Browsing by Author "Patel, Kunal"

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    A novel injury site-natural antibody targeted complement inhibitor protects against lung transplant injury.
    (American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 2021-06) Li, Changhai; Patel, Kunal; Tu, Zhenxiao; Yang, Xiaofeng; Kulik, Liudmila; Alawieh, Ali; Allen, Patterson; Cheng, Qi; Wallace, Caroline; Kilkenny, Jane; Kwon, Jennie; Gibney, Barry; Cantu, Edward; Sharma, Ashish; Pipkin, Mauricio; Machuca, Tiago; Emtiazjoo, Amir; Goddard, Martin; Holers, V Michael; Nadig, Satish; Christie, Jason; Tomlinson, Stephen; Atkinson, Carl
    Complement is known to play a role in ischemia and reperfusion injury (IRI). A general paradigm is that complement is activated by self-reactive natural IgM antibodies (nAbs), after they engage postischemic neoepitopes. However, a role for nAbs in lung transplantation (LTx) has not been explored. Using mouse models of LTx, we investigated the role of two postischemic neoepitopes, modified annexin IV (B4) and a subset of phospholipids (C2), in LTx. Antibody deficient Rag1-/- recipient mice were protected from LTx IRI. Reconstitution with either B4 or C2nAb restored IRI, with C2 significantly more effective than B4 nAb. Based on these information, we developed/characterized a novel complement inhibitor composed of single-chain antibody (scFv) derived from the C2 nAb linked to Crry (C2scFv-Crry), a murine inhibitor of C3 activation. Using an allogeneic LTx, in which recipients contain a full nAb repertoire, C2scFv-Crry targeted to the LTx, inhibited IRI, and delayed acute rejection. Finally, we demonstrate the expression of the C2 neoepitope in human donor lungs, highlighting the translational potential of this approach.
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    C3a receptor antagonism as a novel therapeutic target for chronic rhinosinusitis.
    (Mucosal immunology, 2018-09) Mulligan, Jennifer K; Patel, Kunal; Williamson, Tucker; Reaves, Nicholas; Carroll, William; Stephenson, Sarah E; Gao, Peng; Drake, Richard R; Neely, Benjamin A; Tomlinson, Stephen; Schlosser, Rodney J; Atkinson, Carl
    Chronic rhinosinusitis with nasal polyps (CRSwNP) is an inflammatory disease with an unknown etiology. Recent studies have implicated the complement system as a potential modulator of disease immunopathology. We performed proteomic pathway enrichment analysis of differentially increased proteins, and found an enrichment of complement cascade pathways in the nasal mucus of individuals with CRSwNP as compared to control subjects. Sinonasal mucus levels of complement 3 (C3) correlated with worse subjective disease severity, whereas no significant difference in systemic C3 levels could be determined in plasma samples. Given that human sinonasal epithelial cells were the predominate sinonasal source of C3 and complement anaphylatoxin 3a (C3a) staining, we focused on their role in in vitro studies. Baseline intracellular C3 levels were higher in CRSwNP cells, and following exposure to Aspergillus fumigatus (Af) extract, they released significantly more C3 and C3a. Inhibition of complement 3a receptor (C3aR) signaling led to a decrease in Af-induced C3 and C3a release, both in vitro and in vivo. Finally, we found in vivo that C3aR deficiency or inhibition significantly reduced inflammation and CRS development in a mouse model of Af-induced CRS. These findings demonstrate that local sinonasal complement activation correlates with subjective disease severity, and that local C3aR antagonism significantly ameliorates Af-induced CRS in a rodent model.
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    Donor pretreatment with nebulized complement C3a receptor antagonist mitigates brain-death induced immunological injury post-lung transplant.
    (American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 2018-10) Cheng, Qi; Patel, Kunal; Lei, Biao; Rucker, Lindsay; Allen, D Patterson; Zhu, Peng; Vasu, Chentha; Martins, Paulo N; Goddard, Martin; Nadig, Satish N; Atkinson, Carl
    Donor brain death (BD) is an inherent part of lung transplantation (LTx) and a key contributor to ischemia-reperfusion injury (IRI). Complement activation occurs as a consequence of BD in other solid organ Tx and exacerbates IRI, but the role of complement in LTx has not been investigated. Here, we investigate the utility of delivering nebulized C3a receptor antagonist (C3aRA) pretransplant to BD donor lungs in order to reduce post-LTx IRI. BD was induced in Balb/c donors, and lungs nebulized with C3aRA or vehicle 30 minutes prior to lung procurement. Lungs were then cold stored for 18 hours before transplantation into C57Bl/6 recipients. Donor lungs from living donors (LD) were removed and similarly stored. At 6 hours and 5 days post-LTx, recipients of BD donor lungs had exacerbated IRI and acute rejection (AR), respectively, compared to recipients receiving LD lungs, as determined by increased histopathological injury, immune cells, and cytokine levels. A single pretransplant nebulized dose of C3aRA to the donor significantly reduced IRI as compared to vehicle-treated BD donors, and returned IRI and AR grades to that seen following LD LTx. These data demonstrate a role for complement inhibition in the amelioration of IRI post-LTx in the context of donor BD.
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    Why are medical students 'checking out' of active learning in a new curriculum?
    (Medical education, 2014-03) White, Casey; Bradley, Elizabeth; Martindale, James; Roy, Paula; Patel, Kunal; Yoon, Michelle; Worden, Mary Kate

    Objectives

    The University of Virginia School of Medicine recently transformed its pre-clerkship medical education programme to emphasise student engagement and active learning in the classroom. As in other medical schools, many students are opting out of attending class and others are inattentive while in class. We sought to understand why, especially with a new student-centred curriculum, so many students were still opting to learn on their own outside of class or to disengage from educational activities while in class.

    Methods

    Focus groups were conducted with students from two classes who had participated in the new curriculum, which is designed to foster small-group and collaborative learning. The sessions were audio-recorded and then transcribed. The authors read through all of the transcripts and then reviewed them for themes. Quotes were analysed and organised by theme.

    Results

    Interview transcripts revealed candid responses to questions about learning and the learning environment. The semi-structured nature of the interviews enabled the interviewers to probe unanticipated issues (e.g. reasons for choosing to sit with friends although that diminishes learning and attention). A content analysis of these transcripts ultimately identified three major themes embracing multiple sub-themes: (i) learning studio physical space; (ii) interaction patterns among learners, and (iii) the quality of and engagement in learning in the space.

    Conclusions

    Students' reluctance to engage in class activities is not surprising if classroom exercises are passive and not consistently well designed or executed as active learning exercises that students perceive as enhancing their learning through collaboration. Students' comments also suggest that their reluctance to participate regularly in class may be because they have not yet achieved the developmental level compatible with adult and active learning, on which the curriculum is based. Challenges include helping students better understand the nature of deep learning and their own developmental progress as learners, and providing robust faculty development to ensure the consistent deployment of higher-order learning activities linked with higher-order assessments.