Impact of immune system humanization on atherosclerosis in dyslipidemic immunocompromised mice

Background and Aims: Given the key role of immune response during atherosclerosis and the therapeutic interest on biologics targeting human immune cells, the need of experimental models to translate molecular mechanisms and test therapeutic approaches for atherosclerosis is continuously increasing. Here we provide an immune and metabolic characterization of an innovative immunodeficient mouse humanized with human hematopoietic cells on an atheroprone background. Methods: LDLR-KO mice were crossed with the immunodeficient C57BL/6J strain Rag2-KO/IL2rg-KO/CD47-KO (TKO, IMSR_JAX:025730) to generate an immunocompromised dyslipidemic mouse (TKO-LDLR KO mice) recipient of human hematopoietic stem cells (hCD34+). Results: TKO-LDLR KO were first characterized for their immune and metabolic profile. TKO mice are deficient in mature lymphocytes and NK cells and this profile was conserved in TKO-LDLR KO mice. Under high cholesterol diet, TKO-LDLR KO develop marked dyslipidemia, steatosis and atherosclerosis. This profile confirms the suitability of TKO-LDLR KO mice for atherosclerosis studies. Next we tested the impact of immune system humanization on atherosclerosis. TKO-LDLR KO pups received a low-dose irradiation (200 cGy) and thereafter 2 x 10^5 hCD34+ were injected in the liver. Engraftment of human leukocytes (hCD45+) was evaluated after two months by flow cytometry analysis from tail blood. This approach allows to reconstitute between 10-30% of hCD45+, mainly B and T cells. hCD45 were detected also in the thymus (95%), spleen (20%) and liver (25%). The humanization with hCD34+ cells did not affect cholesterol levels (939,894,41 vs 987,448,82 mg/dL), but worsen atherosclerosis development by en face analysis and lesion area at the aortic valve, compared to non-humanized TKO-LDLR KO mice. Conclusions: We have generated and characterized the humanized dyslipidemic TKO-LDLR KO mouse. This mouse model presents human B and T cells and represents an important toll to investigate the impact of human adaptive immune cell pharmacological modulation in the context of atherosclerosis.