A monoclonal antibody to CD11d reduces the inflammatory infiltrate into the injured spinal cord: a potential neuroprotective treatment

Saville, Leyana R.; Pospisil, C.H.; Mawhinney, Leah; Feng, Bo; Simedrea, F.C.; Peters, Anneli; O’Connell, Peta J.; Weaver, Lynne C.; Dekaban, Gregory A.

doi:10.1016/j.jneuroim.2004.07.002

Cited by 118 publications

(127 citation statements)

References 68 publications

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“…This dose was optimized in spinal cord-injured rats and found to improve functional recovery (Gris et al, 2004;Mabon et al, 2000;Saville et al, 2004). A third group of spinal cord-injured mice was administered saline to control for any effects of IgG administration.…”

Section: Antibody Treatmentmentioning

confidence: 99%

“…The expression of VCAM-1 and ICAM-3 is upregulated on damaged endothelial cells, allowing leukocytes to bind and migrate into the damaged tissue after injury (Schnell et al, 1999). A monoclonal antibody (mAb) 217L directed against the CD11d subunit of the CD11/CD18 integrin substantially decreased the number of neutrophils and macrophages in the cord after SCI in the rat (Mabon et al, 2000;Saville et al, 2004). This treatment resulted in decreased secondary damage (Bao et al, 2004a(Bao et al, , 2004b(Bao et al, , 2005, and significantly improved locomotor and autonomic recovery and decreased neuropathic pain (Gris et al, 2004;Oatway et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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CD11d Antibody Treatment Improves Recovery in Spinal Cord-Injured Mice

Geremia

Feng²,

Rosenzweig³

et al. 2012

Journal of Neurotrauma

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Acute administration of a monoclonal antibody (mAb) raised against the CD11d subunit of the leukocyte CD11d/CD18 integrin after spinal cord injury (SCI) in the rat greatly improves neurological outcomes. This has been chiefly attributed to the reduced infiltration of neutrophils into the injured spinal cord in treated rats. More recently, treating spinal cord-injured mice with a Ly-6G neutrophil-depleting antibody was demonstrated to impair neurological recovery. These disparate results could be due to different mechanisms of action utilized by the two antibodies, or due to differences in the inflammatory responses between mouse and rat that are triggered by SCI. To address whether the anti-CD11d treatment would be effective in mice, a CD11d mAb (205C) or a control mAb (1B7) was administered intravenously at 2, 24, and 48 h after an 8-g clip compression injury at the fourth thoracic spinal segment. The anti-CD11d treatment reduced neutrophil infiltration into the injured mouse spinal cord and was associated with increased white matter sparing and reductions in myeloperoxidase (MPO) activity, reactive oxygen species, lipid peroxidation, and scar formation. These improvements in the injured spinal cord microenvironment were accompanied by increased serotonin (5-HT) immunoreactivity below the level of the lesion and improved locomotor recovery. Our results with the 205C CD11d mAb treatment complement previous work using this anti-integrin treatment in a rat model of SCI.

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Section: Antibody Treatmentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CD11d Antibody Treatment Improves Recovery in Spinal Cord-Injured Mice

Geremia

Feng²,

Rosenzweig³

et al. 2012

Journal of Neurotrauma

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“…Our laboratories have promoted an anti-inflammatory treatment that limits the influx of activated neutrophils and monocytes into the injured spinal cord with the use of intravenously delivered blocking antibodies that target a key leukocyte integrin, CD11d/CD18. This treatment limits intraspinal inflammation, reduces oxidative damage and lesion size and leads to significant improvement in motor function and reduction of autonomic dysreflexia and neuropathic pain (Bao et al, 2004a(Bao et al, , 2004bGris et al, 2004;Oatway et al, 2005;Saville et al, 2004). We anticipated that this treatment would also avert primary afferent sprouting, as NGF, the likely trigger of this sprouting, is found in the injured cord in areas of high inflammation (Brown et al, 2004).…”

