title: Induction of diabetes in NOD<-->C57BL/6 embryo aggregation chimeras by cyclophosphamide through preferential depletion of C57BL/6 lymphocytes.
abstract: The majority of embryo aggregation (EA) mouse chimeras between non-obese diabetic (NOD) mice and C57BL/6 (B6) mice show clear signs of insulitis frequently accompanied by beta-cell destruction. Less than 5% of these chimeras, however, spontaneously progress to autoimmune diabetes, an incidence far lower than observed in NOD mice. The resistance in chimeras can be accounted for by the target organ chimerism and/or the immune system chimerism. To investigate the mechanism(s) controlling diabetes resistance in these mice, we studied a total of 92 NOD<-->B6 EA chimeras that showed overt lymphoid chimerism and treated 34 chimeras with cyclophosphamide (CY), a compound known to precipitate an acute form of insulin-dependent diabetes mellitus (IDDM) in pre-diabetic NOD mice, by interfering with regulatory mechanisms. We found that CY-treated EA chimeras displayed an increase in the NOD:B6 lymphocyte ratio and 32% of them developed diabetes that could be adoptively transferred to irradiated NOD or NOD-rag-2-/- mice. These findings suggest that lymphocyte chimerism rather than beta-cell chimerism accounts for diabetes resistance in NOD<-->B6 EA chimeras and that the susceptibility to CY-induced diabetes may be related to the proportion of NOD versus B6 lymphoid cells.
authors.affiliation: Department for Cell and Molecular Biology, University of Umeå, Sweden.
authors.forename: F
authors.initials: F
authors.lastname: Colucci
authors.forename: K
authors.initials: K
authors.lastname: Lejon
authors.forename: C M
authors.initials: CM
authors.lastname: Cilio
authors.forename: I
authors.initials: I
authors.lastname: Bergqvist
authors.forename: T
authors.initials: T
authors.lastname: Matsunaga
authors.forename: D
authors.initials: D
authors.lastname: Holmberg
mesh_terms: D000818:Animals; D015551:Autoimmunity; D002678:Chimera / Q000187:drug effects* / Q000276:immunology; D003520:Cyclophosphamide / Q000494:pharmacology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D007113:Immunity, Innate / Q000187:drug effects; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL / Q000196:embryology* / Q000276:immunology*; D016688:Mice, Inbred NOD / Q000502:physiology*
chemical_list: D003520:Cyclophosphamide