title: Islet xenotransplantation using gal-deficient neonatal donors improves engraftment and function.
abstract: Significant deficiencies in understanding of xenospecific immunity have impeded the success of preclinical trials in xenoislet transplantation. Although galactose-α1,3-galactose, the gal epitope, has emerged as the principal target of rejection in pig-to-primate models of solid organ transplant, the importance of gal-specific immunity in islet xenotransplant models has yet to be clearly demonstrated. Here, we directly compare the immunogenicity, survival and function of neonatal porcine islets (NPIs) from gal-expressing wild-type (WT) or gal-deficient galactosyl transferase knockout (GTKO) donors. Paired diabetic rhesus macaques were transplanted with either WT (n = 5) or GTKO (n = 5) NPIs. Recipient blood glucose, transaminase and serum xenoantibody levels were used to monitor response to transplant. Four of five GTKO versus one of five WT recipients achieved insulin-independent normoglycemia; transplantation of WT islets resulted in significantly greater transaminitis. The WT NPIs were more susceptible to antibody and complement binding and destruction in vitro. Our results confirm that gal is an important variable in xenoislet transplantation. The GTKO NPI recipients have improved rates of normoglycemia, likely due to decreased susceptibility of xenografts to innate immunity mediated by complement and preformed xenoantibody. Therefore, the use of GTKO donors is an important step toward improved consistency and interpretability of results in future xenoislet studies.
authors: Emory Transplant Center, Emory University, Atlanta, GA, USA.
authors: P
authors: P
authors: Thompson
authors: I R
authors: IR
authors: Badell
authors: M
authors: M
authors: Lowe
authors: J
authors: J
authors: Cano
authors: M
authors: M
authors: Song
authors: F
authors: F
authors: Leopardi
authors: J
authors: J
authors: Avila
authors: R
authors: R
authors: Ruhil
authors: E
authors: E
authors: Strobert
authors: G
authors: G
authors: Korbutt
authors: G
authors: G
authors: Rayat
authors: R
authors: R
authors: Rajotte
authors: N
authors: N
authors: Iwakoshi
authors: C P
authors: CP
authors: Larsen
authors: A D
authors: AD
authors: Kirk
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000910:Antibodies, Heterophile / Q000276:immunology; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000517:prevention & control*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005700:Galactosyltransferases / Q000172:deficiency*; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D007113:Immunity, Innate; D007124:Immunoenzyme Techniques; D016381:Islets of Langerhans Transplantation; D008253:Macaca mulatta; D013552:Swine; D014019:Tissue Donors; D014183:Transplantation, Heterologous
chemical_list: D000910:Antibodies, Heterophile; D001786:Blood Glucose; D005700:Galactosyltransferases; C047006:N-acetyllactosaminide alpha-1,3-galactosyltransferase