title: Alleviation of instant blood-mediated inflammatory reaction in autologous conditions through treatment of human islets with NF-κB inhibitors.
abstract: BACKGROUND
  The instant blood-mediated inflammatory response (IBMIR) has been shown as a major factor that causes damage to transplanted islets. Withaferin A (WA), an inhibitor of nuclear factor (NF) κB, was shown to suppress the inflammatory response in islets and improve syngeneic islet graft survival in mice. We investigated how treating islets with NF-κB inhibitors affected IBMIR using an in vitro human autologous blood islet model.
  
  
  METHODS
  Human islets were pretreated with or without NF-κB inhibitors WA or CAY10512 before mixing autologous blood in a miniaturized in vitro tube model. Plasma samples were collected at multiple time points and used for the measurement of C-peptide, proinsulin, thrombin-antithrombin (TAT) complex, and a panel of proinflammatory cytokines. Infiltration of neutrophils into islets was analyzed using immunohistochemistry.
  
  
  RESULTS
  Rapid release of C-peptide and proinsulin was observed 3 hr after mixing islets and blood in the control group, but not in the NF-κB inhibitor-treated groups, whereas TAT levels were elevated in all three groups with a peak at 6 hr. Significant elevation of proinflammatory cytokines was observed in the control group after 3 hr, but not in the treatment groups. Significant inhibition of neutrophil infiltration was also observed in the WA group compared with the control (P<0.001) and CAY10512 (P<0.001) groups.
  
  
  CONCLUSIONS
  A miniaturized in vitro tube model can be useful in investigating IBMIR. The presence of NF-κB inhibitor could alleviate IBMIR, thus improving the survival of transplanted islets. Protection of islets in the peritransplant phase may improve long-term graft outcomes.
authors.affiliation: 1 The Institute of Biomedical Studies, Baylor University, Waco, TX. 2 Islet Cell Laboratory, Baylor Research Institute, Dallas, TX. 3 Baylor Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX. 4 Address correspondence to: Bashoo Naziruddin, Ph.D., 3410 Worth Street, Suite 950, Dallas, TX 75246.
authors.forename: Mazhar A
authors.initials: MA
authors.lastname: Kanak
authors.forename: Morihito
authors.initials: M
authors.lastname: Takita
authors.forename: Takeshi
authors.initials: T
authors.lastname: Itoh
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: SoRelle
authors.forename: Shyam
authors.initials: S
authors.lastname: Murali
authors.forename: Faisal
authors.initials: F
authors.lastname: Kunnathodi
authors.forename: Rauf
authors.initials: R
authors.lastname: Shahbazov
authors.forename: Michael C
authors.initials: MC
authors.lastname: Lawrence
authors.forename: Marlon F
authors.initials: MF
authors.lastname: Levy
authors.forename: Bashoo
authors.initials: B
authors.lastname: Naziruddin
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007249:Inflammation / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D020556:Neutrophil Infiltration; D011183:Postoperative Complications / Q000276:immunology / Q000517:prevention & control*; D014182:Transplantation, Autologous; D054358:Withanolides / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D016207:Cytokines; D016328:NF-kappa B; D054358:Withanolides; C009684:withaferin A