Effect of triple costimulation blockade on islet allograft survival in sensitized mice.
BACKGROUND
Islet allograft rejection in sensitized recipients is difficult to control by costimulation blockade using anti-CD154 and cytotoxic T-lymphocyte antigen-4 immunoglobulin (CTLA4Ig). Because leukocyte function antigen (LFA) 1 is highly expressed on memory T cells, adding an LFA-1 blockade may inhibit memory T-cell activities. We examined the effects on islet allograft survival of triple costimulation blockade in presensitized recipient mice.


METHODS
C57BL/6 mice were sensitized by transplantation under the kidney capsule or intraperitoneal injection of Balb/c islets. Four weeks after transplantation, sensitization was confirmed by flow-cytometric detection of alloreactive antibodies. Diabetes was induced by a single intravenous injection of streptozotocin. Recipients were transplanted with 200 Balb/c islets under the right kidney capsule. Graft function was assessed by daily blood glucose and body weight records. Transplanted animals were divided into 3 treatment groups: group 1, control antibody; group 2, anti-CD154 and CTLA-4 Ig double therapy; group 3, anti-CD154, CTLA4Ig, and anti-LFA-1 triple therapy. Injections were administered every second day from day -2 to day 8.


RESULTS
Naïve mice rejected islet allografts between days 7 and 29 (mean 16 +/- 6 d; n = 5), sensitized mice in group 1 between days 0 and 14 (mean 7 +/- 5 d; n = 8), in group 2 between days 4 and 16 (mean 8 +/- 4 d; n = 7), and in group 3 between days 4 and 26 (mean 11 +/- 7 d; n = 10).


CONCLUSIONS
Triple costimulation blockade with anti-CD154, CTLA4Ig, and anti-LFA-1 was not sufficient to improve islet allograft survival in sensitized recipients.
Diab
R
R
Department of Laboratory Medicine, Division of Clinical Immunology and Transfusion Medicine, Karolinska Institutet, Stockholm, Sweden.
Iwata
T
T
Corbascio
M
M
Tibell
A
A
Ekberg
H
H
Holgersson
J
J
Kumagai-Braesch
M
M
D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D001786:Blood Glucose / Q000378:metabolism; D060908:CTLA-4 Antigen; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000601:surgery*; D006084:Graft Rejection / Q000097:blood; D006085:Graft Survival / Q000502:physiology*; D007074:Immunoglobulin G / Q000276:immunology; D016381:Islets of Langerhans Transplantation / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012086:Reoperation; D014184:Transplantation, Homologous / Q000276:immunology / Q000473:pathology / Q000502:physiology*
D015703:Antigens, CD; D001786:Blood Glucose; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D007074:Immunoglobulin G