Rapid induction of autoantibodies against Nogo‐A and MOG in the absence of an encephalitogenic T cell response: implication for immunotherapeutic approaches in neurological diseases

Abstract

Vaccinations against various antigens of the central nervous system (CNS) are gaining increasing interest as a therapeutic approach in a variety of neurological diseases such as spinal cord injury, ischemic stroke, Alzheimer disease, or spongiform encephalopathy. In the present work, the time window after spinal cord injury allowing potentially therapeutic antibody to penetrate the damaged blood-brain barrier (BBB) was measured by intravenous injection of a monoclonal anti-Nogo-A antibody. Although an influx of Nogo antibodies at the lesion site was detectable up to 2 wk after injury, a significant decrease in BBB permeability was noticed within the first week. Clearly, therefore, a vaccination protocol with a rapid antibody response is required for acute therapeutic interventions after CNS trauma. We designed a conjugate vaccine paradigm with particular focus on the safety and the kinetics of the antibody response. As antigen targets, we used Nogo-A and the strongly encephalitogenic myelin-oligodendrocyte glycoprotein (MOG). Intrasplenic autoimmunization of rats with a Nogo-A-specific region fused to the Tetanus toxin C-fragment (TTC) resulted in a fast IgM response against Nogo-A. A specific switch to IgG was observed as soon as 4-7 days after intrasplenic immunization in TTC-primed animals. In spite of the induction of a specific IgG response after intrasplenic immunization, no signs of experimental autoimmune disease (EAE) or inflammatory infiltrates on histological examinations were observable. In contrast to subcutaneous immunization with MOG, in vitro cytokine secretion assays (IL-2, IL-10, and IFN-gamma) did not reveal activation of MOG-specific T cells after intrasplenic immunization. Our findings have critical implications for future strategies in the development of safe and efficient therapeutic vaccines for neurological diseases.

Defining Limits of Treatment with Humanized Neutralizing Monoclonal Antibody for West Nile Virus Neurological Infection in a Hamster Model

“…Similarly low CSF concentration/serum concentration ratios have been observed for other peripherally administered MAbs in mice, rats, and humans (1,8,14,21,23,24). Despite encephalitis and CNS inflammation in the hamsters, only a small fraction of the peripherally administered hE16 efficiently crosses the bloodbrain barrier and inhibits and/or controls infection.…”

Intrathecally infused antibodies against Nogo-A penetrate the CNS and downregulate the endogenous neurite growth inhibitor Nogo-A

“…Intrathecal or intraventricular delivery, therefore, seems an excellent system for the application of therapeutic antibodies to the CNS. In contrast, earlier studies showed that circulating systemic antibodies against Nogo-A penetrated very poorly into the CNS due to a rapid resealing of the blood -brain barrier (Merkler et al, 2003).…”

Autoantibodies to myelin basic protein catalyze site-specific degradation of their antigen

“…It was shown that elevated levels of the autoantibody catalytic activity correlated with an autoimmune response in human and mice models (16,21,35). Moreover, data from several laboratories indicate that autoantibodies can readily penetrate the blood-brain barrier (36)(37)(38)(39).…”