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Abstract: Tacrolimus‐associated thrombotic microangiopathy (TA‐TMA) is a rare complication. TA‐TMA is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ damage due to thrombus. We report asymptomatic TA‐TMA diagnosed by laboratory tests in pig‐to‐rhesus corneal xenotransplantation. Corneal transplantation had been conducted from a wild‐type SNU miniature pig to a rhesus macaque. The veterinary records were retrospectively reviewed in this case. The immunosuppressive regimen consisted of rituximab, basiliximab, and IVIg as inductive therapies, and steroids with tacrolimus (0.1 mg/kg/day) as maintenance therapies. Although there were no clinical symptoms, increased levels of lactate dehydrogenase, total bilirubin, blood urea nitrogen, and creatinine and decreased levels of hemoglobin and platelet were observed in laboratory tests on Day (D) 61. Systemic TA‐TMA was tentatively diagnosed. Tacrolimus was discontinued starting on D71. Dalteparin, clopidogrel bisulfate (D77‐D99), and IVIg (D72) were administered as a conservative treatment. Abnormal laboratory results were reversed on D99. When low‐dose tacrolimus (0.07 mg/kg/day) was re‐administered on D131 to prevent rejection of the graft, TMA was detected again by laboratory tests on D161, confirming the initial diagnosis. Discontinuation of tacrolimus on D162 and re‐administration of Dalteparin (D161‐D196) corrected the laboratory values on D161. This report shows that in pig‐to‐rhesus corneal xenotransplantation, clinically asymptomatic TMA can be induced by tacrolimus, and the discontinuation of tacrolimus and administration of anticoagulant seems sufficient to correct the laboratory TMA. [ABSTRACT FROM AUTHOR]

Background: We aimed to investigate (a) the long‐term survival of corneal grafts from α1,3‐galactosyltransferase gene‐knockout miniature (GTKOm) pigs in non‐human primates as a primary outcome and (b) the effect of anti‐CD20 antibody on the survival of corneal grafts from GTKOm pigs as a secondary outcome. Methods: Nine rhesus macaques undergoing full‐thickness corneal xenotransplantation using GTKOm pigs were systemically administered steroid, basiliximab, intravenous immunoglobulin, and tacrolimus with (CD20 group) or without (control group) anti‐CD20 antibody. Results: Graft survival was significantly longer (P =.008) in the CD20 group (>375, >187, >187, >83 days) than control group (165, 91, 72, 55, 37 days). When we compared the graft survival time between older (>7‐ month‐old) and younger (≤7‐month‐old) aged donor recipients, there was no significant difference. Activated B cells were lower in the CD20 group than control group (P =.026). Aqueous humor complement C3a was increased in the control group at last examination (P =.043) and was higher than that in the CD20 group (P =.014). Anti‐αGal IgG/M levels were unchanged in both groups. At last examination, anti‐non‐Gal IgG was increased in the control group alone (P =.013). Conclusions: The GTKOm pig corneal graft achieved long‐term survival when combined with anti‐CD20 antibody treatment. Inhibition of activated B cells and complement is imperative even when using GTKO pig corneas. [ABSTRACT FROM AUTHOR]

The article discusses that the shortage of human donor corneas has stimulated interest in corneal xenotransplantation, with porcine corneas being considered a feasible source. Partial-thickness acellular porcine corneal grafts are in use but there has been no clinical application of fresh (cellular) porcine corneas, which is considered true “xenotransplantation” by the World Health Organization.

Background: Xenotransplantation using fresh porcine corneas has been suggested as a feasible alternative to overcome the shortage of human donor corneas. Successful long‐term survival of grafts without evidence of xenozoonosis in clinically applicable pig‐to‐non‐human primate corneal transplantation model has brought researchers close to human clinical trials. Accordingly, we aimed to prepare a clinical trial protocol to conduct the first corneal xenotransplantation. Methods: We developed the clinical trial protocol based on international consensus statement on conditions for undertaking clinical trials of corneal xenotransplantation developed by the International Xenotransplantation Society. Detailed contents of the protocol have been modified with reference to comments provided by ophthalmologists and multidisciplinary experts, including an infectionist, an organ transplantation specialist, a clinical pharmacologist, a neuropsychiatrist, a laboratory medicine doctor, and a microbiologist. Results: Two patients with bilateral legal corneal blindness (best‐corrected visual acuity ≤20/200 in the better eye and ≤20/1000 in the candidate eye) or with (impending) corneal perforation will be enrolled. During the screening period, participants and their family members will have two separate deep consideration periods before signing informed consent forms. Each patient will undergo corneal xenotransplantation using fresh corneas from Seoul National University miniature pigs. Commercially available immunosuppressants will be administered and systemic infection prophylaxis will be performed according to the program schedule. After transplantation, each patient will be monitored at a specialized clinic to investigate safety up to 2 years and efficacy up to 1 year. Conclusions: A detailed clinical trial protocol for the first corneal xenotransplantation reflecting the global guidelines is provided. [ABSTRACT FROM AUTHOR]

Background: To investigate alpha Gal (Gal alpha1-3Gal beta 1-4GlcNAc-R) expression of the porcine cornea in vitro, in vivo and after xenotransplantation., Methods: Using the GS-IB4 lectin (Griffonia simplifolia I isolectin B4), the expression of alpha Gal was evaluated in the normal porcine cornea and in cultured corneal stromal and endothelial cells of the second passages. The distribution of alpha Gal epitopes was also evaluated in corneal grafts at 4, 7 and 10 days after pig-to-rat orthotopic corneal transplantation., Results: The expression of alpha Gal was mostly confined to the anterior stromal keratocytes of the normal porcine cornea. However, reactivity for GS-IB4 was markedly increased during cell culture passage (P)-by 18.0% (P1) and 39.0% (P2) in cultivated keratocytes, and by 62.1% (P1) and 87.1% (P2) in cultured endothelial cells. The expression of alpha Gal epitopes was gradually enhanced in all corneal layers of the graft after transplantation., Conclusion: Alpha Gal expression in the cornea was gradually induced during in vitro culture and after xenotransplantation, suggesting a role of putative Gal-related acute humoral rejection in porcine corneal xenotransplantation.