Kunal Patel

C3a receptor antagonism as a novel therapeutic target for chronic rhinosinusitis

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.

Donor pretreatment with nebulized complement C3a receptor antagonist mitigates brain-death induced immunological injury post-lung transplant

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.

Dietary vitamin D3 deficiency exacerbates sinonasal inflammation and alters local 25(OH)D3 metabolism.

Rationale Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) have been shown to be vitamin D3 (VD3) deficient, which is associated with more severe disease and increased polyp size. To gain mechanistic insights into these observational studies, we examined the impact of VD3 deficiency on inflammation and VD3 metabolism in an Aspergillus fumigatus (Af) mouse model of chronic rhinosinusitis (Af-CRS). Methods Balb/c mice were fed control or VD3 deficient diet for 4 weeks. Mice were then sensitized with intraperitoneal Af, and one week later given Af intranasally every three days for four weeks while being maintained on control or VD3 deficient diet. Airway function, sinonasal immune cell infiltrate and sinonasal VD3 metabolism profiles were then examined. Results Mice with VD3 deficiency had increased Penh and sRaw values as compared to controls as well as exacerbated changes in sRaw when coupled with Af-CRS. As compared to controls, VD3 deficient and Af-CRS mice had reduced sinonasal 1α-hydroxylase and the active VD3 metabolite, 1,25(OH)2D3. Differential analysis of nasal lavage samples showed that VD3 deficiency alone and in combination with Af-CRS profoundly upregulated eosinophil, neutrophil and lymphocyte numbers. VD3 deficiency exacerbated increases in monocyte-derived dendritic cell (DC) associated with Af-CRS. Conversely, T-regulatory cells were decreased in both Af-CRS mice and VD3 deficient mice, though coupling VD3 deficiency with Af-CRS did not exacerbate CD4 or T-regulatory cells numbers. Lastly, VD3 deficiency had a modifying or exacerbating impact on nasal lavage levels of IFN-γ, IL-6, IL-10 and TNF-α, but had no impact on IL-17A. Conclusions VD3 deficiency causes changes in sinonasal immunity, which in many ways mirrors the changes observed in Af-CRS mice, while selectively exacerbating inflammation. Furthermore, both VD3 deficiency and Af-CRS were associated with altered sinonasal VD3 metabolism causing reductions in local levels of the active VD3 metabolite, 1,25(OH)2D3, even with adequate circulating levels.

Organ Preservation, Ischemia Reperfusion Injury, and Nanotherapeutics in Transplantation

Over the past 30 years, solid organ transplantation has advanced tremendously in many facets, with great strides made in organ selection and allocation to the monitoring and treatment of rejection. Despite these breakthroughs, organ preservation and chronic rejection rates have remained largely unchanged. Recent trends in translational research have begun to address this issue, and future directions for organ preservation will have far-reaching implications for the field of transplantation as a whole. In this chapter, we will highlight the current trends and innovations in preservation techniques, with a special focus on the role that nanotechnology is playing in this frontier.

Nanotechnological Approaches to Immunosuppression and Tolerance Induction

Purpose of ReviewSeveral pre-clinical studies have engineered nanoparticles for immune regulation and have shown promising results in the fields of autoimmunity and cancer. In solid organ transplantation, the use of nanoparticle-based immune regulation has only just begun to emerge but holds significant promise for the improvement of our current standard of care immunosuppressive regimens. In this review, we will shed light on the current status of nanoparticle-engineered immunotherapeutics and the potential application of these technologies to the field of organ transplantation. Further, we discuss different strategies for delivery and potential cellular targeting moieties that could be utilized to obviate the need for high-dose systemic immunosuppressive regimens.Recent FindingsRecent studies have shown the potential of immunosuppressive-laden nanoparticles to increase bioavailability, drug release, and specifically target immune cell compartments as methods to provide recipient immunosuppressive sparing strategies.SummaryNanoparticle-centered immunosuppressive strategies hold the potential to usher in a new era in transplant recipient management and could hold the key to minimizing off-target effects of immunosuppressants, along with prolonging transplant survival.

Utilization of Machine Perfusion and Nanotechnology for Liver Transplantation

Over the past four decades, advances in the technology supporting solid organ transplantation have been remarkable. Transplantation is now entering a new era where multidisciplinary approaches, including the use of bioengineering, are being utilized in the pursuit of perfection for the field. In this review article, we will introduce and recap two broad categories that are on the verge of revolutionizing the utilization of donor organs and delivery of immunosuppression, metabolic additives, and gene therapies. Machine perfusion techniques and nanotechnology are areas of significant interest in the transplantation community and make up the next generation of bench to bedside research endeavors. In this review, we will summarize the progress made in the field of machine perfusion and nanotechnology as it applies to liver transplantation.

Laparoscopic repair of gastro-duodenal fistula secondary to band erosion.

Laparoscopic gastric banding is one of the most common surgical treatments for morbid obesity performed worldwide. The procedure, however, has many well-documented risks and complications, including band erosion. We present here a gastric banding patient who was referred to our tertiary care centre after secondarily forming an entero-enteric fistula with complaints of pain, nausea, vomiting and severe reflux. She was successfully treated with laparoscopic dissection and due to her existing anatomy, and the patients desire for continued weight loss, she was converted to Roux-en-Y gastric bypass.