TY - JOUR
T1 - Localized cytotoxic T cell–associated antigen 4 and antioxidant islet encapsulation alters macrophage signaling and induces regulatory and anergic T cells to enhance allograft survival
AU - Barra, Jessie M.
AU - Kozlovskaya, Veronika
AU - Burnette, Ka Lia S.
AU - Banerjee, Ronadip R.
AU - Fraker, Christopher A.
AU - Kharlampieva, Eugenia
AU - Tse, Hubert M.
N1 - Publisher Copyright:
© 2023 American Society of Transplantation & American Society of Transplant Surgeons
PY - 2023/4
Y1 - 2023/4
N2 - The loss of functional β-cell mass is a hallmark of type 1 diabetes. Islet transplantation represents a promising alternative approach, but immune-mediated graft destruction remains a major challenge. We sought to use islet encapsulation technologies to improve graft survival and function without systemic immunosuppression. We hypothesized islet encapsulation with nanothin coatings consisting of tannic acid (TA), an antioxidant; poly(N-vinylpyrrolidone) (PVPON), a biocompatible polymer; and cytotoxic T cell–associated antigen 4 immunoglobulin (CTLA-4-Ig), an inhibitory immune receptor, will elicit localized immunosuppression to prolong islet allograft function and suppress effector T cell responses. In the absence of systemic immunosuppression, we demonstrated (PVPON/TA/CTLA-4-Ig)-encapsulated NOD.Rag islet grafts maintain function significantly longer than control IgG-containing (PVPON/TA/IgG) and nonencapsulated controls after transplantation into diabetic C57BL/6 mice. This protection coincided with diminished proinflammatory macrophage responses mediated by signal transducer and activator of transcription 1 signaling, decreased proinflammatory T cell effector responses, and CTLA-4-Ig-specific concomitant increases in anergic CD4+ T cells and regulatory T cells. Our results provide evidence that conjugation of CTLA-4-Ig to (PVPON/TA) coatings can suppress T cell activation, enhance regulatory T cell populations, prolong islet allograft survival, and induce localized immunosuppression after transplantation.
AB - The loss of functional β-cell mass is a hallmark of type 1 diabetes. Islet transplantation represents a promising alternative approach, but immune-mediated graft destruction remains a major challenge. We sought to use islet encapsulation technologies to improve graft survival and function without systemic immunosuppression. We hypothesized islet encapsulation with nanothin coatings consisting of tannic acid (TA), an antioxidant; poly(N-vinylpyrrolidone) (PVPON), a biocompatible polymer; and cytotoxic T cell–associated antigen 4 immunoglobulin (CTLA-4-Ig), an inhibitory immune receptor, will elicit localized immunosuppression to prolong islet allograft function and suppress effector T cell responses. In the absence of systemic immunosuppression, we demonstrated (PVPON/TA/CTLA-4-Ig)-encapsulated NOD.Rag islet grafts maintain function significantly longer than control IgG-containing (PVPON/TA/IgG) and nonencapsulated controls after transplantation into diabetic C57BL/6 mice. This protection coincided with diminished proinflammatory macrophage responses mediated by signal transducer and activator of transcription 1 signaling, decreased proinflammatory T cell effector responses, and CTLA-4-Ig-specific concomitant increases in anergic CD4+ T cells and regulatory T cells. Our results provide evidence that conjugation of CTLA-4-Ig to (PVPON/TA) coatings can suppress T cell activation, enhance regulatory T cell populations, prolong islet allograft survival, and induce localized immunosuppression after transplantation.
KW - cytotoxic T cell–associated antigen 4 immunoglobulin
KW - encapsulation
KW - islet transplantation
KW - tannic acid
KW - type 1 diabetes
UR - http://www.scopus.com/inward/record.url?scp=85150235386&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85150235386&partnerID=8YFLogxK
U2 - 10.1016/j.ajt.2023.01.007
DO - 10.1016/j.ajt.2023.01.007
M3 - Article
C2 - 36731781
AN - SCOPUS:85150235386
SN - 1600-6135
VL - 23
SP - 498
EP - 511
JO - American Journal of Transplantation
JF - American Journal of Transplantation
IS - 4
ER -