Anti-LFA-1 improves pig islet xenograft function in diabetic mice when long-term acceptance is induced by CTLA4Ig/anti-CD40L.
BACKGROUND
It has been previously demonstrated that addition of anti-LFA-1 to a combination of CTLA4Ig and anti-CD40L induces the permanent acceptance of dopaminergic fetal pig xenografts when transplanted into the brain of wild-type mice. The purpose of this study was to test whether this costimulation blockade also can induce acceptance of adult pig islets transplanted to C57BL/6 mice with streptozotocin-induced diabetes.


METHODS
Recipients were treated with CTLA4Ig/anti-CD40L+/-anti-LFA-1 or isotype control antibodies during the first week after transplantation. Half of the costimulation blockade-treated recipients had their grafts removed after 8 weeks. The other half was observed up to 5 months.


RESULTS
Recipients treated with CTLA4Ig/anti-CD40L/anti-LFA-1 had significantly lower blood glucose and gained more weight than CTLA4Ig/anti-CD40L-treated recipients. CTLA4Ig/anti-CD40L-treated recipients exhibited unstable blood glucose. IPGTT of these recipients revealed a slow recovery to normal blood glucose levels at week 4. In comparison, CTLA4Ig/anti-CD40L/anti-LFA-1 treated recipients exhibited a significantly superior glucose clearance. CTLA4Ig/anti-CD40L+/-anti-LFA-1 treated recipients did not produce anti-pig IgG, whereas control antibody-treated mice did. CD4+ T cells from costimulation blockade-treated recipients proliferated less than CD4+ T cells from control antibody-treated mice when co-cultured with syngeneic antigen presenting cells loaded with pig islet antigens.


CONCLUSIONS
CTLA4Ig/anti-CD40L/anti-LFA-1-treated recipients had superior islet function compared with CTLA4Ig/anti-CD40L-treated recipients. However, both costimulation blockade regimens led to islet graft acceptance up to 5 months after a 1-week treatment.
Kumagai-Braesch
Makiko
M
Department of Transplantation Surgery, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
Ekberg
Henrik
H
Wang
Feng
F
Osterholm
Cecilia
C
Ehrnfelt
Cecilia
C
Sharma
Amit
A
Lindeborg
Ellinor
E
Holgersson
Jan
J
Corbascio
Matthias
M
D000069594:Abatacept; D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D023201:CD40 Ligand / Q000276:immunology*; D049109:Cell Proliferation; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000601:surgery*; D000939:Epitopes; D005260:Female; D005947:Glucose / Q000494:pharmacology; D018796:Immunoconjugates / Q000494:pharmacology*; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology; D007515:Islets of Langerhans / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D016381:Islets of Langerhans Transplantation; D007962:Leukocytes / Q000473:pathology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D013552:Swine; D013997:Time Factors; D014183:Transplantation, Heterologous
D000906:Antibodies; D001786:Blood Glucose; D000939:Epitopes; D018796:Immunoconjugates; D007074:Immunoglobulin G; D016169:Lymphocyte Function-Associated Antigen-1; D023201:CD40 Ligand; D000069594:Abatacept; D005947:Glucose