Amyloid-ß specific regulatory T cells attenuate Alzheimer's disease pathobiology in APP/PS1 mice.

BACKGROUND: Regulatory T cells (Tregs) maintain immune tolerance. While Treg-mediated neuroprotective activities are now well-accepted, the lack of defined antigen specificity limits their therapeutic potential. This is notable for neurodegenerative diseases where cell access to injured brain regions is required for disease-specific therapeutic targeting and improved outcomes. To address this need, amyloid-beta (Aß) antigen specificity was conferred to Treg responses by engineering the T cell receptor (TCR) specific for Aß (TCRAß). The TCRAb were developed from disease-specific T cell effector (Teff) clones. The ability of Tregs expressing a transgenic TCRAß (TCRAß -Tregs) to reduce Aß burden, transform effector to regulatory cells, and reverse disease-associated neurotoxicity proved beneficial in an animal model of Alzheimer's disease. METHODS: TCRAß -Tregs were generated by CRISPR-Cas9 knockout of endogenous TCR and consequent incorporation of the transgenic TCRAb identified from Aß reactive Teff monoclones. Antigen specificity was confirmed by MHC-Aß-tetramer staining. Adoptive transfer of TCRAß-Tregs to mice expressing a chimeric mouse-human amyloid precursor protein and a mutant human presenilin-1 followed measured behavior, immune, and immunohistochemical outcomes. RESULTS: TCRAß-Tregs expressed an Aß-specific TCR. Adoptive transfer of TCRAß-Tregs led to sustained immune suppression, reduced microglial reaction, and amyloid loads. 18F-fluorodeoxyglucose radiolabeled TCRAß-Treg homed to the brain facilitating antigen specificity. Reduction in amyloid load was associated with improved cognitive functions. CONCLUSIONS: TCRAß-Tregs reduced amyloid burden, restored brain homeostasis, and improved learning and memory, supporting the increased therapeutic benefit of antigen specific Treg immunotherapy for AD.

Can Condylectomy Alone Achieve Facial Symmetry in Patients With Hemimandibular Hyperplasia (Condylar Hyperplasia Type 2)?

The purpose of the present study was to evaluate the 3-dimensional orofacial changes occurring after proportional condylectomy in patients with unilateral condylar hyperplasia type 2 (hemimandibular hyperplasia). Eight patients underwent proportional condylectomy that was not followed by orthognathic surgery or orthodontic treatment for at least 1 year. The precondylectomy and postcondylectomy photographs and radiographs were analyzed cephalometrically and compared. The average length of the condylar segment removed was 13 mm and this resulted in almost equal heights of the ramus-condyle units of both sides. Evaluations in the vertical plane improved after surgery; however, when the preoperative asymmetry was significant, the residual asymmetry continued to be notable after condylectomy. Transverse plane evaluations improved after condylectomy, and chin position was satisfactorily centralized in all patients. In the horizontal plane, mandibular setback occurred, and this was considered favorable when the preoperative skeletal profile was class III, whereas the opposite was when the patient was class I before surgery. The occlusion improved gradually over the postoperative months by the intrusion on the affected side and extrusion on the unaffected side into a bilaterally balanced posterior contacts with residual anterior open bite. In conclusion, condylar hyperplasia type 2 patients with mild asymmetry and low esthetic demands can benefit from proportional condylectomy as the sole treatment to both stop the hyperplastic condylar growth and improve the asymmetry to some extent. Surgeons should be able to predict the change that is expected to occur after proportional condylectomy and discuss this with the patient before surgery.