RESUMO
Phosphodiesterase 4 (PDE4) inhibitors are approved for the treatment of some moderate to severe inflammatory conditions. However, dose-limiting side effects in the central nervous system and gastrointestinal tract, including nausea, emesis, headache, and diarrhea, have impeded the broader therapeutic application of PDE4 inhibitors. We sought to exploit the wealth of validation surrounding PDE4 inhibition by improving the therapeutic index through generation of an antibody-drug conjugate (ADC) that selectively targets immune cells through the CD11a antigen. The resulting ADC consisted of a human αCD11a antibody (based on efalizumab clone hu1124) conjugated to an analog of the highly potent PDE4 inhibitor GSK256066. Both the human αCD11a ADC and a mouse surrogate αCD11a ADC (based on the M17 clone) rapidly internalized into immune cells and suppressed lipololysaccharide (LPS)-induced TNFα secretion in primary human monocytes and mouse peritoneal cells, respectively. In a carrageenan-induced air pouch inflammation mouse model, treatment with the ADC significantly reduced inflammatory cytokine production in the air pouch exudate. Overall, these results provide compelling evidence for the feasibility of delivering drugs with anti-inflammatory activity selectively to the immune compartment via CD11a and the development of tissue-targeted PDE4 inhibitors as a promising therapeutic modality for treating inflammatory diseases.
Assuntos
Aminoquinolinas/metabolismo , Antígenos CD11/metabolismo , Imunoconjugados/administração & dosagem , Inflamação/imunologia , Inibidores da Fosfodiesterase 4/metabolismo , Sulfonas/metabolismo , Animais , Células Cultivadas , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Imunoconjugados/farmacologia , Lipopolissacarídeos/efeitos adversos , Camundongos , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Peritônio/efeitos dos fármacos , Peritônio/imunologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Assessing student learning is an integral component of teaching undergraduate dietetics students. Traditional grading can be cumbersome for instructors, encouraging extrinsic motivation for students and hindering clear understanding of whether students have met course learning outcomes. Specifications grading is a reimagined assessment paradigm that empowers both students and instructors to focus on achievement of learning objectives. This report examines the deployment of specifications grading in an undergraduate dietetics course, using qualitative methods to determine the impact on students' learning and experiences. Employing specifications grading may help dietetics educators foster self-regulation and mastery learning for students, as well as increase grading transparency.