title: Alpha 1-antitrypsin reduces inflammation and enhances mouse pancreatic islet transplant survival.
abstract: The promise of islet cell transplantation cannot be fully realized in the absence of improvements in engraftment of resilient islets. The marginal mass of islets surviving the serial peritransplant insults may lead to exhaustion and thereby contribute to an unacceptably high rate of intermediate and long-term graft loss. Hence, we have studied the effects of treatment with alpha 1-antitrypsin (AAT) in a syngeneic nonautoimmune islet graft model. A marginal number of syngeneic mouse islets were transplanted into nonautoimmune diabetic hosts and islet function was analyzed in control and AAT treated hosts. In untreated controls, marginal mass islet transplants did not restore euglycemia. Outcomes were dramatically improved by short-term AAT treatment. Transcriptional profiling identified 1,184 differentially expressed transcripts in AAT-treated hosts at 3 d posttransplantation. Systems-biology-based analysis revealed AAT down-regulated regulatory hubs formed by inflammation-related molecules (e.g., TNF-α, NF-κB). The conclusions yielded by the systems-biology analysis were rigorously confirmed by QRT-PCR and immunohistology. These data suggest that short-term AAT treatment of human islet transplant recipients may be worthy of a clinical trial.
authors.affiliation: Harvard Medical School, Beth Israel Deaconess Medical Center (BIDMC), Boston, MA, USA. mkoulman@bidmc.harvard.edu
authors.forename: Maria
authors.initials: M
authors.lastname: Koulmanda
authors.forename: Manoj
authors.initials: M
authors.lastname: Bhasin
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Fan
authors.forename: Dusan
authors.initials: D
authors.lastname: Hanidziar
authors.forename: Nipun
authors.initials: N
authors.lastname: Goel
authors.forename: Prabhakar
authors.initials: P
authors.lastname: Putheti
authors.forename: Babak
authors.initials: B
authors.lastname: Movahedi
authors.forename: Towia A
authors.initials: TA
authors.lastname: Libermann
authors.forename: Terry B
authors.initials: TB
authors.lastname: Strom
mesh_terms: D000818:Animals; D002470:Cell Survival; D003921:Diabetes Mellitus, Experimental / Q000628:therapy; D003922:Diabetes Mellitus, Type 1 / Q000628:therapy; D007107:Immune System; D007249:Inflammation; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology*; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016896:Treatment Outcome; D000515:alpha 1-Antitrypsin / Q000378:metabolism*
chemical_list: D007328:Insulin; D000515:alpha 1-Antitrypsin