Table 5.
Anti-CD11d Antibodies
| Paper | Animal model and injury model | Intervention and timing | Experimental groups |
Reported outcomes: • Histologic/biochemical/physiological • Behavioral |
|---|---|---|---|---|
| Gris Neuroimmunol2009 |
Model: Female Wistar Rat, 250-300 g Injury: T4 Clip Compression 50 g × 1 min |
Anti-CD11d mAb217L IV • 1 mg/kg @ 2, 24, and 48 h PI IB7 control mAb IV • 1 mg/kg @ 2, 24, and 48 h PI |
SCI + • Anti-CD11d mAb • IB7 No SCI (n = 10) n = 3 for RNA analysis and n = 5 for histology per group per time points at 12h, 3d, 7d or 21d PI |
Histologic/Biochemical/Physiological: CD11d mAb reduced hematogenous macrophage infiltration (CD8α expression) in the lesion by ∼35% at 3d PI, 7d and 21d. • Up to 1500 genes were differentially expressed in CD11d mAb-treated vs. IB7-treated animals. CD11d mAb reduced expression of pro-inflammatory cytokines like IL-6, Il-1β and others and increased expression of mediators that promote adaptive immune cell responses and wound healing. • CD11d mAb decreased apoptosis (TUNEL) and increased expression of pro-survival, anti-apoptotic genes like Survivin, Selenium Glutathione Peroxidase and IGF-1. Behavioral: Not reported |
| Ditor J Neurosurg Spine2006 |
Model: Female Wistar Rat, 250-300 g Injury: T4 Clip Compression 50 g |
Anti-CD11d mAb 217L IV • 1 mg/kg @ 2, 24, and 48 h PI or @ 6, 24, and 48 h PI or @ 12, 24, and 48 h PI or @ 24 and 48 h PI IB7 control mAb IV • 1 mg/kg @ 2, 24, and 48 h PI or @ 6, 24, and 48 h PI or @ 12, 24, and 48 h PI or @ 24 and 48 h PI |
SCI + • Anti-CD11d mAb (n = 43) • IB7 (n = 44) No SCI (n = 10) |
Histologic/Biochemical/Physiological: MPO activity and ED-1 expression showed decreases in intraspinal neutrophils and macrophages after treatments at 2, 6 & 12 h PI. Oxidative enzyme expression decreased with treatment onset delayed up to 12h. Lipid peroxidation and DNA oxidation were reduced with treatment onset up to 6 h. Protein nitration and oxidation were decreased with onsets of 2 h and 12 h, respectively. Behavioral: BBB scores and autonomic dysreflexia were examined after treatments commencing at 6h PI and additional doses at 24 & 48 h. BBB scores were increased by anti-CD11d mAb treatment at 3-5 wk after injury. At 5w after SCI, mAb decreased autonomic dysreflexia. |
| Bao J Neurochem2005 |
Model: Female Wistar Rat, 220 g Injury: T4 Clip Compression 50 g |
Anti-CD11d mAb 217L IV • 1 mg/kg @ 2h or 2, 24, and 48 h PI IB7 control mAb IV • 1 mg/kg @ 2h or 2, 24, and 48 h PI |
SCI + • Anti-CD11d mAb (n = 35) • IB7 (n = 37) No SCI (n = 14) |
Histologic/Biochemical/Physiological: Used immunohistochemistry, fluorescent methods of detecting reactive oxygen species (ROS), & western blotting. Tissue sections or homogenates of the lesion were examined at 6 & 24 h after SCI (1 treatment at 2 h) or 72 h & 1w after SCI (3 treatments at 2, 24, 48 h). Treatments reduced ROS production at 6 h-1w after SCI. The single treatment decreased expression of the oxidative enzyme (NDAPH) subunit gp91phox, production of hydroxynonenal -bound proteins (indicating lipid peroxidation), activation of caspase-3 (apoptosis) and numbers of dead cells at 6-72 h after SCI. ROS and gp91phox were predominant in neutrophils. Behavioral: Not reported. |
| Gris J Exp Neurol2005 |
Model: Female Wistar Rat, 250 g Injury: T4 Clip Compression 50 g |
Anti-CD11d mAb 217L IV • 1 mg/kg @ 2, 24, and 48 h PI Methylprednisolone IV • 30 mg/kg @ 2h PI, then 15 mg/kg @ 24 and 48 h PI IB7 control mAb IV • 1 mg/kg @ 2, 24, and 48 h PI |
SCI + • Anti-CD11d mAb (n = 17) • Methylprednisolone (n = 13) • Anti-CD11d mAb + MP (n = 7) • IB7 or saline control (n = 21) |
