Modulating the immune response in spinal cord injury

KEYWORDS:

• Spinal cord injury (SCI)
• immune system
• inflammation
• infection
• immunomodulation
• methylprednisolone
• minocycline
• intravenous immunoglobulin G (IVIG)
• stem cells
• rehabilitation

1. Neuroinflammation and the immunological response to SCI

In spinal cord injury (SCI), the primary mechanical trauma is followed by a secondary injury cascade which expands the susceptible perilesional region and produces further permanent damage [1]. Neuroinflammation, which is the local immune reaction, is a key component of this cascade. As by-products of post-injury cellular necrosis (DNA, ATP, and K⁺) are released into the microenvironment, activated microglia rapidly secrete inflammatory cytokines leading to the infiltration of peripheral immune cells through the compromised blood–spinal cord barrier. This leads to a cyclical increase in chemoattractants and activated immune cells which can propagate the local inflammatory reaction for weeks to months after injury. Furthermore, uncontrolled destruction of neural tissue can lead to inappropriate antigen presentation and the generation of autoantibodies that negatively affect recovery during the chronic phase [2].

In contrast, the systemic immune system is often suppressed after SCI leading to higher rates of pneumonia, urinary tract infection, and sepsis [3]. The coexistence of systemic immunodeficiency with an excessive local immune reaction suggests that controlled immunomodulatory interventions, as opposed to absolute immunosuppression, may be better suited for SCI.

2. Immunomodulatory therapies

2.1. Methylprednisolone

Methylprednisolone sodium succinate (MPSS) is a potent glucocorticoid and currently the only drug therapy in clinical use as a neuroprotective treatment for SCI. MPSS has a widespread immunosuppressive activity by inducing immune cell apoptosis and reducing inflammatory cytokine release. Moreover, in the spinal cord, it inhibits lipid peroxidation and protects oligodendrocytes from apoptosis [4]. A series of clinical trials and meta-analyses completed over the last 30 years have demonstrated motor score improvements for patients when given intravenous (IV) MPSS within 8 h of injury. While gains were modest, even small improvements in motor function can have tremendous impacts on patients’ quality of life, selfcare, and vocational abilities. Furthermore, unlike the longer 48-h dosing protocol, the 24-h National Acute Spinal Cord Injury Study II (NASCIS II) dosing protocol has been shown to be relatively safe in SCI [5]. An upcoming 2016 AOSpine guideline will recommend that MPSS be administered to patients with acute blunt SCI within 8 h of injury (optimally within 3 h) using the 24-h NASCIS II protocol, provided the patient has no significant medical comorbidity. The senior author particularly recommends this treatment strategy for cervical injury where even minor improvements in motor function can have tremendous effects on patients’ long-term quality of life.

The additional immunomodulatory strategies discussed below are relevant for both clinicians and scientists as they are highly likely to see translation to patients within the next 10 years.

2.2. Minocycline

Minocycline is a tetracycline-class antibiotic with high central nervous system (CNS) penetrance. It is capable of potently inhibiting microglia and downregulating the release of inflammatory factors including interleukin-1β, cyclooxygenase-2, and tumor necrosis factor-α. In animal models, it has been shown to reduce inflammatory cell infiltration, promote motor tract regeneration, and improve behavioral outcomes [6]. A Phase II randomized controlled trial (N = 52) of IV minocycline was completed which demonstrated a trend toward motor score improvement in incomplete cervical SCI cases without any serious adverse events [7]. Based on these results, a Phase III trial entitled ‘Minocycline in Acute Spinal Cord Injury’ has been started with results expected in 2018 [8].

2.3. IV immunoglobulin G

An additional, clinically relevant immunomodulatory pharmacological treatment for SCI is intravenous immunoglobulin G (IVIG). As a successful therapy for both immunodeficiencies and autoimmune diseases in humans, IVIG has the potential to address the paradoxical immune responses of excessive inflammation in the CNS and concomitant immunosuppression against invading pathogens after SCI. We and others have shown that a single dose of IVIG administered acutely after SCI can reduce inflammatory cytokines and neutrophil invasion and activation in the lesioned cord, leading to improved recovery in the chronic phase of SCI in rats [9,10]. The further adjunctive role of IVIG in boosting the systemic immune responses to protect against microbial infections has yet to be investigated.

2.4. Monoclonal antibodies

Another immunomodulatory approach is to prevent infiltration of leukocytes into the injured spinal cord. This can be accomplished by using monoclonal antibodies (mAb) that target interaction between leukocyte adhesion molecules and endothelial cell ligands, such as the mAb against CD11d/CD18, which inhibits entry of neutrophils and monocytes in the injured spinal cord and promotes functional recovery in rats [11].

