The 2021 IXA Keith Reemtsma Lecture: Moving xenotransplantation to the clinic

Cooper, D. K. C.

doi:10.1111/xen.12723

Cited by 12 publications

(11 citation statements)

References 50 publications

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“…In this study, no remarkable difference in blood cytokine levels was associated with systemic immune rejection, suggesting that TKO-sensitization would have no detrimental effects on subsequent organ allotransplantation. This observation is consistent with the majority of previous research findings, in which non-human primates or humans were sensitized to pig allergens [ 33 ].…”

Section: Discussionsupporting

confidence: 93%

Innate Immune Response Analysis in Meniscus Xenotransplantation Using Normal and Triple Knockout Jeju Native Pigs

Yoon

Min

Park³

et al. 2022

IJMS

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Although allogenic meniscus grafting can be immunologically safe, it causes immune rejection due to an imbalanced tissue supply between donor and recipient. Pigs are anatomically and physiologically similar to adult humans and are, therefore, considered to be advantageous xenotransplantation models. However, immune rejection caused by genetic difference damages the donor tissue and can sometimes cause sudden death. Immune rejection is caused by genes; porcine GGTA1, CMAH, and B4GLANT2 are the most common. In this study, we evaluated immune cells infiltrating the pig meniscus transplanted subcutaneously into BALB/c mice bred for three weeks. We compared the biocompatibility of normal Jeju native black pig (JNP) meniscus with that of triple knockout (TKO) JNP meniscus (α-gal epitope, N-glycolylneuraminic acid (Neu5Gc), and Sd (a) epitope knockout using CRISPR-Cas 9). Mast cells, eosinophils, neutrophils, and macrophages were found to have infiltrated the transplant boundary in the sham (without transplantation), normal (normal JNP), and test (TKO JNP) samples after immunohistochemical analysis. When compared to normal and sham groups, TKO was lower. Cytokine levels did not differ significantly between normal and test groups . Because chronic rejection can occur after meniscus transplantation associated with immune cell infiltration, we propose studies with multiple genetic editing to prevent immune rejection.

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Section: Discussionsupporting

confidence: 93%

Innate Immune Response Analysis in Meniscus Xenotransplantation Using Normal and Triple Knockout Jeju Native Pigs

Yoon

Min

Park³

et al. 2022

IJMS

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“…Studies in an experimental model that (in view of the ‘4th xenoantigen’) does not accurately reflect the clinical situation are likely to overestimate the remaining barriers to clinical success, 151 , 152 and managing immunosuppressed NHPs under laboratory conditions is significantly more difficult than managing a human patient in a hospital setting.…”

Section: What Experimental Results Would Justify a Formal Clinical Tr...mentioning

confidence: 99%

Cardiac xenotransplantation: from concept to clinic

Reichart

Cooper

Längin

et al. 2022

Cardiovascular Research

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For many patients with terminal/advanced cardiac failure, heart transplantation is the most effective, durable treatment option, and offers the best prospects for a high quality of life. The number of potentially life-saving donated human organs is far fewer than the population who could benefit from a new heart, resulting in increasing numbers of patients awaiting replacement of their failing heart, high waitlist mortality, and frequent reliance on interim mechanical support for many of those deemed among the best candidates but who are deteriorating as they wait. Currently, mechanical assist devices supporting left ventricular or biventricular heart function are the only alternative to heart transplant that is in clinical use. Unfortunately, the complication rate with mechanical assistance remains high despite advances in device design and patient selection and management, and the quality of life of the patients even with good outcomes is only moderately improved. Cardiac xenotransplantation from genetically multi-modified (GM) organ-source pigs is an emerging new option as demonstrated by consistent long-term success of heterotopic (non-life-supporting) abdominal and life-supporting orthotopic porcine heart transplantation in baboons, and by a recent ‘compassionate use’ transplant of the heart from a GM pig with 10 modifications into a terminally ill patient who survived for two months. In this review, we discuss pig heart xenotransplantation as a concept, including pathobiological aspects related to immune rejection, coagulation dysregulation, and detrimental overgrowth of the heart, as well as GM strategies in pigs to prevent or minimize these problems. Relevant results of heterotopic and orthotopic heart transplantation experiments in the pig-to-baboon model, microbiological and virologic safety concepts, and efficacy requirements for initiating formal clinical trials are additional topics discussed. An adequate regulatory and ethical framework as well as stringent criteria for the selection of patients will be critical for the safe clinical development of cardiac xenotransplantation, which we expect will be clinically tested during the next few years.

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“…However, there are other possible contributing factors, e.g., relating to complement, that may be playing a role in the vigorous serum cytotoxicity of NHPs to TKO pig organs (Fig. 2b) [36, 37]. To date, this problem has prevented consistent success of organ transplantation in the TKO pig-to-NHP model, although therapy with an anti-CD154 agent appears to overcome this barrier in some cases [39].…”

Section: Identification Of Pig “Non-gal” Xenoantigens and The Product...mentioning

confidence: 99%

The Long and Winding Road to Clinical Xenotransplantation: A Personal Journey

Cooper¹

2022

Eur Surg Res

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The recent clinical pig heart transplant carried out at the University of Maryland in Baltimore is hopefully the first of many xenotransplants that will resolve the problem of the lack of availability of organs from deceased human donors. I offer my personal recollections of how xenotransplantation research has progressed since the mid-1980s, when the pig-to-nonhuman primate (NHP) organ transplant model was established. Initially, hyperacute rejection or early antibody-mediated rejection was almost uniform. Among the milestones that were subsequently achieved are (i) the introduction of the first genetically-engineered pigs that expressed a human complement-regulatory protein, CD55, which was associated with prolonged graft function, extending to several weeks; (ii) the observation that conventional immunosuppressive therapy did not prevent an adaptive immune response, whereas the administration of an agent that blocked the CD40/CD154 T cell costimulation pathway was successful in this respect; (iii) the identification of the major pig carbohydrate xenoantigen as galactose-α1,3-galacose (Gal), followed by gene-editing to delete its expression, and the demonstration of prolonged survival of organs from these pigs in NHPs; (iv) the resolution of coagulation dysfunction between pig and primate by the introduction of genes for human coagulation-regulatory proteins; (v) the recognition of a prolonged systemic inflammatory response to a xenograft and its suppression either by drug therapy or by further gene-editing, and (vi) identification of two pig ‘nonGal’ xenoantigens and the production of triple-knockout (TKO) pigs. However, whereas many humans do not have antibodies against TKO pig cells, all Old World NHPs do have antibodies against these cells. This has provided an unexpected new barrier to testing TKO pig organ transplants in NHPs. The optimal gene-edited pig for clinical xenotransplantation may be one with 10 genetic manipulations. A pig with this genetic background provided the heart for the recent first clinical xenotransplant. In view of the current barrier to progress in the TKO pig-to-NHP model, the time has surely come when we need to consider moving from the laboratory to the clinic. Selection of patients for the first clinical trials is briefly discussed.

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The 2021 IXA Keith Reemtsma Lecture: Moving xenotransplantation to the clinic

Cited by 12 publications

References 50 publications

Innate Immune Response Analysis in Meniscus Xenotransplantation Using Normal and Triple Knockout Jeju Native Pigs

Innate Immune Response Analysis in Meniscus Xenotransplantation Using Normal and Triple Knockout Jeju Native Pigs

Cardiac xenotransplantation: from concept to clinic

The Long and Winding Road to Clinical Xenotransplantation: A Personal Journey

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