Mixed allogeneic chimerism with wild-type strains ameliorates atherosclerosis in apolipoprotein E-deficient mice

Naoki Ishimori; Kazuya Iwabuchi; Satoshi Fujii; Keiko Watano; Chikako Iwabuchi; Manabu Ato; Hitoshi Chiba; Shinya Tanaka; Akira Kitabatake; Kazunori Onoé

Mixed allogeneic chimerism with wild-type strains ameliorates atherosclerosis in apolipoprotein E-deficient mice

^*Division of Immunobiology, Research Section of Pathophysiology, Institute for Genetic Medicine, and Departments of
^†Cardiovascular Medicine,
^‡Laboratory Medicine, and
^§Molecular and Cellular Pathology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan

Correspondence: Kazunori Onoé, Division of Immunobiology, Research Section of Pathophysiology, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-0815, Japan. E-mail:kazunori{at}imm.hokudai.ac.jp

Abstract

Atherosclerosis involves inflammatory processes between vasculartissues and hematocytes with a hyperlipidemic background. To examinewhether variations of hematocytes constitute one of the geneticcomponents in atherosclerosis, irradiated apolipoprotein E(apoE)-deficient (apoE^−/−) mice with hypercholesterolemiaand preexisting atherosclerotic lesions were reconstituted withmixed bone marrow cells (BMC) from syngeneic and wild-type(apoE^+/+; atherosclerosis-resistant SJL or -susceptibleB10.S) mice. Stable mixed allogeneic chimeras with small amounts ofserum apoE were established without any detrimentalcomplications. Compared with untreated apoE^−/− miceor apoE^−/− mice transplanted with syngeneic BMC alone,significant reduction of the cholesterol level and significant lesionregression were observed in the mixed chimeras. Furthermore, mixedchimeras given SJL BMC showed marked reductions in numbers of lesionscompared with those reconstituted with B10.S BMC. Cholesterol levels inthe former SJL chimeras, however, were significantly higher than thosein the latter B10.S chimeras. These findings indicate that theresistance of SJL to atherosclerosis resides in the bone marrow-derivedcells.