Expression of Complement Regulatory Proteins in Accommodated Xenografts Induced by Anti-α-Gal IgG1 in a Rat-to-Mouse Model

Abstract

Anti-graft antibodies are often associated with graft rejection. Under special conditions, grafts continue to function normally even in the presence of anti-graft antibodies and complement. This condition is termed accommodation. We developed a xenograft accommodation model in which baby Lewis rat hearts are transplanted into Rag/GT-deficient mice, and accommodation is induced by repeated i.v. injections of lowdose anti-a -Gal IgG 1 . The accommodated grafts survived a bolus dose of anti-a -Gal IgG 1 , while freshly transplanted second grafts were rejected. To study the mechanism of anti-a -Gal IgG 1 -mediated accommodation, both real-time PCR and immunohistochemical staining revealed elevated expression of DAF, Crry and CD59 in the accommodated grafts. In vitro exposure of rat endothelial cells to anti-a -Gal IgG 1 also induced the up-regulation of DAF, Crry and CD59, as revealed by Western blot analyses, and was associated with an acquired resistance to antibody and complementmediated lysis in vitro. Collectively, these studies suggest that the up-regulation of complement regulatory proteins may abrogate complement-mediated rejection and permit the development of xenograft accommodation.

Four Stages and Lack of Stable Accommodation in Chronic Alloantibody Mediated Renal Allograft Rejection in Cynomolgus Monkeys

“…To establish accommodation in some models requires acute complement depletion (73), especially the absence of activation of the terminal complement cascade (74,75 ), the up-regulation of complement regulatory components (DAF and CD59) (51,76 ) or the induction of anti-apoptotic proteins (Bcl-2, Bcl-xl, HO-1) or other cytoprotective proteins (nitric oxide, indolamine 2,3 dioxygenase) (52, 77 , 78 ). Low alloantibody titer or sub-saturating quantities of alloantibody may preferentially induce anti-apoptotic gene expression and accommodation (79,80 ).…”

C4d Deposition without Rejection Correlates with Reduced Early Scarring in ABO-Incompatible Renal Allografts

“…Inhibition of the complement cascade distal to C4 cleavage by factors such as decay-accelerating factor, CD59, and heparan sulfate may play a vital role in determining whether grafts exposed to such antibody develop AMR or show accommodation. 23,33,34 Indeed, recent studies in a heart xenograft model similar to that noted already demonstrated elevated expression of decay-accelerating factor, CD59, and Crry (a rodent complement regulatory protein) on capillary endothelial cells of accommodating grafts. 34 The regulation of expression of these factors in human allografts and how this is affected by binding of antibodies against blood group and HLA antigens expressed on the graft remain important areas for future study.…”

Correlation of Donor-Specific Antibodies, Complement and Its Regulators with Graft Dysfunction in Cardiac Antibody-Mediated Rejection

“…Furthermore, there are only limited studies that correlate the presence of complement split products in the biopsy with circulating alloantibodies (7,9). [7][8][9], every 8 weeks for months [10][11][12], every 3 months for months [13][14][15][16][17][18][19][20][21][22][23][24], every 4 months for months [25][26][27][28][29][30][31][32][33][34][35][36] …”