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Assesing the role of B7‐1 in Diabetic Nephropathy
Author(s) -
Herrera Marcela,
Soderberg Magnus,
Molne Joan,
Santamaria Beatriz,
Balverde Angela,
Heasman Stephanie,
Jermutus Lutz,
Baker David,
Moreno Carol
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.lb730
Subject(s) - albuminuria , diabetic nephropathy , cd80 , abatacept , podocyte , medicine , t cell , immunology , immune system , cancer research , antibody , in vitro , chemistry , kidney , cytotoxic t cell , proteinuria , cd40 , rituximab , biochemistry
Diabetic Nephropathy (DN) remains an unmet medical challenge as its prevalence is projected to continue to increase and specific medicines for treatment remain undeveloped. Activation of the immune system, in particular T‐cells, is emerging as a possible mechanism underlying DN disease progression in humans and animal models. We hypothesized that inhibition of T‐cell activation will ameliorate DN. Interaction of B7‐1 (CD80) on the surface of antigen presenting cells with its binding partners, CTLA4 (CD152) and CD28 on T‐cells, is essential for T‐cell activation. In this study we used a soluble CTLA4‐Fc fusion protein to block cell surface B7‐1, preventing the cellular interaction and inhibiting T‐cell activation. The CTLA4‐Fc Abatacept was dosed i.p. in the Streptozotocin‐induced Diabetic Nephropathy mouse model in both prevention and intervention modes. Renal damage was assessed by albuminuria and renal B7.1 positive cells and lymphocytes were measured by immunohistochemistry. Gene expression interrogated by real‐time PCR and protein expression by Western blotting. Differentiated human immortalized podocytes were used for in vitro studies. When CTLA4‐Fc was dosed in an animal model of DN, it reduced albuminuria in both prevention and intervention modes. The number of T‐cells infiltrating the kidneys of DN animals correlated with the degree of albuminuria and treatment with CTLA4‐Fc reduced the number of renal T‐cells. As B7‐1 induction has been recently proposed to underlie podocyte damage in DN, CLTA4‐Fc could be efficacious in DN by protecting podocytes. However, this does not appear to be the case as B7‐1 was not expressed in: 1) kidneys of DN animals; 2) stimulated human podocytes in culture; or 3) glomeruli of DN patients. We conclude that CTLA4‐Fc ameliorates DN by blocking T‐cell activation and not by protecting podocytes.