In vivo analysis of human immune responses in immunodeficient rats.

Abstract : BACKGROUND: Humanized immune system immunodeficient mice have been extremely useful for the in vivo analyses of immune responses in a variety of models, including organ transplantation and GVHD but they have limitations. Rat models are interesting complementary alternatives presenting advantages over mice, such as their size and their active complement compartment. Immunodeficient rats have been generated but human immune responses have not yet been described. METHODS: We generated immunodeficient RRGS rats (for Rat Rag-/- Gamma chain-/- hSIRPa-positive) combining Rag1 and Il2rg deficiency with the expression of human SIRPalpha, a negative regulator of macrophage phagocytosis allowing repression of rat macrophages by human CD47-positive cells. We then immune humanized RRGS animals with human PBMCs to set up a human acute GVHD model. Treatment of GVHD was done with a new porcine anti-human lymphocyte serum (LIS1) active through complement-dependent cytotoxicity. We also established a tumor xenograft rejection model in these human PBMCs immune system RRGS animals by subcutaneous implantation of a human tumor cell line. RESULTS: RRGS animals receiving human PBMCs showed robust and reproducible reconstitution, mainly by T and B cells. A dose-dependent acute GVHD process was observed with progressive weight loss, tissue damage and death censoring. LIS1 antibody completely prevented acute GVHD. In the human tumor xenograft model, detectable tumors were rejected upon hPBMCs injection. CONCLUSIONS: Human PBMC can be implanted in RRGS animals and elicit acute GVHD or rejection of human tumor cells and these are useful models to test new immunotherapies.