1 글쓴이 : 관리자
Bin Zhou, Mohammad Habiby Kermany, Qing Cai, Chun Cai, Tai June Yoo
Departments of Medicine, Molecular Sciences, and Otolaryngology and Neuroscience Institute, University of Tennessee, Memphis, TN
ImmuGen, Inc. Memphis, TN
Alzheimer’s disease (AD) is characterized by progressive cognitive and behavioral decline, impacting on both sufferers and their care givers. It is the most common cause of dementia among people of age 65 and older. It is irreversible, progressive brain disease. Pathologically, two key features are evident at the microscopic level in the post-mortem AD brain: extracellular amyloid plaques and intracellular neurofibrillary tangles (NFT).
The accumulations of Aβ may initiate a cascade of events resulting in clinical dementia forming the basis of amyloid hypotheses. Aβ is itself cleaved from the amyloid precursor protein (APP) by the amyloidogenic pathway involving the enzymes b ?secretase and r- secretase. Cleavage of APP produces monomers which oligomerize to form fibrils and, ultimately, the amyloid plaques pathognomonic of AD. In general drugs are divided into 5 categories (1) Amyloid (APP processing, Amyloid Plaques)
(2) Tau (kinase inhibitors, microtubules stabilizing agents) (3) Inflamation (nonstroidal antiinflamtory agent) (4) neurotransmitter pathways (acetylcholine estrase inhibitors, NMDA antagonists) (5) others (vascular risk reduction, vitamins, hormones).
Monoclonal antibody against Aβ was both effective, but also harmful. Elan Corp’s AN112 had severe brain inflammation in 16 out of 350n patients.
We have developed gene vaccines which repair damaged neural system, improve vascular structure, and regulate immune system for the benefit of host by dampening inflammation, decreasing amyloid plaques. They contain IL-10, 1L-4, TGF beta, Aβ1-42, ApoE ?2, and BDNGF genes. In APP transgenic mice, these gene vaccines were able to improve and restore the memory functions, by water maze tests and they also decrease the amyloid plaques markedly in the brain.
These are both preventative and therapeutic in this APP transgenic mice model. Thus these vaccines need to be tested if they are effective in human AD patients.
Autoimmune inner ear disease, including Meniere’s disease is devastating disease. The main feature of these disorders is the development and persistence of inflammatory processes in the apparent absence of pathogens, leading to destruction of target tissues.
We are able to establish disease remission and re-acquire immune homeostasis by transiently introducing immune regulatory elements by DNA vaccine and gene therapy.
Mice and guinea pigs were immunized with β-tubulin and hearing loss was induced. They demonstrate low density of the spiral ganglion as well as cochlear hair cell damage.
Increased ABR thresolds were shown in these animals. Serum antibody reactive to antigen was elevated. CD4 T cells as well as Th1 cytokine mediated autoimmune response were involved and CD4+CD25+Foxp3+ cells were linked to this disease.
Adoptive immunotherapy via T cell delivery of the IL-12p40 subunit was performed by iv injection of 2x106 T cell hybridoma transfected with IL-12p40 gene.
ABR as well as DPOAE threshold for β-tubulin immunized mice at 2 weeks and 6 weeks were measured. Distortion product traces of 8, 16, 32 KHz frequency at 80 dB SPL intensity in tubulin immunized were measured. DPOAE show low response to immunized group. Therapeutic group show restoration of hearing level at 6 weeks after therapy.
In mice and guinea pig, β-tubulin DNA gene constructs (ImmuGen 007) as well as ImmuGen 008,009 and 0010 were injected intra-muscularly. Total of 100 ug of plasmid (mice) and 250 ug of plasmid in guinea pigs were injected. On week in guinea pie and 2 weeks in mice after, we performed hearing test again. They have restored normal hearing.
In summary, T cells, cytokines as well as antibodies play as significant role in this autoimmune hearing loss. CD4+CD25+Foxp3 positive T-cells decrease as the lesion got worse. DNA vaccine therapy as well as T cells transfected with IL-12p40 could restore autoimmune disease.
Tai June Yoo, male, scientist, graduated from University of California Berkley in 1963. He worked for University of Tennessee Memphis since 1987.
2010-09-15 오후 1:07:46 [Read:11079]