Immune Responses of HLA Highly Sensitized and Nonsensitized Patients to Genetically Engineered Pig Cells

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An important question in xenotransplantation is whether an allotransplant can safely be carried out in a patient who has become sensitized to a pig xenograft. To answer this question, we have searched the literature. We primarily limited our review to the clinically relevant pig-to-non-human primate (NHP) model and found five studies that explored this topic. No NHP that had received a pig graft developed antibodies to alloantigens, and in vitro studies indicated no increased humoral and/or cellular alloreactivity. We carried out a small in vitro study ourselves that confirmed this conclusion. There have been three experiments in which patients undergoing dialysis were exposed to wild-type pig kidneys and three clinical studies related to bridging a patient in hepatic failure to liver allotransplantation. Despite the development of anti-pig antibodies, all subsequent organ (kidney or liver) allografts were successful (except possibly in one case). In addition, pig fetal islets were transplanted into patients with kidney allografts; there was no increase in panel-reactive alloantibodies and the kidney grafts continued to function satisfactorily. In conclusion, the limited data suggest that, after sensitization to pig antigens, there is no evidence of antibody-mediated or accelerated cellular rejection of a subsequent allograft.

Section: Hla Sensitization Is Detrimentalmentioning

confidence: 99%

Is sensitization to pig antigens detrimental to subsequent allotransplantation?

Hara

Zhang

et al. 2018

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“…Wild‐type (WT) pig cells express galactose‐α1,3‐galactose (Gal), N‐glycolylneuraminic acid (Neu5Gc), and the product of porcine β1,4‐N‐acetylgalactosaminyltransferase 2 (β4GalNT2) indicated as Sd a (which might be a different product from human β4GalNT2) . As humans do not express any of these three glycans (though many express a human version of Sd a ), they develop antibodies to these xenoantigens …”

Section: Introductionmentioning

confidence: 99%

Carbohydrate antigen expression and anti‐pig antibodies in New World capuchin monkeys: Relevance to studies of xenotransplantation

Shaikh

Iwase

et al. 2019

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Background: Old World non-human primates (OWNHPs) are used for preclinical pigto-NHP studies. However, like pigs, OWNHPs express Neu5Gc, and therefore do not develop natural anti-Neu5Gc antibodies. New World NHPs (NWNHPs) have been reported not to express Neu5Gc. We investigated the potential of NWNHPs in xenotransplantation research. Methods:We investigated expression of Gal, Neu5Gc, and Sd a antigens on RBCs and PBMCs from humans, selected OWNHPs, and capuchin monkeys (a NWNHP). Serum anti-Gal and anti-Neu5Gc IgM and IgG levels were measured by ELISA. Binding of primate serum IgM and IgG to pig RBCs was measured by flow cytometry.

“…Some HLA‐sensitized wait list patients have anti‐HLA antibodies that cross‐react with swine leukocyte antigens (SLAs), thus placing them at a greater risk of rejection of a pig kidney graft, but there are other HLA‐sensitized patients who do not appear to have antibodies that cross‐react with SLA . Highly HLA‐sensitized patients who do not have anti‐SLA antibodies may therefore be very suitable candidates for kidney xenotransplantation.…”

Section: The Problem Of the Hla‐sensitized Patientmentioning

confidence: 99%

Chronic dialysis in patients with end‐stage renal disease: Relevance to kidney xenotransplantation

Jagdale

Cooper

Iwase

et al. 2018

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Renal allotransplantation clearly offers better survival and quality of life for end‐stage renal disease (ESRD) patients than chronic dialysis. The median waiting time for a deceased donor kidney in a suitable ESRD patient is 3.9 years. The initial candidates for pig kidney xenotransplantation will be those with ESRD unlikely to receive an allograft within a reasonable period of time. It is thus reasonable to ascertain whether clinical trials of xenotransplantation might likewise offer superior outcomes. Chronic dialysis in patients with ESRD is associated with poor quality of life, significant morbidity, and relatively high mortality, with only 56% surviving 3 years and 42% at 5 years. However, a significant number of these patients, because of comorbidities, frailty, etc, would not be considered for renal allotransplantation and likely not for xenotransplantation. As genetically engineered pig kidneys have satisfactorily supported life in immunosuppressed nonhuman primates for many months or even more than a year, consideration in carefully selected patients could be given to pig kidney xenotransplantation. We suggest that, in order to give a patient the best possible outcome, the pig kidney could be transplanted pre‐emptively (before dialysis is initiated). If it fails at any stage, the patient would then begin chronic dialysis and continue to await an allograft. The present (limited) evidence is that failure of a pig graft would not be detrimental to a subsequent allograft.