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Xenotransplantation of purified pre‐natal porcine beta cells in mice normalizes diabetes when a short anti‐CD4–CD8 antibody treatment is combined with transient insulin injections
Author(s) -
Veld Peter In't,
Pavlovic Dejan,
Bogdani Marika,
PipeleersMarichal Miriam,
Pipeleers Daniel
Publication year - 2006
Publication title -
xenotransplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.052
H-Index - 61
eISSN - 1399-3089
pISSN - 0908-665X
DOI - 10.1111/j.1399-3089.2006.00328.x
Subject(s) - islet , antibody , cd8 , xenotransplantation , medicine , beta cell , endocrinology , transplantation , insulin , immune system , diabetes mellitus , immunosuppression , andrology , immunology
Background: Pre‐natal porcine endocrine islet cell grafts were recently shown to contain immature beta cells with a marked potential for growth and differentiation following transplantation, and hence for a progressive and long‐term correction of diabetes in immune‐incompetent mice. The present study investigates whether these grafts are also capable of correcting hyperglycemia in immune‐competent mice receiving a short treatment with anti‐CD4–CD8 antibodies. Methods: Pure endocrine islet cell grafts with 0.5 to 1.0 million beta cells were prepared from pre‐natal pigs and transplanted under the kidney capsule of alloxan‐diabetic CBA/Ca mice. Survival, growth and function of implanted beta cells were followed by measuring plasma porcine C‐peptide and glucose, and graft insulin content at start and at post‐transplant (PT) week 35. The effect was studied of a 5‐day treatment with non‐depleting anti‐CD4 YTS177 and depleting anti‐CD8 YTS169 antibody, either without or with transient insulin injections. Results: Without antibody treatment, all graft recipients remained porcine C‐peptide negative and died. Antibody treatment decreased CD4‐expression and percentage CD8 cells for 10 and 18 weeks respectively. It resulted in a 30 week‐survival of nine out of 14 graft recipients; all nine had progressively become C‐peptide positive but only one proceeded to normoglycemia. When antibody treatment was combined with transient insulin injections, 11 out of 14 graft recipients survived long‐term, eight became C‐peptide positive and six were normoglycemic at PT week 30. In both groups, surviving recipients exhibited a graft insulin content that was 6‐ to 9‐fold higher than at implantation. Conclusions: Pre‐natal porcine beta cells grow and differentiate when transplanted in diabetic immune‐competent mice that have been transiently immune suppressed with anti‐CD4 and anti‐CD8 monoclonal antibodies. They develop metabolic control when recipients are also transiently treated with insulin injections.