Restoring Immune Response After Spinal Cord Injury

Posted by Sam Maddox in Research News on April 29, 2016 # Health

Autonomic dysreflexia (AD)* is double trouble for those who experience it (usually seen in spinal cord injuries above T6). First there’s the spiked blood pressure issue, which can be dangerous and has to be treated as a medical emergency. Now comes evidence that AD degrades the immune system, adding a long-term issue: risk from infections, the leading cause of death in the SCI community.

Phillip G. Popovich, Ph.D., who directs the Center for Brain and Spinal Cord Repair at The Ohio State University, previously reported that AD causes chronic immune suppression after spinal cord injury. This is quite obvious by comparing the spleen (a blood filter and part of the immune system) of an injured animal and one from a normal animal. SCI reduces spleen size by 40 percent. He now has data showing just how AD messes with the nervous system, and he’s also found a possible treatment.

Collaborating with Cincinnati Children's Hospital Medical Center, Popovich and team published a paper in Nature Neuroscience this month titled “Silencing spinal interneurons inhibits immune suppressive autonomic reflexes caused by spinal cord injury.”

Yutaka Yoshida, a scientist in the Division of Developmental Biology at Cincinnati Children’s, is co-lead author. First author is Masaki Ueno, a member of Yoshida’s lab. The Japan Science and Technology Agency also contributed.

The gist of the paper is that nerve trauma activates abnormal growth in the microcircuitry of the spinal cord. This nerve growth, or plasticity, activates anti-inflammatory reflexes that limit immune system response.

In a mouse model of spinal cord injury, the Ohio State group reports that new circuitry activates responses beyond

spinal segments in the thoracic spinal cord. In mice without injury, these are the nerves that hook up with the lymph tissues that help create immune cells.

In an interview with MedicalResearch.com, Popovich had this to say:

We found that after a period of one month, the number of connections between spinal cord interneurons and autonomic neurons that directly control immune function increases dramatically.

Also, this newly formed circuitry is “hyperactive”. Discharge of neurons in this circuit causes hormones to be released into the blood and immune organs that overstimulate immune cells, causing them to die.

Fortunately, we were able to show that the hyperactive spinal cord circuitry can be silenced. We used a novel technique known as “chemogenetics” to silence excitatory interneurons in the aberrant circuit. When the circuitry was silenced, immune cells were protected in spinal cord injury mice.

Chemogenetics manipulates specific receptors on the surface of cells to either activate them or silence them. In the case of nerve growth post-injury, the new nerves have specific genetic identities; therefore the scientists were able to modify them with a custom silencer (hM4Di-DREADD). This reversed the reflex that was knocking down immune response.

OK, sounds good but the usual research cautions apply: Chemogenetic silencing is quite experimental and remains years away from testing in people. But it shows the system is being understood on a molecular basis and that damaging processes can be repaired.

More from Popovich, from MedicalResearch.com:

We still do not understand why spinal cord injury does not cause AD or immune suppression in all individuals, even in those that are affected by high level SCI.

We also need to understand how and why spinal cord circuit rewiring occurs and when it does. Are there critical periods during which interventions will work better? For example, can we block the rewiring?

We show that tremendous plasticity develops within autonomic circuitry controlling immune organs. Does a similar type of reorganization develop in other neuronal networks controlling other organs and how does the autonomic plasticity affect motor and sensory functions? Is there cross-talk between these different modalities that are affected by circuit rewiring?

Finally, for those in which the rewiring has already been established for many years, is it possible to reorganize this circuitry using existing drugs or rehabilitation therapies and will such interventions affect AD and immune function?

OK, AD and immune weakness are not good for several reasons. He’s one more, from the Jan Schwan group in Berlin, reported in Brain four years ago: “Functional neurological recovery after spinal cord injury is impaired in patients with infections.”

Using data from the U.S. Model Systems SCI System, they looked at how those with infections (pneumonia or post-op wound infections) compared to others with similar injuries and no infections. The bottom line is that infection significantly reduces recovery.

From the paper:

Infections associated with spinal cord injury, such as pneumonia and/or postoperative wound infections, qualify as independent risk factors for poor neurological outcome after motor complete spinal cord injury. Infections constitute a clinically relevant target for protecting the limited endogenous functional regeneration capacity. Upcoming interventional trials might gain in efficacy with improved patient stratification and might benefit from complementary protection of the intrinsic recovery potential after spinal cord injury.

*AD, a sudden onset of high blood pressure (BP), is a complex mis-coordination within the nervous system. Say there’s a problem, such as a distended bowel or an ingrown toenail. The person can’t feel it but the body’s sensory alert system responds; the message that would normally reach the brain (tend to that bowel!) is blocked at the injury site. The autonomic nervous system, which caretakes functions we don’t have to think about (heart rate, for example) gets wind that something is going on, and responds by narrowing the blood vessels. Higher BP is detected by the brain, by way of the heart, but system can’t sort it all out. So here comes AD, high BP, headache and gooseflesh, potential for stroke. The source has to be tracked down; most of the time it’s related to bladder and bowel management.