Current status of pig heart xenotransplantation

Mohiuddin, Muhammad M.; Reichart, Bruno; Byrne, Guerard W.; McGregor, Christopher G.A.

doi:10.1016/j.ijsu.2015.08.038

Cited by 79 publications

(62 citation statements)

References 52 publications

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“…Blockade of CD40/CD154 costimulatory pathway has emerged as a promising therapeutic modality in allotransplantation, xenotransplantation as well as autoimmune disease models[14, 25–27]. Although the treatment with anti-CD154 Ab has proven effective in xenotransplantation[28, 29], anti-CD154 Ab has yielded to antagonistic anti-CD40 Ab in the field of transplantation because of the thrombotic complications[11].…”

Section: Discussionmentioning

confidence: 99%

Anti‐CD40 antibody‐mediated costimulation blockade promotes long‐term survival of deep‐lamellar porcine corneal grafts in non‐human primates

Kim

Choi

Lee

et al. 2017

Xenotransplantation

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Background Corneal xenotransplantation is an effective solution for the shortage of human donor corneas, and the porcine cornea may be a suitable candidate for the donor cornea because of its optical similarity with humans. However, it is necessary to administer additional immunosuppressants to overcome antigenic differences. We aimed to investigate the feasibility of porcine corneas with anti-CD40 antibody-mediated co-stimulation blockade in a clinically applicable pig-to-nonhuman primate corneal xenotransplantation model. Methods Five Chinese rhesus macaques underwent deep-lamellar corneal transplantation using clinically acceptable sized (7.5 mm diameter) porcine corneal grafts. The anti-CD40 antibody was intravenously administered on a programmed schedule. Graft survival, central corneal thickness, and intraocular pressure were evaluated. Changes in effector and memory T and B cell subsets and anti-αGal and donor-specific antibodies were investigated in the blood, and the changes in complement levels in the aqueous humor and blood were evaluated. Memory cell profiles in the anti-CD40 antibody-treated group were compared with those in from the anti-CD154 antibody-treated group or rejected controls presented in our previous report. The changes in anti-αGal, non-αGal, and donor-specific antibodies after 6 months were compared with baseline values. Results Anti-CD40 antibody-mediated co-stimulation blockade resulted in the successful survival of xenocorneal grafts (> 389, > 382, > 236, > 201, and > 61 days), with 80% reaching 6 months of survival. Injection of anti-CD40 antibody considerably reduced the infiltration of inflammatory cells into the grafts and significantly blocked the complement response in the aqueous humor (p = 0.0159, Mann-Whitney U test). Systemic expansion of central or effector memory T cells was abrogated in the anti-CD40 antibody-treated primates compared with those in the rejected controls (p<0.05, Mann-Whitney U test) or those in the anti-CD154 antibody-treated primates (p>0.05, Mann-Whitney U test). The levels of anti-αGal, non-αGal, and donor-specific antibodies at 6 months were not significantly increased compared with baseline levels (p > 0.05, Wilcoxon signed rank test). Conclusions An anti-CD40 antibody-mediated blockade appears to be effective immunosuppressive approach for porcine corneal deep lamellar xenotransplantation in primates.

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Section: Discussionmentioning

confidence: 99%

Anti‐CD40 antibody‐mediated costimulation blockade promotes long‐term survival of deep‐lamellar porcine corneal grafts in non‐human primates

Kim

Choi

Lee

et al. 2017

Xenotransplantation

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“…Differences in methods for cardiac xenotransplantation, i.e. heterotopic, orthotopic and intra-thoracic heterotopic, have all been well described [20], however, despite heterotopic transplantation having the benefit of unlimited growth in the abdomen as opposed to orthotopic heart transplantation into the mediastinum, the heterotopic abdominal approach is not life-supporting and true orthotopic models have been complicated by an entity known as perioperative cardiac xenograft dysfunction (PCXD) requiring additional investigation, currently ongoing.…”

Section: Short Communicationmentioning

confidence: 99%

Role of Intrinsic Factors in the Growth of Transplanted Organs Following Transplantation

2017

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Shortages in the availability of transplantable organs have forced the transplant community to seek alternative methods to increase the supply of available organs. In our recent study following α-1,3-galactocyltransferase knockout (GalT-KO) pig-to-baboon kidney xenotransplantation, we found that certain recipients developed increased serum creatinine, possibly due to the rapid growth of orthotopic pig grafts in smaller baboon recipients. To test our hypothesis, we assessed whether the growth of outbred (Yorkshire) organ transplants (kidney and lung) in miniature swine was regulated by intrinsic (graft) factors. Yorkshire kidneys reached 3.7× their initial volume over 3 months vs. 1.2× for miniature swine kidneys over a similar time period. A similar pattern was seen in porcine lung allografts as well. Following xenotransplantation, a review of our results suggests that there is a threshold for kidney graft volume of 25 cm3/kg of recipient body weight at which cortical ischemia is induced in transplanted GalT-KO kidneys in baboons. These results suggest that intrinsic factors are in part responsible for the growth of donor organs and this should be taken into consideration for growth-curve-mismatched transplants.

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“…The maximal survival of a pig-to-NHP orthotopic heart is 57 days. 82 According to the International Society for Heart and Lung Transplantation guidelines, a clinical trial should only be considered when approximately 60% survival of life-supporting pig organs in non-human primates has been achieved for a minimum of 90 days, with at least 10 animals surviving for this minimum period. Furthermore, evidence should suggest that longer survival (>6 months) can be achieved.…”

Section: The Future Of Transplantation Is Xenotransplantation and Itmentioning

confidence: 99%

Advances in the immunology of heart transplantation

Madsen

2017

The Journal of Heart and Lung Transplantation

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Current status of pig heart xenotransplantation

Cited by 79 publications

References 52 publications

Anti‐CD40 antibody‐mediated costimulation blockade promotes long‐term survival of deep‐lamellar porcine corneal grafts in non‐human primates

Anti‐CD40 antibody‐mediated costimulation blockade promotes long‐term survival of deep‐lamellar porcine corneal grafts in non‐human primates

Role of Intrinsic Factors in the Growth of Transplanted Organs Following Transplantation

Advances in the immunology of heart transplantation

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