Section: Sci Treatment Strategies That Promote Neuroprotectionmentioning

confidence: 99%

The dark side of neuroplasticity

Brown

Weaver

2012

Experimental Neurology

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Whether dramatic or modest, recovery of neurological function after spinal cord injury (SCI) is greatly due to neuroplasticity -the process by which the nervous system responds to injury by establishing new synaptic connections or by altering the strength of existing synapses. However, the same neuroplasticity that allows locomotor function to recover also produces negative consequences such as pain and dysfunction of organs controlled by the autonomic nervous system. In this review we focus specifically on structural neuroplasticity (the growth of new synaptic connections) after SCI and on the consequent development of pain and autonomic dysreflexia, a condition of episodic hypertension. Neuroplasticity after SCI is stimulated by the deafferentation of spinal neurons below the lesion and by the expression of growth-promoting neurotrophins such as nerve growth factor (NGF). A broad range of therapeutic strategies that affect neuroplasticity is being developed for the treatment of SCI. At one end of the spectrum are therapeutic strategies that directly or indirectly increase NGF in the injured spinal cord, and have the most robust effects on neuroplasticity. At the other end of the spectrum are neuroprotective strategies focused on supporting and rescuing uninjured, or partially injured, axons; these might limit the deafferentation stimulus for neuroplasticity. In the middle of this spectrum are strategies that block axon growth inhibitors without necessarily providing a growth stimulus. The literature supports the view that the negative consequences of neuroplasticity develop more commonly with therapies that directly stimulate nerve growth than they develop in the untreated injured cord. Compared to these conditions, neuroplasticity with negative outcomes is less prevalent after treatments that that neutralize axon growth inhibitors, and least apparent after strategies that promote neuroprotection.

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“…A partial list of these pre-clinical therapies is summarized in Table 1. These various experiments, including the use of clodronate liposomes [64,65], anti-CD11d antibodies [92][93][94][95], minocycline [96], silica dust [1,97,98], colchicine and chloroquine [98,99], activated protein C [49], and nitrogen mustard [100,101] have been reviewed previously [1,5,98] and will not be discussed further. Additionally, because 2 other review articles in this issue provide an overview of the use of MMP inhibitors for SCI [80] and provide new strategies to manipulate microglia (and macrophage) metabotropic glutamate receptors [102], we will not discuss these topics any further.…”

Section: Experimental Therapiesmentioning

confidence: 99%

“…Additionally, the implications of recent Gr1-mediated neutrophil depletion data are described in the context of myeloid cell heterogeneity and downstream wound healing cascades. IL-6 is a pro-inflammatory cytokine that promotes the differentiation of monocytes into macrophages [92][93][94][95] and can also elicit monocyte recruitment [103]. When over-expressed in the injured spinal cord using genetically modified cellular vectors, excess IL-6 enhanced the endogenous neutrophil and monocyte response to SCI and exacerbated lesion pathology [104].…”

Section: Experimental Therapiesmentioning

confidence: 99%

Emerging Concepts in Myeloid Cell Biology after Spinal Cord Injury

Hawthorne

Popovich

2011

Neurotherapeutics

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Summary: Traumatic spinal cord injury (SCI) affects the activation, migration, and function of microglia, neutrophils and monocyte/macrophages. Because these myeloid cells can positively and negatively affect survival of neurons and glia, they are among the most commonly studied immune cells. However, the mechanisms that regulate myeloid cell activation and recruitment after SCI have not been adequately defined. In general, the dynamics and composition of myeloid cell recruitment to the injured spinal cord are consistent between mammalian species; only the onset, duration, and magnitude of the response vary. Emerging data, mostly from rat and mouse SCI models, indicate that resident and recruited myeloid cells are derived from multiple sources, including the yolk sac during development and the bone marrow and spleen in adulthood. After SCI, a complex array of chemokines and cytokines regulate myelopoiesis and intraspinal trafficking of myeloid cells. As these cells accumulate in the injured spinal cord, the collective actions of diverse cues in the lesion environment help to create an inflammatory response marked by tremendous phenotypic and functional heterogeneity. Indeed, it is difficult to attribute specific reparative or injurious functions to one or more myeloid cells because of convergence of cell function and difficulties in using specific molecular markers to distinguish between subsets of myeloid cell populations. Here we review each of these concepts and include a discussion of future challenges that will need to be overcome to develop newer and improved immune modulatory therapies for the injured brain or spinal cord.

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A monoclonal antibody to CD11d reduces the inflammatory infiltrate into the injured spinal cord: a potential neuroprotective treatment

Cited by 118 publications

References 68 publications

CD11d Antibody Treatment Improves Recovery in Spinal Cord-Injured Mice

CD11d Antibody Treatment Improves Recovery in Spinal Cord-Injured Mice

The dark side of neuroplasticity

Emerging Concepts in Myeloid Cell Biology after Spinal Cord Injury

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