BACKGROUND:  New innovations for modulating the growth of neuronal cells are needed as potential therapeutic agents for neurodegenerative disorders and CNS trauma. Major Histocompatibility Complex class I (MHCI) is well known for its functions in the immune system. Recently, it has been shown that MHCI-deficient mice have abnormalities in synaptic plasticity, neurodevelopment, and have more extensive loss of synapses and reduced axon regeneration after sciatic nerve transection, suggesting that MHCI participates in maintaining synapses and axon regeneration (1-4). We have taken the approach of studying 1) transgenic mice that are engineered to over-express MHCI on their neurons and 2) the effects of recombinant soluble MHCI on wildtype neurons in culture.

INNOVATION:  We found that ectopic expression of neuronal MHCI on transgenic neurons inhibited the outgrowth of co-cultured wildtype neurons. Moreover, addition of purified soluble recombinant MHCI to neuronal cultures inhibited neurite outgrowth from wildtype neurons. In both model systems, the neuroinhibitory effects of MHCI could be circumvented by addition of a MHCI-specific monoclonal antibody to the cultures. This data, along with the inventor's recent in vivo studies of neurorepair after injury, strongly suggests that MHCI plays a role in modulating neuronal outgrowth.

POTENTIAL APPLICATIONS 

• The application of Class I MHC protein, recombinant vectors, antibodies or other types of molecules that modulate the expression and/or activity of MHCI could be used to inhibit or enhance the growth of neurons. Based on such technology, viable strategies may be potentially developed to be used for the treatment of brain injury and/or neuro-degenerative disorders.

ADVANTAGES

• Multiple approaches are potentially available for the development of tools that effect the expression and/or activity of Class I MHC for therapeutic purposes.

DEVELOPMENT-TO-DATE:  Transgenic C57BL/6 mice that have enhanced levels of neuronal MHCI have been evaluated for MHCI's effects on neurodevelopment and neurorepair. Purified recombinant MHCI molecules have been tested on cultures of wildtype mouse neurons.

Related Papers (Selected)

• Corriveau, R.A., G.S. Huh, and C.J. Shatz. 1998. Regulation of class I MHC gene expression in the developing and mature CNS by neural activity. Neuron 21:505-520.
• Huh, G.S., L.M. Boulanger, H. Du, P.A. Riquelme, T.M. Brotz, and C.J. Shatz. 2000. Functional requirement for class I MHC in CNS development and plasticity. Science 290:2155-2159.
• Syken, J., T. Grandpre, P.O. Kanold, and C.J. Shatz. 2006. PirB restricts ocular-dominance plasticity in visual cortex. Science 313:1795-1800.
• Zanon, R.G., and A.L. Oliveira. 2006. MHC I upregulation influences astroglial reaction and synaptic plasticity in the spinal cord after sciatic nerve transection. Exp Neurol 200:521-531.

Reference: UCLA Case No. 2000-118

US Patent Application: 2003/0049254