title: Diabetes acceleration or prevention by a coxsackievirus B4 infection: critical requirements for both interleukin-4 and gamma interferon.
abstract: Type 1 diabetes acceleration in nonobese diabetic (NOD) mice through coxsackievirus B4 (CVB4) infection requires a preexisting critical mass of autoreactive T cells in pancreatic islets, and in the absence of this insulitic threshold, CVB4 infection leads to long-term disease protection. To understand this acceleration and protection process, we challenged 8- and 12-week-old NOD mice containing a disruption in interleukin-4 (IL-4) or gamma interferon (IFN-gamma) genes (NOD IL-4-/- and NOD IFN-gamma-/-, respectively) with a diabetogenic, pancreatropic Edwards strain of CVB4. The elimination of IL-4 did not alter the rate of insulitis or diabetes development in NOD mice, while the elimination of IFN-gamma delayed these events several weeks. CVB4 infection in 8-week-old mice only significantly accelerated the onset of diabetes in a subset of standard, but not IL-4- or IFN-gamma-deficient, NOD mice. Long-term diabetes protection was established in standard NOD mice as well as in the NOD IFN-gamma-/- mice that did not rapidly develop disease following CVB4 infection at 8 weeks of age. When mice were infected at 12 weeks of age, the onset of diabetes was accelerated in NOD IL-4-/- mice, while neither acceleration nor long-term protection was elicited in NOD IFN-gamma-/- mice. No differences were observed in the kinetics of CVB4 clearance in pancreases from NOD, NOD IL-4-/-, and NOD IFN-gamma-/- mice. Collectively, these results suggest that at the insulitis threshold at which CVB4 infection can first accelerate the onset of diabetes in NOD mice, IL-4 as well as IFN-gamma contributes to this pathogenic process. The protective mechanism against diabetes elicited in NOD mice infected with CVB4 prior to the development of a critical threshold level of insulitis requires neither IL-4 nor IFN-gamma.
authors.affiliation: Department of Pathology, University of Florida, Box 100275 JHMHC, 1600 SW Archer Rd., Gainesville, FL 32610, USA.
authors.forename: David V
authors.initials: DV
authors.lastname: Serreze
authors.forename: Clive
authors.initials: C
authors.lastname: Wasserfall
authors.forename: Eric W
authors.initials: EW
authors.lastname: Ottendorfer
authors.forename: Michael
authors.initials: M
authors.lastname: Stalvey
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Pierce
authors.forename: Charles
authors.initials: C
authors.lastname: Gauntt
authors.forename: Brian
authors.initials: B
authors.lastname: O'Donnell
authors.forename: James B
authors.initials: JB
authors.lastname: Flanagan
authors.forename: Martha
authors.initials: M
authors.lastname: Campbell-Thompson
authors.forename: Tamir M
authors.initials: TM
authors.lastname: Ellis
authors.forename: Mark A
authors.initials: MA
authors.lastname: Atkinson
mesh_terms: D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000517:prevention & control; D029822:Enterovirus B, Human; D004769:Enterovirus Infections / Q000150:complications*; D005260:Female; D007371:Interferon-gamma / Q000502:physiology*; D015847:Interleukin-4 / Q000502:physiology*; D007515:Islets of Langerhans / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D010179:Pancreas / Q000821:virology
chemical_list: D015847:Interleukin-4; D007371:Interferon-gamma