2011 - BSS 2011 Symposium

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Moderated Posters 1

5.37 - Donor Specific Antibodies Induce Glomerulitis in Mouse Renal Allografts

Presenter: Hsiao-Hsuan, Kuo, Cleveland, United States
Authors: Hsiao-Hsuan Kuo1, Ran Fan1, William Baldwin1

Donor Specific Antibodies Induce Glomerulitis in Mouse Renal Allografts

Hsiao-Hsuan Kuo1, Ran Fan1, William Baldwin1

1Department of Immunology, Lerner Research Institutes, Cleveland, OH, USA

Clinically, antibody-mediated rejection (AMR) has been associated with acute glomerulitis and chronic glomerulopathy, but a causal link has not been established. In AMR circulating donor specific antibodies to HLA are associated with C4d deposits and macrophages in peritubular and glomerular capillaries. In one report, glomerular platelet aggregates were noted but these were also observed in cell-mediated rejection and calcineurin inhibitor toxicity. We have used a passive transfer model to demonstrate that antibodies can cause acute transplant glomerulitis in the absence of T cells in murine renal allografts.

B10.A kidneys were transplanted to B6 rag-/- mice. After postoperative inflammation subsided, a mixture of IgG1, 2a and 2b monoclonal antibodies to H-2a (or isotype controls) were transferred i.p. in single or multiple doses.  By 1 hr after a single dose of alloantibodies, C4d and C3d deposited on peritubular and glomerular capillaries in a strong, diffuse pattern.   Extensive aggregates of P-selectin positive platelets co-localized with C4d and C3d. Capillaries also contained platelet-monocyte conjugates. Within 4 hrs after a single dose of alloantibodies, intact platelets were decreased while C4d and C3d deposits were still intense. When 4 doses of alloantibodies were transferred every other day for one week to replicate a more sustained alloantibody response and recipients were sacrificed an hour after the last dose, increased Mac2 positive macrophages were localized to the glomeruli in a focal and segmental pattern. Macrophage counts on 100 glomeruli per allograft established that 50% of the glomeruli in alloantibody treated recipients had ≥5 macrophages per glomerulus compared to 5% in controls. Glomeruli with increased macrophages also contained platelet aggregates. These glomeruli had extensive cell proliferation by Ki67 staining.

In summary, our model demonstrated that alloantibodies cause pathologic features of transplant glomerulitis. It also established that antibodies initiate rapid localization of platelets in glomeruli followed by macrophages. We are using our model now to test clinically relevant complement and platelet inhibitors on the development of glomerulitis.

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