The respective relevance of sensitization to alloantigens and xenoantigens in pig organ xenotransplantation

Cooper, D. K. C.; Habibabady, Zahra; Kinoshita, K; Hara, Hidetaka; Pierson, Richard N.

doi:10.1016/j.humimm.2022.06.003

Cited by 17 publications

(12 citation statements)

References 73 publications

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“…The autopsy showed findings that were uncharacteristic of typical rejection ( Griffith et al., 2022 ). Surprisingly, most humans have anti-porcine Sd a antibodies; ∼96% of humans express Sd a , and only 1%–2% have naturally occurring anti-human Sd a antibodies ( Cooper et al., 2022 ). This discrepancy may in part be due to a similar antigen known as Cad, which has been called “super” Sd a (meaning that it is a strong form of Sd a ).…”

Section: Common Human Enzyme Deficienciesmentioning

confidence: 99%

ABO blood group antigens and differential glycan expression: Perspective on the evolution of common human enzyme deficiencies

Jajosky

Zheng

et al. 2023

iScience

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Section: Common Human Enzyme Deficienciesmentioning

confidence: 99%

ABO blood group antigens and differential glycan expression: Perspective on the evolution of common human enzyme deficiencies

Jajosky

Zheng

et al. 2023

iScience

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“… 160–162 This is in contrast to the evidence that indicates that prior allosensitization may be detrimental to a subsequent allograft whereas it has been clearly documented that the anti-HLA alloantibodies do not cross-react with pig antigens. 162 , 163 …”

Section: Selection Of Patientsmentioning

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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“…These results correlate well with those of Eyestone et al 61 and indicate that additional transgenic expression of selected human proteins (eg, CD46, CD55) on TKO pig cells may have a protective effect after pig-to-NHP organ transplantation. 6 THE IMPACT OF SENSITIZATION TO HLA OR SLAS This topic has recently been comprehensively reviewed previously, 62 and the data will only be summarized here.…”

Section: Investigating the Optimal Pig Phenotype When An Ownhp Is To ...mentioning

confidence: 99%

“…This topic has recently been comprehensively reviewed previously, 62 and the data will only be summarized here.…”

Section: The Impact Of Sensitization To Hla or Slasmentioning

confidence: 99%

“…The data indicate that a primary xenograft does not induce a humoral or accelerated cell-mediated immune response that would jeopardize the survival of a secondary allograft. 53,62,66,67 However, the results must be interpreted cautiously because not only are the number of reports few, but also exposure to pig antigens has been, at times, relatively brief. There have also been varying periods between developing sensitization to pig antigens and subsequent exposure to alloantigens.…”

Section: The Impact Of Sensitization To Hla or Slasmentioning

confidence: 99%

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What Have We Learned From In Vitro Studies About Pig-to-primate Organ Transplantation?

et al. 2022

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Natural preformed and de novo antibodies against pig antigens are a major cause of pig xenograft rejection in nonhuman primates (NHPs). In vivo studies in pig-to-NHP models are time consuming. In vitro assays, for example, antibody binding to pig cells, complement-dependent cytotoxicity assays, provide valuable information quickly and inexpensively. Using in vitro assays for several years, it has been documented that (1) during the first year of life, humans and NHPs develop anti-wild-type pig antibodies, but humans develop no or minimal antibody to triple-knockout (TKO) pig cells. (2) Some adult humans have no or minimal antibodies to TKO pig cells and are therefore unlikely to rapidly reject a TKO organ, particularly if the organ also expresses human "protective" proteins. (3) There is good correlation between immunoglobulin (Ig)M (but not IgG) binding and complement injury. (4) All Old World NHPs develop antibodies to TKO pig cells and are not optimal recipients of TKO organs. ( 5) galactosyltransferase gene-knockout/β4GalNT2KO pigs are preferred for Old World NHPs. ( 6) Humans develop anti-pig IgE and IgA antibodies against pig cells, but their role remains uncertain. ( 7) In a small percentage of allosensitized humans, antibodies that cross-react with swine leukocyte antigens may be detrimental to a pig organ xenograft. (8) Prior sensitization to pig antigens is unlikely to be detrimental to a subsequent allograft. ( 9) Deletion of expression of Gal and Neu5Gc is associated with a reduction in the T-cell response to pig cells. All of these valuable observations have largely predicted the results of in vivo studies.

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The respective relevance of sensitization to alloantigens and xenoantigens in pig organ xenotransplantation

Cited by 17 publications

References 73 publications

ABO blood group antigens and differential glycan expression: Perspective on the evolution of common human enzyme deficiencies

ABO blood group antigens and differential glycan expression: Perspective on the evolution of common human enzyme deficiencies

Cardiac xenotransplantation: from concept to clinic

What Have We Learned From In Vitro Studies About Pig-to-primate Organ Transplantation?

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