title: B-cell depletion extends the survival of GTKO.hCD46Tg pig heart xenografts in baboons for up to 8 months.
abstract: Xenotransplantation of genetically modified pig organs offers great potential to address the shortage of human organs for allotransplantation. Rejection in Gal knockout (GTKO) pigs due to elicited non-Gal antibody response required further genetic modifications of donor pigs and better control of the B-cell response to xenoantigens. We report significant prolongation of heterotopic alpha Galactosyl transferase "knock-out" and human CD46 transgenic (GTKO.hCD46Tg) pig cardiac xenografts survival in specific pathogen free baboons. Peritransplant B-cell depletion using 4 weekly doses of anti-CD20 antibody in the context of an established ATG, anti-CD154 and MMF-based immunosuppressive regimen prolonged GTKO.hCD46Tg graft survival for up to 236 days (n = 9, median survival 71 days and mean survival 94 days). B-cell depletion persisted for over 2 months, and elicited anti-non-Gal antibody production remained suppressed for the duration of graft follow-up. This result identifies a critical role for B cells in the mechanisms of elicited anti-non-Gal antibody and delayed xenograft rejection. Model-related morbidity due to variety of causes was seen in these experiments, suggesting that further therapeutic interventions, including candidate genetic modifications of donor pigs, may be necessary to reduce late morbidity in this model to a clinically manageable level.
authors: Cardiothoracic Surgery Research Program, National Heart Lung & Blood Institute/NIH, Bethesda, MD, USA. mohiuddinm@mail.nih.gov
authors: M M
authors: MM
authors: Mohiuddin
authors: P C
authors: PC
authors: Corcoran
authors: A K
authors: AK
authors: Singh
authors: A
authors: A
authors: Azimzadeh
authors: R F
authors: RF
authors: Hoyt
authors: M L
authors: ML
authors: Thomas
authors: M A
authors: MA
authors: Eckhaus
authors: C
authors: C
authors: Seavey
authors: D
authors: D
authors: Ayares
authors: R N
authors: RN
authors: Pierson
authors: K A
authors: KA
authors: Horvath
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000917:Antibody Formation / Q000276:immunology; D001402:B-Lymphocytes / Q000378:metabolism*; D005434:Flow Cytometry; D005700:Galactosyltransferases / Q000235:genetics*; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology*; D006801:Humans; D007124:Immunoenzyme Techniques; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D051916:Membrane Cofactor Protein / Q000235:genetics*; D010215:Papio; D015996:Survival Rate; D013552:Swine; D014183:Transplantation, Heterologous / Q000276:immunology*
chemical_list: D007166:Immunosuppressive Agents; D051916:Membrane Cofactor Protein; D005700:Galactosyltransferases; C063053:xylosylprotein 4-beta-galactosyltransferase