Histologic/Biochemical/Physiological: 2w PI, the anti-CD11d mAb and MP treatments caused an increase in CGRP-immunoreactive fibres in laminae III-V of T9 but not at L4/5. At T9, the lesion area tended to be smaller after MP treatment and was significantly smaller after anti-C11d mAb. The treatments also increased resting mean arterial pressure at 2w. Behavioral: MP and combined MP/anti-CD11d mAb treatments decreased autonomic dysreflexia and increased resting mean arterial pressure at 2 but not 6w PI. Lack of additive advantage of combined treatment was notable. |
| Oatway J Neurosci2005 |
Model: Male Wistar Rats, 250–350 g Injury: T12 Clip Compression 50 g |
Anti-CD11d mAb 217L IV • 1 mg/kg @ 2, 24, and 48 h PI Saline • @ 2, 24, and 48 h PI |
SCI + • Anti-CD11d mAb (n = 19) • Saline (n = 22) No SCI (n = 6) |
Histologic/Biochemical/Physiological: Buildup of rostral serotonergic fibres in the dorsal horn was reduced by treatment and more fibres were found caudually in the IML and dorsal and ventral horns. Lateral serotonergic projections imply treatment-induced sparing of fibres with collateral sprouting. Compact myelin was also increased. Retrograde labeling of raphe-spinal axons showed more axons traversing the lesion site in some treated rats. Behavioral: BBB scores and mechanical allodynia correlated with changes in rostral and caudal serotonergic projections. Anti-CD11d mAb led to higher BBB scores from 1-4 wk PI. Mechanical allodynia was reduced from 2-4 wk after injury. |
| Weaver J Neurotrauma2005 |
Model: Male or Female, Wistar Rat, 250–300 g Injury: • T4 Severe Clip Compression 50 g • T12 Moderately Severe Clip Compression 35 g |
Anti-CD11d mAb 217L IV • 1 mg/kg @ 2, 24, and 48 h PI Methylprednisolone IV • 30 mg/kg @ 2 h PI, then 15 mg/kg @ 24 and 48 h PI IB7 control mAb IV • 1 mg/kg @ 2, 24, and 48 h PI |
SCI + • Anti-CD11d mAb (n = 29, from Gris, et al., 2004) • Methyl prednisolone (n = 26) • Anti-CD11d mAb + MP (n = 7) • IB7 or saline control (n = 33) Males used for motor and pain Females used for motor |
Histologic/Biochemical/Physiological: Adjacent to the lesion centre, both treatments increased neurofilament at 6wk after T4 and at 12w after T12 injury. MP and mAb increased myelin staining, at 2w after T4 SCI, but the combination had no effect. At 6w after T4 and 12w after T12, MP treatment increased myelin adjacent to but not within the lesion centre, while mAb treatment increased myelin at sites closer to the lesion centre. Behavioral: MP and combinatory treatment had no effect on BBB scores 6w after T4 SCI or 12w after T12 SCI. MP had no consistent effect on at-level or below-level mechanical allodynia when monitored for 12 w after T12 injury. |
| Bao J Neurochem2004 (a) |
Model: Female Wistar Rat, 220 g Injury: T4 Clip Compression 50 g |
Anti-CD11d mAb 217L IV • 1 mg/kg @ 2 h or 2, 24, and 48 h PI IB7 isotype control mAb IV • 1 mg/kg @ 2 h or 2 h + 24 h + 48 h PI |
SCI + • Anti-CD11d mAb (n = 43) • IB7 (n = 41) No SCI (n = 15) |
Histologic/Biochemical/Physiological: Used immunohistochemistry on spinal cord sections & Western Blotting of homogenates of the lesion area at 6, 24 & 72 h after SCI (1 treatment at 2 h) or at 1 w after 3-dose regimen. ED-1 expression (macrophage marker) and MPO activity (neutrophils) decreased at 6-72 h after SCI. Anti-CD11d mAb treatment decreased lipid peroxidation, expression of iNOS & protein nitration at 6-72 h post injury. By one week MPO activity and lipid peroxidation in control and anti-CD11d mAb-treated rats were similar to those of uninjured rats. Behavioral: Not reported. |
| Bao J Neurochem2004 (b) |
Model: Female Wistar Rat, 220 g Injury: T4 Clip Compression 50 g |
Anti-CD11d mAb 217L IV • 1 mg/kg @ 2 h PI IB7 control mAb IV • 1 mg/kg @ 2 h |
SCI + • Anti-CD11d mAb • IB7 No SCI n = 17/group |
