American Transplant Congress

Abstract number: A-268

Keywords: Heart, Pig, Primates

Session Information

Session Name: Poster Session A: Xenotransplantation

Session Type: Poster Session

Date: Saturday, May 30, 2020

Session Time: 3:15pm-4:00pm

Presentation Time: 3:30pm-4:00pm

Location: Virtual

*Purpose: Advances in genome engineering technology allow for multiplex genetic modifications in pigs designed to address immunologic and coagulation incompatibilities in order to facilitate xenotransplantation. Heterotopic heart xenograft survival was compared between porcine donors with GGTA1KO.hCD55 versus triple-carbohydrate-xenoantigen knock-out (TKO) swine carrying additional potentially beneficial genes.

*Methods: Cynomolgus macaques underwent heterotopic xenoheart transplantation with GGTA1KO.hCD55 (Group A, n=4) or GTKO.β4GKO.CMAHKO.hCD46.hCD55.hCD59.hCD39.hHLA-E.hCD47.hβ2M porcine donors (Group B, n=3). All animals received peri-transplant anti-rhesus ATG (5 mg/kg IV), anti-CD20, and ongoing αCD154, mycophenolate mofetil, and methylprednisolone. Two animals in Group A and all animals in Group B received complement inhibition with cobra venom factor (CVF) (100 ug/kg IV on day -1). Group A animals received daily rapamycin while Group B did not.

*Results: Two Group A animals died with surviving heart xenografts at day 4 and day 30 from intra-abdominal bleeding and infection, respectively. One Group A heart failed with antibody mediated rejection (AMR) at POD 65, and another exhibited acute cellular mediated rejection and AMR2 at recipient euthanasia for failure to thrive on POD 80. Assays of fibroblasts and endothelial cells from Group B pigs confirmed expression of hCD46, hCD55, hCD59, hCD39, HLA-E, β2M, and hCD47. Two Group B recipients died with beating grafts at day 0 and 3 from intra-abdominal bleeding and acute renal failure respectively. The third recipient was euthanized on day 126 in the setting of recurrent thrombocytopenia, gradually deteriorating graft contractility, with graft pathology showing arterial fibrinoid necrosis, ACR1R, and thrombotic microangiopathy (TMA).

*Conclusions: We observed the longest survival in one of Group B heart recipients suggesting that expression of multiple human complement regulatory proteins and CD39 in the xenograft is associated with prolonged graft survival. However, these genetic modifications do not provide complete protection from TMA. Rapamycin did not appear to confer a significant benefit in this model.

To cite this abstract in AMA style:

Ahrens K, O JM, Sommer W, Becerra D, Patel PM, Dehnadi A, Kan Y, Layer J, Morrissette J, Costa T, Hanekamp IM, Allan JS, Youd M, Pierson RN, Qin W, Burdorf L, Azimzadeh AM, Westlin W, Yang L, Madsen JC. Expression of Multiple Human Complement Regulatory Proteins Results in Prolonged Heterotopic Xenoheart Survival in an NHP Model [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/expression-of-multiple-human-complement-regulatory-proteins-results-in-prolonged-heterotopic-xenoheart-survival-in-an-nhp-model/. Accessed November 21, 2024.

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