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Alleviation of instant blood-mediated inflammatory reaction in autologous conditions through treatment of human islets with NF-?B inhibitors.

ABSTRACT: 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) ?B, was shown to suppress the inflammatory response in islets and improve syngeneic islet graft survival in mice. We investigated how treating islets with NF-?B inhibitors affected IBMIR using an in vitro human autologous blood islet model.Human islets were pretreated with or without NF-?B 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.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-?B 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.A miniaturized in vitro tube model can be useful in investigating IBMIR. The presence of NF-?B inhibitor could alleviate IBMIR, thus improving the survival of transplanted islets. Protection of islets in the peritransplant phase may improve long-term graft outcomes.

SUBMITTER: Kanak MA

PROVIDER: S-EPMC4206260 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Alleviation of instant blood-mediated inflammatory reaction in autologous conditions through treatment of human islets with NF-κB inhibitors.

Kanak Mazhar A MA Takita Morihito M Itoh Takeshi T SoRelle Jeffrey A JA Murali Shyam S Kunnathodi Faisal F Shahbazov Rauf R Lawrence Michael C MC Levy Marlon F MF Naziruddin Bashoo B

Transplantation 20140901 5

<h4>Background</h4>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.<h4>Methods</h4>Human islets were pretreated with or ...[more]

PMID: 24798306

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Project description:IntroductionFaecal blood loss has been measured using autologous erythrocytes labelled with radioactive chromium for several decades, using generally similar methods. We conducted a systematic review of studies employing this technology to determine the degree of blood loss associated with use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclo-oxygenase-2 selective inhibitors (coxibs).MethodsA systematic search of PubMed and the Cochrane Library (to December 2006) was conducted to identify randomized trials in which treatment with aspirin, NSAIDs, or coxibs was continued for at least 7 days, and with at least 7 days of washout for crossover trials. Rates of faecal blood loss associated with these agents were determined in the randomized trials identified. Comparators were placebo, active, or no treatment. Outcomes of interest were mean daily faecal blood loss, and the number or proportion of individuals recording faecal blood above 5 ml/day and above 10 ml/day.ResultsForty-five reports of 47 trials were included, including 1,162 individuals, mostly healthy volunteers and predominantly young men. Only 136 patients (as opposed to healthy volunteers; 12%) were included, and these were mostly older people with an arthritic condition. Most NSAIDs and low-dose (325 mg) aspirin resulted in a small average increase in faecal blood loss of 1 to 2 ml/day from about 0.5 ml/day at baseline. Aspirin at full anti-inflammatory doses resulted in much higher average levels of blood loss of about 5 ml/day. Some individuals lost much more blood than average, at least for some of the time, with 5% of those taking NSAIDs having daily blood loss of 5 ml or more and 1% having daily blood loss of 10 ml or more; rates of daily blood loss of 5 ml/day or 10 ml/day were 31% and 10%, respectively, for aspirin at daily doses of 1,800 mg or greater.ConclusionAt baseline, or with placebo, faecal blood loss is measured at 1 ml/day or below. With low-dose aspirin and some NSAIDs, average values may be two to four times this, and anti-inflammatory doses of aspirin result in much higher average losses. A small proportion of individuals respond to aspirin or NSAIDs with much higher faecal blood loss of above 5 ml/day or 10 ml/day. There are significant limitations regarding the quality and validity of reporting of these studies, such as limited size and inclusion of inappropriate participants. The potential for blood loss and consequent anaemia requires more study.

Project description:PurposeFive patients who underwent uncomplicated retinal pigment epithelium (RPE)-choroid transplantation for neovascular age-related macular degeneration developed a destructive inflammatory reaction causing subretinal fluid accumulation and extensive RPE atrophy in the graft. We hypothesized that this inflammation could be caused by an auto-immune response against the graft, resulting in circulating auto-antibodies. The aim of our study was to examine a potential autoimmune origin, which would allow a more targeted therapy approach.MethodsFive above-mentioned patients and four control groups of five patients each were included: 1) after uncomplicated RPE-choroid transplantation, 2) after full macular translocation, 3) treated with anti-vascular endothelial growth factor, and 4) healthy controls. Histopathology of rejected graft tissue was performed using standard procedures. Presence of RPE-choroid autoantibodies in serum was examined by indirect immunofluorescence and Western blot, and human leukocyte antigen (HLA) typing was performed.ResultsHistopathological examination of an explanted graft showed infiltration of T-lymphocytes and macrophages in the choroid and RPE, and an increased number of B-cell lymphocytes were found in the choroid. Indirect immunofluorescence showed weak RPE-choroid autoantibody immunoreactivity in three patients of different groups. Western blot did not show specific RPE-choroid autoantibody immunoreactivity and no difference of HLA genotypes between the groups was found.ConclusionsAlthough local mononuclear inflammatory cell infiltration and a high number of B-lymphocytes were observed in an explanted graft, we did not detect serological evidence of an autoimmune origin of the postoperative inflammation using direct immunofluorescence and Western Blot. Alternatively, the graft failure may have been caused by local innate inflammation, triggered by breakdown of tolerance. Based on our current findings of this small study group, we have no rationale to pursue therapies targeted towards autoreactive graft failure. More research is needed to confirm our findings.

Dataset Information

Alleviation of instant blood-mediated inflammatory reaction in autologous conditions through treatment of human islets with NF-?B inhibitors.

Publications

Alleviation of instant blood-mediated inflammatory reaction in autologous conditions through treatment of human islets with NF-κB inhibitors.

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