Histologic/Biochemical/Physiological: Used immunohistochemistry on spinal cord sections & western blotting or chemical staining of homogenates of the lesion area at 6, 24 & 72h after SCI (1 treatment at 2 h). Anti-CD11d mAb treatment decreased COX-2 expression, RNA & DNA oxidation, and protein carbonylation. Expression of APE/Ref-1, a DNA repair enzyme increased. All effects likely result from treatment-induced reduction of free radical formation after SCI. Behavioral: Not reported |
| Gris J Neurosci2004 |
Model: Model: Male and Female Wistar Rat, 250-300 g Injury: • T4 Severe Clip Compression 50g • T12 Moderate Clip Compression 35 g |
Anti-CD11d mAb 217L IV • 1 mg/kg @ 2, 24, and 48 h PI IB7 control mAb IV • 1 mg/kg @ 2, 24, and 48 h PI |
SCI + • Anti-CD11d mAb (n = 29) • IB7 (n = 28) n = 16 male (motor and pain) n = 41 female (motor and autonomic) |
Histologic/Biochemical/Physiological: Anti-CD11d mAb treatment led to tissue sparing PI. In the T4 severe injury: 2w levels of compact myelin and 6w levels of myelin and neurofilaments were increased. In the T12 moderate injury: 12w levels of necrosis were decreased, while myelin and neurofilaments were increased. Behavioral: BBB scores improved 5 & 6w after severe T4 SCI (females) and autonomic dysreflexia was attenuated at 2 & 6w PI. BBB scores were higher 4-12 w after moderately severe T12 SCI (9.7 vs 7.8), as were inclined plane scores at 5-12w and grid walk scores at 8-12w. Neuropathic pain was reduced following T12 injury in mAb-treated rats from 4-12w PI. |
| Saville J Neuro-Immunology2004 |
Model: Female Wistar Rat, 250g Injury: T4 Clip Compression • Severe (50 g) • Moderate (35 g) |
Anti-CD11d mAb IV 217L • 1.0 mg/kg @ 2, 24, 48, 72, and 96h PI Anti-CD11d mAb IV 236L & 226H • 1.0 mg/kg @ 24 h or 2 and 24 h or 2, 24, and 48 h PI MP IV • 30 mg/kg @ 2 h PI, then 15 mg/kg @ 24, and 48 hPI Control mAb IV • 1.0 mg/kg @ 24 h or 2 and 24 h or 2, 24, and 48 h PI |
SCI + • Anti-CD11d mAbs • MP • Control mAb n = 5-10/group (175 total) |
Histologic/Biochemical/Physiological: Flow cytometry and immunohistochemistry demonstrated CD11d expression by splenic macrophages & blood leukocytes using 217L & 236L. 217L reduced macrophages and neutrophils in lesion site from 18-72h post injury after severe or moderate injury. Dosing of 217 mAb was most effective at 2, 24, 48 h regimen. 236L & 226H had effects similar to 217L. At 7d after SCI, neutrophil and macrophage numbers in lesion were like controls. MP also reduced inflammatory cells in lesion from 18-72h. At 7d after MP treatment neutrophils were increased and macrophages decreased in lesion. Behavioral: Not reported. |
| Mabon Exp Neurol2000 |
Model: Male Wistar Rat, 250-300g Injury: T4 Transection |
Anti-CD11d mAb IV • 1 mg/kg or 5 mg/kg @ 24 h PRIOR SCI, 2h, and 24 h PI Methylprednisolone IV • 15 mg/kg or 30 mg/kg @ 30 min, 2h, and 24 h PI IB7 control mAbs • 1 mg/kg @ 24 h PRIOR SCI, 2 h, and 24 h PI |
SCI + • Anti-CD11d mAbs (226H, n = 9; 236L, n = 8; 226B, n = 8) • MP (n = 5) • IB7 (n = 9) • No Treatment Control (n = 4) |
Histologic/Biochemical/Physiological: At 2d after SCI, macrophages: decreased at injury site with 226H &236L anti-CD11d mAbs when compared to isotype control (1 mg/kg had a greater effect than 5 mg/kg). No effect of 226B. Neutrophils: decreased at injury site only with 236L (both doses equally effective). MP: decreased macrophages < the mAb treatments, did not decrease neutrophils. Staining of cord revealed macrophages and neutrophils in/near the lesion expressing CD11d. Behavioral: Not reported. |
SCI: spinal cord injury; d: day, days; h: hour, hours; w: week, weeks; PI: post-injury;
T8: thoracic vertebra 8; C5: cervical vertebra 5; IP: intraperitoneal; IV: intravenous; SC: subcutaneous;
Ab: antibody; BBB: Basso, Beattie and Bresnahan locomotor test; COX: cyclooxygenase; MP: Methylprednisolone; MPO: Myeloperoxidase; ROS: reactive oxygen species.