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.
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.
Veld
Peter In't
PI
Diabetes Research Center, Brussels Free University - VUB and JDRF Center for Beta Cell Therapy in Diabetes, Brussels, Belgium. intveld@vub.ac.be
Pavlovic
Dejan
D
Bogdani
Marika
M
Pipeleers-Marichal
Miriam
M
Pipeleers
Daniel
D
D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D001786:Blood Glucose / Q000378:metabolism; D015704:CD4 Antigens / Q000276:immunology*; D016827:CD8 Antigens / Q000276:immunology*; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000628:therapy*; D005333:Fetus / Q000166:cytology; D006085:Graft Survival / Q000276:immunology; D007150:Immunohistochemistry; D007328:Insulin / Q000627:therapeutic use*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000637:transplantation*; D051379:Mice; D013552:Swine / Q000196:embryology; D014183:Transplantation, Heterologous / Q000276:immunology / Q000379:methods*
D000906:Antibodies; D001786:Blood Glucose; D015704:CD4 Antigens; D016827:CD8 Antigens; D007328:Insulin