2.5. Therapeutic hypothermia

Therapeutic hypothermia has been successfully applied as a neuroprotectant after neonatal hypoxic–ischemic encephalopathy and adult inhospital cardiac arrest [12]. In preclinical models of brain or spine trauma, local or systemic cooling has been shown to promote recovery by reducing the metabolic demand of the highly active CNS, restricting inflammatory cell infiltration, and stabilizing the blood–brain barrier [13]. However, despite these promising data, multicenter randomized clinical trials showed lack of efficacy of hypothermia in adults [14] and increased mortality risk in children [15] with severe acute traumatic brain injury. Moreover, bradycardia, deep vein thrombosis, and respiratory infection constitute serious risks of systemic hypothermia. However, a pilot study of patients with complete SCI (N = 14) demonstrated no increase in adverse events and a trend toward neurologic improvement with early treatment (mean = 9 h) [16]. Given these results, the University of Miami is planning to undertake a randomized controlled trial of systemic hypothermia in acute SCI (ARCTIC) [8].

2.6. Cell therapies

Given the extensive loss of neural tissue following SCI, and the limited regenerative capacity of the CNS, cell therapies with immunomodulatory properties have attracted attention as a potential SCI treatment.

Mesenchymal stem cells (MSCs) are potent connective tissue regenerating cells possessing both local and systemic immunomodulatory functions. The neuroprotective effects of MSCs are mediated by their expression of pro-survival factors and ability to reduce peripheral inflammatory cell activation and infiltration. With the potential to differentiate into multiple cell lineages, and an outstanding track record of safety, straightforward isolation, and low immunogenicity, MSCs are well aligned as a promising therapeutic cell-based candidate for immunomodulation in SCI [17]. Indeed, numerous animal studies have demonstrated enhanced recovery with MSC administration prompting several ongoing Phase I, II, and III clinical trials [8].

Neural progenitor cells (NPCs) – which have the ability to differentiate to neurons, oligodendrocytes, and astrocytes – have also been shown to exert immunomodulatory effects in CNS disease. In addition to replacing lost neurons and creating new functional circuits after SCI, NPCs have been shown to inhibit detrimental CNS-reactive T cells and macrophages and to secrete protective cytokines and neurotrophic factors [18]. Importantly, these cells can be administered via multiple routes (intravascular, intrathecal, and intraparenchymal) and be combined with biomaterials or growth factors to maximize gain in functional recovery. Nonetheless, the immunomodulatory and neurotrophic properties of these cells may decay over time both in vitro and in vivo in the CNS [19]. Therefore, further work is needed to better exploit the beneficial effects of NPCs after transplantation.

Transplantation of autologous macrophages activated with peripheral nerve segments [20] or skin [21] can improve locomotion following SCI. However, more preclinical studies are needed before we fully leverage the therapeutic value of macrophages in SCI, as these cells are heterogeneous in function and some subpopulations may exert detrimental effects [22].

2.7. Rehabilitation

Physical therapy has been shown to improve systemic immune function [23] and is a widely used approach to maximize functional recovery in SCI. However, establishment of the optimal timing, frequency, modality, and intensity of exercise after SCI has to be further defined. Until this is completed, we recommend mobilizing and rehabilitating patients at the earliest possible safe timepoint.

Psychological stress is a common comorbidity of SCI that correlates with poor quality of life and increases systemic [24] and spinal cord inflammation [25]. Although poor psychological well-being did not impair motor function in rats [24], it did cause cognitive and affective impairments [25]. As chronic stress increases risk of infections and cardiovascular disease, which are the two leading causes of death among patients with SCI [26], positive psychological interventions may result in improved outcomes in patients with SCI.

3. Looking forward

The immune system is a pivotal component in the pathophysiology of SCI and can dictate the extent of recovery after trauma. Given the critical nature of the local and systemic immunological and inflammatory changes after SCI, modulation of the neuroinflammatory response is an extremely promising area of translational research. We strongly recommend both clinicians and scientists to remain abreast of developments in this rapidly evolving field.

Declaration of interest

MG Fehlings is supported by the DeZwirek Family Foundation and the Gerry and Tootsie Halbert Chair in Neural Repair and Regeneration. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Acknowledgments

Thank you to Madeleine O’Higgins, PhD for copyediting this work.

Additional information

Funding

This paper was not funded.