From Nerves to Immunity

Ten years ago, pediatric neuroblastoma patients at the University of California, San Diego (UCSD), were receiving an experimental antibody treatment. Though it successfully treated their tumors, it left the children in intense pain. Sensitive to the lightest touch all over their bodies, the children would lie in their beds, practically naked.

The immunotherapy was given over the course of four days and repeated every few months. "And we're talking kids, who are 6 and 7, who are sick, but who are fighting and screaming to not come back," says Linda Sorkin, a pain researcher at UCSD called upon for help in understanding the mysterious side effect. The pain clinicians were able to manage the pain with opiates and anesthetics, but wondered about better options.

"It had all the earmarks of neuropathic pain," says Sorkin, except that nerve damage was not causing it. To model the situation, she gave the antibody to rats, which developed sensitivity to light touch with the same time course as the kids. "We looked at the electrical activity of the peripheral nerves and saw increased spontaneous activity." As a neuroscientist working on pain for many years, she'd never considered that something besides a specialized pain receptor could instigate pain. "It got me thinking about things that could activate nerves that were due to immune system responses."

Mechanistic investigations led to the proinflammatory cytokine tumor necrosis factor (TNF). Sorkin has shown that TNF mimics the effect of the chemotherapeutic antibody, inducing spontaneous nerve firing and pain sensitization. Now, what she terms "the TNF-induced neuroimmune cascade" is the focus of her research on neuropathic pain.