Very late antigen 1 blockade markedly promotes survival of corneal allografts.

OBJECTIVE To investigate the role of very late antigen 1 (VLA-1) (also known as integrin receptor alpha(1)beta(1)) in corneal transplantation inflammation and allograft survival. METHODS Cell infiltration and vasculogenesis (both angiogenesis and lymphangiogenesis) associated with allodisparate corneal transplantation were assessed in VLA-1-deficient conditions and controls by immunofluorescent microscopic studies. Corneal allograft survival was also assessed after anti-VLA-1 antibody treatment and in VLA-1 knockout recipient mice. RESULTS Anti-VLA-1 antibody treatment leads to a profound reduction in the granulocytic, monocytic, and T-cell infiltration after corneal transplantation. In addition, corneal angiogenesis and lymphangiogenesis were both significantly suppressed in VLA-1 knockout mice. Remarkably, universal graft survival was observed in both anti-VLA-1 antibody treatment and knockout mice. CONCLUSIONS Very late antigen 1 blockade markedly reduces inflammation and inflammation-induced tissue responses, including vasculogenic responses, associated with corneal transplantation and promotes allograft survival. CLINICAL RELEVANCE These studies offer insights into important integrin-mediated mechanisms of corneal transplant-related inflammation and provide possible new integrin-based immunotherapies for transplant rejection.

[1]  Tatiana V. Petrova,et al.  Lymphangiogenesis in development and human disease , 2005, Nature.

[2]  P. Brown.  Lymphatic system: Unlocking the drains , 2005, Nature.

[3]  D. Sheppard,et al.  The Lymphangiogenic Vascular Endothelial Growth Factors VEGF-C and -D Are Ligands for the Integrin α9β1* , 2005, Journal of Biological Chemistry.

[4]  S. Ben-Horin,et al.  The role of very late antigen-1 in immune-mediated inflammation. , 2004, Clinical immunology.

[5]  K. Maruyama,et al.  Inhibition of hemangiogenesis and lymphangiogenesis after normal-risk corneal transplantation by neutralizing VEGF promotes graft survival. , 2004, Investigative ophthalmology & visual science.

[6]  M. Dana,et al.  Vascular endothelial growth factor receptor-3 mediates induction of corneal alloimmunity , 2004, Nature Medicine.

[7]  D. Boumpas,et al.  Lessons learned from anti-CD40L treatment in systemic lupus erythematosus patients , 2004, Lupus.

[8]  Jingtai Cao,et al.  VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. , 2004, The Journal of clinical investigation.

[9]  A. Berman,et al.  Integrins: Structure and Signaling , 2003, Biochemistry (Moscow).

[10]  H. Dvorak,et al.  T1α/podoplanin deficiency disrupts normal lymphatic vasculature formation and causes lymphedema , 2003, The EMBO journal.

[11]  V. Koteliansky,et al.  Functional Overlap and Cooperativity Among αv and β1 Integrin Subfamilies During Skin Angiogenesis , 2003 .

[12]  Claus Cursiefen,et al.  Corneal Lymphangiogenesis: Evidence, Mechanisms, and Implications for Corneal Transplant Immunology , 2003, Cornea.

[13]  D. Jackson,et al.  LYVE-1, the lymphatic system and tumor lymphangiogenesis. , 2001, Trends in immunology.

[14]  R. Dana,et al.  The critical role of lymph nodes in corneal alloimmunization and graft rejection. , 2001, Investigative ophthalmology & visual science.

[15]  M. Dana,et al.  Blockade of CD40-CD154 costimulatory pathway promotes survival of allogeneic corneal transplants. , 2001, Investigative ophthalmology & visual science.

[16]  M. Dana,et al.  Twenty-five–Year Panorama of Corneal Immunology: Emerging Concepts in the Immunopathogenesis of Microbial Keratitis, Peripheral Ulcerative Keratitis, and Corneal Transplant Rejection , 2000, Cornea.

[17]  M. Dana,et al.  ICAM-1 deficiency suppresses host allosensitization and rejection of MHC-disparate corneal transplants. , 2000, Transplantation.

[18]  V. Koteliansky,et al.  Regulation of inflammation by collagen-binding integrins α1β1 and α2β1 in models of hypersensitivity and arthritis , 2000 .

[19]  A. Pozzi,et al.  Elevated matrix metalloprotease and angiostatin levels in integrin alpha 1 knockout mice cause reduced tumor vascularization. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[20]  M. Dana,et al.  Role of tumor necrosis factor receptors TNFR-I (P55) and TNFR-II (P75) in corneal transplantation. , 1999, Transplantation.

[21]  G. Oliver,et al.  Prox1 Function Is Required for the Development of the Murine Lymphatic System , 1999, Cell.

[22]  K. Alitalo,et al.  Cardiovascular failure in mouse embryos deficient in VEGF receptor-3. , 1998, Science.

[23]  M. Dana,et al.  Topical modulation of interleukin-1 activity in corneal neovascularization. , 1998, Cornea.

[24]  M. Dana,et al.  Topical interleukin 1 receptor antagonist promotes corneal transplant survival. , 1997, Transplantation.

[25]  R. Jaenisch,et al.  Deletion of integrin alpha 1 by homologous recombination permits normal murine development but gives rise to a specific deficit in cell adhesion. , 1996, Developmental biology.

[26]  D. Sheppard,et al.  The lymphangiogenic vascular endothelial growth factors VEGF-C and -D are ligands for the integrin alpha9beta1. , 2005, The Journal of biological chemistry.

[27]  J. Partanen,et al.  Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins , 2004, Nature Immunology.

[28]  V. Koteliansky,et al.  Functional overlap and cooperativity among alphav and beta1 integrin subfamilies during skin angiogenesis. , 2003, The Journal of investigative dermatology.

[29]  M. Detmar,et al.  The alpha(1)beta(1) and alpha(2)beta(1) integrins provide critical support for vascular endothelial growth factor signaling, endothelial cell migration, and tumor angiogenesis. , 2002, The American journal of pathology.

[30]  M. Detmar,et al.  The α1β1 and α2β1 Integrins Provide Critical Support for Vascular Endothelial Growth Factor Signaling, Endothelial Cell Migration, and Tumor Angiogenesis , 2002 .

[31]  V. Koteliansky,et al.  Regulation of inflammation by collagen-binding integrins alpha1beta1 and alpha2beta1 in models of hypersensitivity and arthritis. , 2000, The Journal of clinical investigation.

[32]  M. Hemler.  VLA proteins in the integrin family: structures, functions, and their role on leukocytes. , 1990, Annual review of immunology.

[33]  T. Suie.  Department of Ophthalmology , 1969 .