Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5

In vivo evaluation of immunomodulated hearts in a heterotopic abdominal heart transplantation model in the pig
A. Bähr1, S. Michel2, N. Hornaschewitz1, L. Oberberger1, N. Klymiuk1, B. Reichart2, C. Kupatt1
1Klinik und Poliklinik für Innere Medizin I, Klinikum rechts der Isar der Technischen Universität München, München; 2Herzchirurgische Klinik, Klinikum der Universität München, München;

Background: The T-cell costimulation blocker LEA29Y is a promising candidate for ameliorating cellular rejection mechanisms in xenotransplantation settings. We have established a transgenic pig line with LEA29Y expression under the control of a ubiquitously active CAG promoter. These pigs have been characterized with regard to their immunological phenotype and were found to have a severely impacted immune system (Bähr et al., PlosOne 2016).  In the current study, we applied the LEA29Y heart to a model of heterotopic abdominal heart allotransplantation (aHTx) to examine local T-cell costimulation blockade by LEA29Y in an in-vivo setting.

Methods: Abdominal HTx of LEA29Y hearts was performed into German landrace pig recipients, with vena cava inferior anastomosed to the pulmonary artery and the aorta connected to the bulbus aorticum of the graft (Langendorff-mode).  Gradual  waning of pharmacological  immunosuppression (corticosterois, tacrolimus, mycophenolat mofetil) over 21 days was applied to test self-sufficient graft protection by LEA29Y. The fate of LEA29Y grafts and wildtype controls was followed for up to 5 weeks by transabdominal sonography and histological evaluation after explantation.

Results: Circulating T cell count and activity as well as circulating LEA29Y indicated a graft-dependent immunosuppression of the host system that was, however, lower than compared to systemic LEA29Y application.  Functionally, 3 out of 7 LEA29Y hearts were beating at explantation and displayed a decreased immune cell influx and amount of myocardial fibrosis, whereas 0 of 4 control hearts were beating at the end of the experiment, displaying massive immune cell influx and fibrosis.

Summary and outlook: Using LEA29Y expressing pig hearts allowed for a unique investigation of its effect on graft survival after tapering of all other immunosupression. Our results indicate a significant positive effect for graft protection of transgenic LEA29Y expression in some, but not all, transplanted hearts.  By examining swine leucocyte antigen (SLA) loci in donors and prospective recipients, we are currently refining transplantation settings to include tissue matching prior to transplantation.


https://dgk.org/kongress_programme/jt2022/aP1965.html