Oral N-acetylcysteine decreases IFN-γ production and ameliorates ischemia-reperfusion injury in steatotic livers.

Type 1 Natural Killer T-cells (NKT1 cells) play a critical role in mediating hepatic ischemia-reperfusion injury (IRI). Although hepatic steatosis is a major risk factor for preservation type injury, how NKT cells impact this is understudied. Given NKT1 cell activation by phospholipid ligands recognized presented by CD1d, we hypothesized that NKT1 cells are key modulators of hepatic IRI because of the increased frequency of activating ligands in the setting of hepatic steatosis. We first demonstrate that IRI is exacerbated by a high-fat diet (HFD) in experimental murine models of warm partial ischemia. This is evident in the evaluation of ALT levels and Phasor-Fluorescence Lifetime (Phasor-FLIM) Imaging for glycolytic stress. Polychromatic flow cytometry identified pronounced increases in CD45+CD3+NK1.1+NKT1 cells in HFD fed mice when compared to mice fed a normal diet (ND). This observation is further extended to IRI, measuring ex vivo cytokine expression in the HFD and ND. Much higher interferon-gamma (IFN-γ) expression is noted in the HFD mice after IRI. We further tested our hypothesis by performing a lipidomic analysis of hepatic tissue and compared this to Phasor-FLIM imaging using "long lifetime species", a byproduct of lipid oxidation. There are higher levels of triacylglycerols and phospholipids in HFD mice. Since N-acetylcysteine (NAC) is able to limit hepatic steatosis, we tested how oral NAC supplementation in HFD mice impacted IRI. Interestingly, oral NAC supplementation in HFD mice results in improved hepatic enhancement using contrast-enhanced magnetic resonance imaging (MRI) compared to HFD control mice and normalization of glycolysis demonstrated by Phasor-FLIM imaging. This correlated with improved biochemical serum levels and a decrease in IFN-γ expression at a tissue level and from CD45+CD3+CD1d+ cells. Lipidomic evaluation of tissue in the HFD+NAC mice demonstrated a drastic decrease in triacylglycerol, suggesting downregulation of the PPAR-γ pathway.

Anti-plasma cell treatment in refractory autoimmune hemolytic anemia in a child with multivisceral transplant.

BACKGROUND: Warm-antibody AIHA is known to complicate solid organ (SOT) and HSCT, the disease maybe refractory to standard therapy. Immunosuppressive therapies as well as IVIG, and rituximab have been the main stay of treatment. Over the past decade, B-lymphocyte targeted, anti-CD-20 antibody has been recognized in the treatment of autoimmune diseases and utilized in AIHA. Bortezomib, a proteasome inhibitor that causes apoptosis of plasma cells, is an appealing targeted therapy in secondary AIHA and has demonstrated efficacy in HSCT patients. From our experience, we advocate for early targeted therapy that combines B cell with plasma cell depletion. CASE REPORT: We describe a 4-year-old-girl with stage III neuroblastoma, complicated with intestinal necrosis needing multivisceral transplant developed warm AIHA 1-year after transplantation, and following an adenovirus infection. She received immunoglobulin therapy, rituximab, sirolimus, plasmapheresis, and long-term prednisolone with no sustained benefit while developing spinal fractures related to the latter therapy. She received bortezomib for intractable AIHA in combination with rituximab with no appreciable adverse effects. Three years later the child remains in remission with normal reticulocyte and recovered B cells. In the interim, she required chelation therapy for iron overload related to blood transfusion requirement during the treatment of AIHA. CONCLUSION: We propose early targeted anti-plasma cell therapy with steroid burst, IVIG, rituximab, and possible plasmapheresis may reduce morbidity in secondary refractory w-AIHA.

The parallel paradigm between intestinal transplant inflammation and inflammatory bowel disease.

PURPOSE OF REVIEW: A significant shift in our understanding of the molecular and cellular basis for inflammatory bowel disease (IBD) mirrors research that has been ongoing in intestinal transplantation. The blurring of lines between these two disease states creates an avenue into potential therapeutic interventions which take advantage of these molecular similarities. RECENT FINDINGS: Traditional knowledge of T-cell involvement in IBD has expanded to highlight the role of T helper 17 (Th17) cells as key effector cells. A similar role has been demonstrated in cellular rejection of intestinal allografts. Genetic polymorphism related to the propagation and function of Th17 cells has been found to confer significant risk of developing autoimmune conditions. Interleukin-23, a cytokine identified as crucial to the expansion of Th17 cells, has become a validated molecular target in psoriatic arthritis and IBD, and could become a target for intestinal transplant therapies. SUMMARY: Intestinal transplant rejection and IBD share a similar phenotype, especially as it relates to key effector cells and gene polymorphisms. Improvements in our understanding of the immune-pathogenesis of IBD, as well as molecular targeting exploiting that knowledge, provide a potential route to improve outcomes for intestinal transplant patients.

Pregnancy in an intestinal transplant recipient.

BACKGROUND: Intestinal transplantation is a relatively new form of therapy for short gut syndrome. Pregnancy after intestinal transplantation is rare. CASE: A 26-year-old small bowel transplant recipient presented for prenatal care. She previously had undergone bariatric surgery and later experienced small bowel necrosis and resection. The resulting short gut syndrome was treated with an isolated small bowel transplant. Medications during this pregnancy included prednisone, esomeprazole, diphenoxylate-atropine, ascorbic acid, tacrolimus, and magnesium supplementation. Throughout her pregnancy, her creatinine level was elevated. Labor was induced at 39 3/7 weeks and resulted in a spontaneous vaginal delivery of a healthy female neonate. Twelve weeks after delivery, the mother was admitted for a rejection reaction that was treated successfully. CONCLUSION: A successful pregnancy in an intestinal transplant recipient resulted in delivery of a healthy term newborn.

Impact of surveillance stool culture guided selection of antibiotics in the management of pediatric small bowel transplant recipients.

Surveillance stool cultures (SSC) have been used in immunocompromised populations to predict the organisms associated with invasive infections and aid in the selection of empiric antibiotic regimens. To evaluate the utility of this approach in pediatric small bowel transplant (SBT) recipients, we conducted a retrospective review of 33 patients who underwent SBT, 16 of whom had SSC done. In no case was the same organism isolated from SSC and subsequent blood, peritoneal fluid or wound cultures. In the first month post-transplantation, blood cultures were positive in 44% and 35% of patients that had and did not have SSC done, respectively (p = 0.73); peritoneal fluid cultures in 44% and 65% (p = 0.30); and wound cultures in 44% and 24% (p = 0.28). There were no significant differences among both groups in time to first infection, duration of ICU stay following SBT, graft survival or long-term patient survival. We conclude that SSC-guided antibiotic selection does not have a significant impact on the incidence of invasive infections in the first month following SBT or on specific indicators of patient outcome. This suggests that empiric antibiotic regimens should be selected based on clinical presentation and hospital flora and susceptibility patterns.