Pre‐clinical heterotopic intrathoracic heart xenotransplantation: a possibly useful clinical technique

Media type: E-Article
Title: Pre‐clinical heterotopic intrathoracic heart xenotransplantation: a possibly useful clinical technique
Contributor: Abicht, Jan‐Michael; Mayr, Tanja; Reichart, Bruno; Buchholz, Stefan; Werner, Fabian; Lutzmann, Isabelle; Schmoeckel, Michael; Bauer, Andreas; Thormann, Michael; Langenmayer, Martin; Herbach, Nadja; Pohla, Heike; Herzog, Rudolf; McGregor, Christopher G. A.; Ayares, David; Wolf, Eckhard; Klymiuk, Nikolai; Baehr, Andrea; Kind, Alexander; Hagl, Christian; Ganswindt, Ute; Belka, Claus; Guethoff, Sonja; Brenner, Paolo
imprint: Wiley, 2015
Published in: Xenotransplantation
Language: English
DOI: 10.1111/xen.12213
ISSN: 0908-665X; 1399-3089
Keywords: Transplantation ; Immunology
Origination:
Footnote:
Description: <jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>As a step towards clinical cardiac xenotransplantation, our experimental heterotopic intrathoracic xenotransplantation model offers a beating and ejecting donor heart while retaining the recipient′s native organ as a backup in case of graft failure. Clinically applicable immunosuppressive regimens (<jats:styled-content style="fixed-case">IS</jats:styled-content>) were investigated first, then treatments known to be effective in hypersensitized patients or those with recalcitrant rejection reactions.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Consecutive experiments were carried out between 2009 and 2013. Twenty‐one genetically modified pigs (<jats:styled-content style="fixed-case">GGTA</jats:styled-content>1‐knockout/<jats:styled-content style="fixed-case">hCD</jats:styled-content>46/± thrombomodulin, in one case <jats:styled-content style="fixed-case">HLA</jats:styled-content>‐E instead) were used as donors. In all experiments, two cycles of immunoabsorption reduced preformed antibodies. Recipient baboons were divided into two groups according to <jats:styled-content style="fixed-case">IS</jats:styled-content> regimen:</jats:p><jats:p>In group one (n = 10), pre‐treatment started either one (anti‐<jats:styled-content style="fixed-case">CD</jats:styled-content>20) or four weeks (anti‐<jats:styled-content style="fixed-case">CD</jats:styled-content>20 plus the proteasome inhibitor bortezomib) prior to transplantation. The extended conventional (as for allotransplantation) immunosuppressive maintenance regimen included anti‐thymocyte globuline, tacrolimus, mycophenolate mofetil, methylprednisolone and weekly anti‐<jats:styled-content style="fixed-case">CD</jats:styled-content>20.</jats:p><jats:p>In group two (n = 11), myeloablative pre‐treatment as in multiple myeloma patients (long and short regimens) was added to extended conventional <jats:styled-content style="fixed-case">IS</jats:styled-content>; postoperative total thoracic and abdominal lymphoid irradiation (<jats:styled-content style="fixed-case">TLI</jats:styled-content>; single dose of 600 <jats:styled-content style="fixed-case">cGY</jats:styled-content>) was used to further reduce antibody‐producing cells.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>In the perioperative course, the surgical technique was safely applied: 19 baboons were weaned off extracorporeal circulation and 17 extubated. Nine animals were lost in the early postoperative course due to causes unrelated to surgical technique or <jats:styled-content style="fixed-case">IS</jats:styled-content> regimen.</jats:p><jats:p>Excluding these early failures, median graft survival times of group 1 and 2 were 18.5 (12–50) days and 16 (7–35) days. Necropsy examination of group 1 donor organs revealed hypertrophy of the left ventricular wall in the six longer‐lasting grafts; myocardial histology confirmed pre‐clinical suspicion of humoral rejection, which was not inhibited by the extended conventional IS including intensified treatments, and signs of thrombotic microangiopathy.</jats:p><jats:p>Grafts of group 2 presented with only mild‐to‐moderate features of humoral rejection and thrombotic microangiopathy, except in one case of delayed rejection on day 17. The other experiments in this group were terminated because of untreatable pulmonary oedema, recurring ventricular fibrillation, Aspergillus sepsis, as well as a combination of a large donor organ and late toxic side effects due to <jats:styled-content style="fixed-case">TLI</jats:styled-content>.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Longer‐term results were difficult to achieve in this model due to the <jats:styled-content style="fixed-case">IS</jats:styled-content> regimens used. However, we conclude that heterotopic intrathoracic heart transplantation may be an option for clinical xenotransplantation.</jats:p></jats:sec>

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