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

Xenotransplantation. 2006 Sep;13(5):415-22. doi: 10.1111/j.1399-3089.2006.00328.x.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / therapeutic use*
  • Blood Glucose / metabolism
  • CD4 Antigens / immunology*
  • CD8 Antigens / immunology*
  • Diabetes Mellitus, Experimental / immunology
  • Diabetes Mellitus, Experimental / therapy*
  • Fetus / cytology
  • Graft Survival / immunology
  • Immunohistochemistry
  • Insulin / therapeutic use*
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / transplantation*
  • Mice
  • Swine / embryology
  • Transplantation, Heterologous / immunology
  • Transplantation, Heterologous / methods*

Substances

  • Antibodies
  • Blood Glucose
  • CD4 Antigens
  • CD8 Antigens
  • Insulin