Effects of CTLA4-Fc on glomerular injury in humorally-mediated glomerulonephritis in BALB/c mice.
The effect of cytotoxic T-lymphocyte-associated molecule 4-immunoglobulin fusion protein (CTLA4-Fc) on humorally-mediated glomerulonephritis was studied in accelerated anti-glomerular basement membrane (anti-GBM) glomerulonephritis induced in BALB/c mice. This strain of mice develops antibody and complement dependent glomerulonephritis under this protocol. Sensitized BALB/c mice developed high levels of circulating autologous antibody titres, intense glomerular deposition of mouse immunoglobulin and complement, significant proteinuria, renal impairment, significant glomerular necrosis and a minor component of crescent formation 10 days after challenge with a nephritogenic antigen (sheep anti-GBM globulin). Early treatment during the primary immune response, or continuous treatment throughout the disease with CTLA4-Fc, significantly suppressed mouse anti-sheep globulin antibody titres in serum, and immunoglobulin and complement deposition in glomeruli. The degree of glomerular necrosis was improved and proteinuria was reduced, particularly in the earlier stages of disease. Late treatment by CTLA4-Fc starting one day after challenge with sheep anti-mouse GBM did not affect antibody production and did not attenuate glomerulonephritis. The low level of crescent formation found in BALB/c mice developing glomerulonephritis was not prevented by the administration of CTLA4-Fc. These results demonstrate that CTLA4-Fc is of benefit in this model of glomerulonephritis by its capacity to attenuate antibody production, without affecting the minor degree of cell-mediated glomerular injury.
Kitching
A R
AR
Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia. richard.kitching@med.monash.edu.au
Huang
X R
XR
Ruth
A-J
AJ
Tipping
P G
PG
Holdsworth
S R
SR
D000069594:Abatacept; D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000188:drug therapy* / Q000473:pathology; D000906:Antibodies / Q000009:adverse effects; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000008:administration & dosage / Q000627:therapeutic use*; D001323:Autoantibodies; D060908:CTLA-4 Antigen; D004195:Disease Models, Animal; D005916:Globulins / Q000009:adverse effects; D018796:Immunoconjugates; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage / Q000627:therapeutic use*; D007678:Kidney Glomerulus / Q000293:injuries* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D012756:Sheep
D000906:Antibodies; D015703:Antigens, CD; D000943:Antigens, Differentiation; D001323:Autoantibodies; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D005916:Globulins; D018796:Immunoconjugates; D007141:Immunoglobulin Fc Fragments; D011993:Recombinant Fusion Proteins; C051951:antiglomerular basement membrane antibody; D000069594:Abatacept