Mouse strain and conditioning regimen determine survival and function of human leucocytes in immunodeficient mice

The innate immune system of severe combined immunodeficient (SCID) mice represents an important barrier to the successful engraftment of human cells. Different genetic and pharmacological strategies improve the graft survival. Non-obese diabetic (NOD)-SCID mice are better hosts for reconstitution with human peripheral blood leucocytes (Hu-PBL) because of their reduced natural killer cell and macrophage activity next to defective T and B cell functions. We investigated effects of TM-β1, a rat monoclonal antibody recognizing the mouse IL-2 receptor β-chain, on Hu-PBL survival and function in NOD-SCID and SCID mice. Relative to untreated littermates, TM-β1 improved Hu-PBL survival in SCID and NOD-SCID mice. Moreover, TM-β1-pretreated NOD-SCID mice displayed significantly better Hu-PBL survival and tissue distribution than TM-β1-pretreated SCID mice. Irradiation of NOD-SCID mice further enhanced the effects of TM-β1. However, these animals died within 3 weeks post-grafting due to graft-versus-host disease. Secondary immune responses were evaluated with Hu-PBL from a donor immune to hepatitis B surface antigen (HBsAg). In TM-β1-pretreated NOD-SCID mice, human HBsAg-specific memory B cells produced high titres of anti-HBsAg immunoglobulin irrespective of the administration of a secondary antigen booster dose. This contrasts with secondary immune responses in TM-β1-pretreated SCID mice where high titred antigen-specific immunoglobulins were produced when the appropriate antigen booster was given. In conclusion, reducing the function of the innate immune system in immunodeficient mice improves survival of the human graft and can result in an activation of the memory B cells without the need for recall antigen exposure.