Beta 3 integrins regulate lymphocyte migration and cytokine responses in heart transplant rejection.
Integrin alpha v beta 3 is important for cell survival, signaling and migration, particularly during angiogenesis and tumorigenesis, where it has been proposed as a therapeutic target. alpha v beta 3 is up-regulated following transplantation and beta 3 polymorphisms are associated with increased acute kidney rejection, suggesting that alpha v beta 3 may also play a role in transplant rejection. Here, using a model of allogeneic heart transplantation, we show that allograft survival is prolonged in beta 3 integrin-deficient (beta 3(-/-)) mice. This is associated with Th2-type immune responses and reduced T-cell infiltration into grafts and T cells from beta 3(-/-) mice show impaired adhesion and migration, consistent with a role for alpha v beta 3 in transmigration. These studies provide evidence that targeting beta 3 integrins impairs recruitment of effector cells and alters cytokine production, so prolonging graft survival. We also show that low doses of blocking antibodies against leukocyte function associated antigen-1 (LFA-1)/alpha L beta 2 and very late antigen-4 (VLA-4)/alpha 4 beta 1, when combined with deletion of beta 3, lead to long-term survival of allografts with no evidence of chronic rejection. Hence we provide strong mechanistic evidence supporting previous genetic studies, demonstrate the involvement of beta 3 integrins in both acute and chronic rejection and identify beta 3 as a new target for immunosuppressive therapy.
Lacy-Hulbert
A
A
Howard Hughes Medical Institute, Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
Ueno
T
T
Ito
T
T
Jurewicz
M
M
Izawa
A
A
Smith
R N
RN
Chase
C M
CM
Tanaka
K
K
Fiorina
P
P
Russell
P S
PS
Auchincloss
H
H
Sayegh
M H
MH
Hynes
R O
RO
Abdi
R
R
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D016207:Cytokines / Q000502:physiology*; D017353:Gene Deletion; D006084:Graft Rejection / Q000473:pathology / Q000503:physiopathology*; D006085:Graft Survival / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D039041:Integrin alpha4beta1 / Q000276:immunology; D039661:Integrin beta3 / Q000235:genetics / Q000502:physiology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000473:pathology / Q000502:physiology*; D014184:Transplantation, Homologous
D000906:Antibodies; D016207:Cytokines; D039041:Integrin alpha4beta1; D039661:Integrin beta3; D016169:Lymphocyte Function-Associated Antigen-1