Selective HDAC6 Inhibition in Systemic Lupus Erythematosus
| dc.contributor.author | Vieson, Miranda Diane | en |
| dc.contributor.committeechair | Luo, Xin | en |
| dc.contributor.committeemember | Huckle, William R. | en |
| dc.contributor.committeemember | LeRoith, Tanya | en |
| dc.contributor.committeemember | Caudell, David L. | en |
| dc.contributor.department | Veterinary Medicine | en |
| dc.date.accessioned | 2017-01-31T09:00:44Z | en |
| dc.date.available | 2017-01-31T09:00:44Z | en |
| dc.date.issued | 2017-01-30 | en |
| dc.description.abstract | Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by abnormalities in multiple components of the immune system resulting in progressive damage to multiple organs. Current treatments for SLE are often intensive and result in side effects and the potential for continued flares and progression of disease. Histone deacetylase (HDAC) enzymes control multiple cellular functions by removing acetyl groups from lysine residues in various proteins. HDAC inhibitors have been investigated as a potential treatment for SLE with promising results, however selective HDAC6 inhibition (HDAC6i) has become a leading candidate for pharmacologic inhibition to reduce the potential for side effects. We hypothesize that HDAC6i will decrease SLE disease by targeting substrates of HDAC6 in multiple components of immunity and organ systems. NZB/W mice were treated with ACY-738 or ACY-1083, followed by evaluation of multiple disease parameters and mechanisms involved in disease pathogenesis within the kidney, bone marrow, and spleen. Within the kidney, HDAC6i decreased glomerular pathology scores, proteinuria, and IgG and C3 deposition. Within glomerular cells, HDAC6i increased alpha-tubulin acetylation and decreased nuclear NF-κB. Within the spleen, there was a dose-dependent decrease in the frequency of Th17 cells and a mild decrease in the frequency of Treg cells. Concurrently, there were decreased levels of IL-12/IL-23 and minimal decreases in TGF-β in the serum. Within the bone marrow, B cell development through Hardy fractions exhibited accelerated progression through later stages as NZB/W mice aged. This accelerated progression may allow B cells to bypass important regulatory checkpoints in maintaining immune tolerance and contribute to autoimmunity. Treatment with an HDAC6i corrected the aberrant B cell development in the bone marrow and RNAseq analysis unveiled six genes (Cebpb, Ccr9, Spib, Nfil3, Lgals1, and Pou2af1) that may play a role in the aforementioned abnormalities. Overall, these findings show that HDAC6i decreased disease in NZB/W mice by targeting multiple components of the immune response, including glomerular cells, T cell subsets in the spleen, and bone marrow B cells. In conclusion, selective HDAC6i is an excellent candidate for pharmacologic therapy for SLE because it targets multiple immune abnormalities involved in SLE pathogenesis while remaining selective and safe. | en |
| dc.description.abstractgeneral | Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by multiple abnormalities in the immune system resulting in progressive immune-mediated damage to multiple organs. Current treatment regimens are often intensive, result in side effects, and may only provide temporary relief of disease. Histone deacetylase (HDAC) inhibition is currently being investigated as a new treatment modality for SLE with aims for improved efficacy and decreased potential for unwanted side effects. HDAC enzymes remove acetyl groups from multiple proteins (substrates) and subsequently regulate their function. HDAC6 is a specific HDAC enzyme that is of particular interest and are the subject of the following studies. These studies hypothesize that HDAC6 inhibition will decrease SLE by targeting multiple protein targets involved in the immune-mediated pathway of disease initiation and progression. NZB/W mice were utilized as a model of the human disease, and were treated by HDAC6 inhibitors during various stages of disease progression. Long-term treatment initiated early in disease decreases disease as evidenced by decreased renal pathology scores, immune complex deposition in the kidneys, decreased T cell subtypes in the spleen, and decreased inflammatory cytokines. HDAC6 inhibition corrects abnormal B cell development within the bone marrow of NZB/W mice, which is otherwise altered during disease progression. Furthermore, HDAC6 inhibition altered gene expression within the bone marrow, and deep sequencing analysis revealed multiple genes that may be involved in the pathway of disease progression. Overall, HDAC6 inhibition targets multiple pathways involved in SLE disease initiation and progression in various organs including the bone marrow, spleen, and kidneys. Because SLE is a disease that is multi-factorial and effects multiple organs, it would be ideal that a potential drug therapy also targets multiple targets and organ systems while remaining safe to use. Based on these studies, HDAC6 inhibitors are excellent candidates for the treatment of SLE. | en |
| dc.description.degree | Ph. D. | en |
| dc.format.medium | ETD | en |
| dc.identifier.other | vt_gsexam:9380 | en |
| dc.identifier.uri | http://hdl.handle.net/10919/74872 | en |
| dc.publisher | Virginia Tech | en |
| dc.rights | In Copyright | en |
| dc.rights.uri | http://rightsstatements.org/vocab/InC/1.0/ | en |
| dc.subject | Autoimmunity | en |
| dc.subject | Histone Deacteylase | en |
| dc.subject | Lupus Nephritis | en |
| dc.subject | B Cell Development | en |
| dc.title | Selective HDAC6 Inhibition in Systemic Lupus Erythematosus | en |
| dc.type | Dissertation | en |
| thesis.degree.discipline | Biomedical and Veterinary Sciences | en |
| thesis.degree.grantor | Virginia Polytechnic Institute and State University | en |
| thesis.degree.level | doctoral | en |
| thesis.degree.name | Ph. D. | en |