Effects of double blockade of CD28 and inducible-costimulator signaling on anti–glomerular basement membrane glomerulonephritis

Abstract

Inducible costimulator (ICOS) is the third member of the CD28 superfamily, expressed on antigen-primed T-cells, enhancing Th2 differentiation. Anti-glomerular basement membrane (anti-GBM) glomerulonephritis results from multiple effects generated by both Th1 and Th2 cells. To evaluate the contribution of these T-cells to the progression of anti-GBM glomerulonephritis, we investigated the effect of double blockade of CD28 and ICOS signaling. Anti-GBM glomerulonephritis was induced in C57BL/6 mice, a Th1-prone strain. CD28 signaling was inhibited with the use of fusion proteins of cytolytic T-lymphocyte-associated antigen-4 (CTLA4 immunoglobulin) and ICOS signaling by the monoclonal antibody (mAb) for ICOS. Blood and urine samples were collected 5 and 14 days after induction of anti-GBM glomerulonephritis. Mice were killed to facilitate histopathologic analyses at the same time. Anti-GBM glomerulonephritis was prevented from functionally deteriorating (eg, proteinuria or increasing serum creatinine) by CTLA4 immunoglobulin or anti-activation-inducible lymphocyte immunomodulatory molecule (AILIM) mAb as an anti-ICOS mAb. Nevertheless, double or single blockade of ICOS signaling showed a weaker inhibitory effect than single blockade of CD28 signaling in terms of the serum immunoglobulin level and histopathologic change. There is no synergistic effect between CTLA4 immunoglobulin and anti-AILIM mAb when simultaneously administered in experimental anti-GBM glomerulonephritis. Double blockade of both CD28 signaling and ICOS signaling is effective for preventing functional deterioration in this model. However, CD28 single blockade is more effective than double blockade both serologically and histopathologically.