Endogenous Expression of B7-H4 Improves Long-term Murine Islet Allograft Survival

Background Allograft rejection is one of the main obstacles for islet transplantation. B7-H4 plays a key role in maintaining T-cell homeostasis by reducing T-cell proliferation and cytokine production. In this study, we investigated whether the endogenous expression of B7-H4 in &bgr; cells from B7-H4 transgenic mice enhances islet allograft survival. Methods B7-H4 transgenic C57BL/6 (B6) mice (RIP.B7-H4) were developed by inserting the entire B7-H4 open reading frame under the rat insulin promoter (RIP). B7-H4 protein expression was examined by flow cytometric analysis and immunohistochemical staining. Islet allograft survival was investigated in streptozotocin-induced diabetic recipient BALB/c (H-2d) mice transplanted with 400 islets from RIP.B7-H4 (H-2b) mice under the kidney capsule. The recipient control group received islets from wild-type B6 donors. Results B7-H4 protein was significantly up-regulated in isolated islets from RIP.B7-H4 compared with wild-type B6 mice (56%±23% vs. 3%±1.2%). B7-H4 was coexpressed with insulin, but not glucagon, suggesting that B7-H4 is expressed in a &bgr;-cell–specific manner. Recipient BALB/c mice transplanted with RIP.B7-H4 islets established euglycemia for 42.3±18.4 days (mean±SD; n=9) compared with controls at 23.1±7.8 days (mean±SD; n=12; P<0.004, log-rank test). Conclusions The endogenous expression of B7-H4 in donor &bgr; cells from transgenic mice prolongs islet allograft survival, confirming the negative role of B7-H4 in regulating alloreactive T-cell responses.

[1]  F. Bach,et al.  Activation of Peroxisome Proliferator-Activated Receptor γ Prolongs Islet Allograft Survival , 2012, Cell transplantation.

[2]  A. Kirk,et al.  CTLA4Ig Prevents Alloantibody Formation Following Nonhuman Primate Islet Transplantation Using the CD40‐Specific Antibody 3A8 , 2012, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[3]  S. Arora,et al.  Belatacept: a new biological agent for maintenance immunosuppression in kidney transplantation , 2012, Expert opinion on biological therapy.

[4]  Jiangnan Xu,et al.  Regulatory T cell migration during an immune response. , 2012, Trends in immunology.

[5]  N. Najafian,et al.  The Role of Coinhibitory Signaling Pathways in Transplantation and Tolerance , 2012, Front. Immun..

[6]  M. Jani,et al.  Abatacept in the long-term treatment of rheumatoid arthritis , 2012, Expert review of clinical immunology.

[7]  M. Schnitzler,et al.  Three‐Year Outcomes From BENEFIT‐EXT: A Phase III Study of Belatacept Versus Cyclosporine in Recipients of Extended Criteria Donor Kidneys , 2012, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[8]  Lieping Chen,et al.  B7-H4 Induces Donor-Specific Tolerance in Mouse Islet Allografts , 2012, Cell transplantation.

[9]  E. Werner,et al.  IDO and Regulatory T Cell Support Are Critical for Cytotoxic T Lymphocyte-Associated Ag-4 Ig-Mediated Long-Term Solid Organ Allograft Survival , 2012, The Journal of Immunology.

[10]  Lieping Chen,et al.  Early Treatment of NOD Mice With B7-H4 Reduces the Incidence of Autoimmune Diabetes , 2011, Diabetes.

[11]  B. Binstadt,et al.  Absence of β2 Integrins Impairs Regulatory T Cells and Exacerbates CD4+ T Cell-Dependent Autoimmune Carditis , 2011, The Journal of Immunology.

[12]  E. Boh,et al.  THERAPEUTIC HOTLINE: Abatacept: our experience of use in two patients with refractory psoriasis and psoriatic arthritis , 2011, Dermatologic therapy.

[13]  M. Azuma,et al.  In Vivo Function of Immune Inhibitory Molecule B7‐H4 in Alloimmune Responses , 2010, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[14]  Wei Zhou,et al.  Programmed Death-1 Signaling Is Essential for the Skin Allograft Protection by Alternatively Activated Dendritic Cell Infusion in Mice , 2009, Transplantation.

[15]  James D. Johnson,et al.  Different Effects of FK506, Rapamycin, and Mycophenolate Mofetil on Glucose-Stimulated Insulin Release and Apoptosis in Human Islets , 2009, Cell transplantation.

[16]  P. Xiong,et al.  B7-H4 transfection prolongs beta-cell graft survival. , 2009, Transplant immunology.

[17]  Lieping Chen,et al.  Local Expression of B7-H4 by Recombinant Adenovirus Transduction in Mouse Islets Prolongs Allograft Survival , 2009, Transplantation.

[18]  M. Willart,et al.  Inducible Costimulator Blockade Prolongs Airway Luminal Patency in a Mouse Model of Obliterative Bronchiolitis , 2008, Transplantation.

[19]  James D. Johnson,et al.  An Odyssey of Islet Transplantation for Therapy of Type 1 Diabetes , 2007, World Journal of Surgery.

[20]  C. Thivolet,et al.  Immunology of pancreatic islet transplantation. , 2006, Diabetes & metabolism.

[21]  M. Jordana,et al.  Generation and Characterization of B7-H4/B7S1/B7x-Deficient Mice , 2006, Molecular and Cellular Biology.

[22]  R. Bretzel,et al.  Ischaemia is linked to inflammation and induction of angiogenesis in pancreatic islets , 2006, Clinical and experimental immunology.

[23]  Lieping Chen,et al.  Suppression of Human T-Cell Responses to β-Cells by Activation of B7-H4 Pathway , 2006, Cell transplantation.

[24]  Lieping Chen,et al.  Suppression of human T-cell responses to beta-cells by activation of B7-H4 pathway. , 2006, Cell transplantation.

[25]  V. Dharnidharka.  Costimulation blockade with belatacept in renal transplantation. , 2005, The New England journal of medicine.

[26]  James D. Johnson,et al.  Improved human pancreatic islet isolation for a prospective cohort study of islet transplantation vs best medical therapy in type 1 diabetes mellitus. , 2005, Archives of surgery.

[27]  M. Dorf,et al.  Recruitment of Foxp3+ T regulatory cells mediating allograft tolerance depends on the CCR4 chemokine receptor , 2005, The Journal of experimental medicine.

[28]  Marcela Brissova,et al.  Intraislet endothelial cells contribute to revascularization of transplanted pancreatic islets. , 2004, Diabetes.

[29]  P. Loke,et al.  B7x: A widely expressed B7 family member that inhibits T cell activation , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[30]  C. Dong,et al.  B7S1, a novel B7 family member that negatively regulates T cell activation. , 2003, Immunity.

[31]  G. Zhu,et al.  B7-H4, a molecule of the B7 family, negatively regulates T cell immunity. , 2003, Immunity.

[32]  H. Waldmann,et al.  Identification of Regulatory T Cells in Tolerated Allografts , 2002, The Journal of experimental medicine.

[33]  Ames,et al.  Islet Transplantation in Seven Patients with Type 1 Diabetes Mellitus Using a Glucocorticoid-Free Immunosuppressive Regimen , 2000 .

[34]  P. Linsley,et al.  Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways , 1996, Nature.